Review Article Recent Advances in Genetic Predisposition ...downloads.hindawi.com/journals/bmri/2013/404053.pdf · Recent Advances in Genetic Predisposition of Myasthenia Gravis ZoiZagoriti,

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 404053 12 pageshttpdxdoiorg1011552013404053

Review ArticleRecent Advances in Genetic Predisposition of Myasthenia Gravis

Zoi Zagoriti1 Manousos E Kambouris1 George P Patrinos1

Socrates J Tzartos12 and Konstantinos Poulas1

1 Laboratory of Molecular Biology and Immunology Department of Pharmacy School of Health Sciences University of Patras26504 Rio Patras Greece

2 Department of Biochemistry Hellenic Pasteur Institute 127 Vas Sofias Avenue 11521 Athens Greece

Correspondence should be addressed to Konstantinos Poulas kpoulasupatrasgr

Received 9 June 2013 Accepted 11 September 2013

Academic Editor Amedeo Amedei

Copyright copy 2013 Zoi Zagoriti et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Myasthenia gravis (MG) is an autoimmune disease mediated by the presence of autoantibodies that bind to components of theneuromuscular junction causing the symptoms of muscular weakness and fatigability Like most autoimmune disorders MG is amultifactorial noninherited disease though with an established genetic constituent The heterogeneity observed in MG perplexesgenetic analysis even more as it occurs in various levels including diverse autoantigens thymus histopathology and age at onsetIn this context of distinct subgroups a plethora of association studies discussed in this review have assessed the involvement ofvarious HLA and non-HLA related loci inMG susceptibility over the past five years As expected certain HLA alleles were stronglyassociated with MG Many of the non-HLA genes such as PTPN22 and CTLA-4 have been previously studied in MG and otherautoimmune diseases and their association with MG has been reevaluated in more cohesive groups of patients Moreover novelrisk or protective loci have been revealed as in the case of TNIP1 and FOXP3 Although the majority of these results have beenderived from candidate gene studies the focal point of all recent genetic studies is the first genome-wide association study (GWAS)conducted on early-onset MG patients

1 Introduction

Myasthenia gravis (MG) is an autoimmune disease affectingcomponents of the neuromuscular junction and thus disrupt-ing the signal transduction over the postsynaptic membrane[1] It is a heterogeneous disease both clinically and biolog-ically delineated by the presence of specific autoantibodieswhich are the main pathogenic and diagnostic feature

MG is well-characterized at the effector stage with threeautoantigens accounting for nearly 90ndash95 of the clinicalcases the major target in 80ndash85 of MG patients is themuscle acetylcholine receptor (AChR) [2] whereas in the restof the MG patients pathogenic autoantibodies are directedtowards themuscle-specific tyrosine kinase (MuSK) [3] or thelow-density lipoprotein receptor-related protein 4 (LRP4) [45] However the presence of only three targets does not meanthat there are only three epitopes and three autoantibodyidiotypes Actually the designation of an extracellular regionof the AChR alpha-subunit as MIRmdashMain Immunogenic

Regionmdashclearly implies a multitude of possible epitopes [67] It is noteworthy that even a single patient might haveautoantibodies against more than one epitopes [7]

Even more heterogeneity can be observed amongpatients the age at onset which usually delineates thegroups of early-onset MG (EOMG) lt 40 years and late-onsetMG (LOMG) gt 40 years is strongly related to the gender andconstitutes a crucial subdivision of the MG population [8]Another cause of heterogeneity is the thymus histopathologyreferring to thymoma or thymus hyperplasia which seemsto ldquoshadowrdquo genetic analysis as it does not fall withinthe EOMGLOMG classification used in most associationstudies In general the EOMG subset is characterized byfemale predominance (sim2-3 1 female to male ratio) andusually by a hyperplastic thymus whereas LOMG showsa male bias with normal or atrophic thymus in most ofthe cases [8] The presence of anti-titin antibodies (ATA)although of no apparent active role in MG is thought tosignify a more homogeneous group of LOMG patients [9]

2 BioMed Research International

Clinically the extent and the severity of the symptoms theprogression rate (ocular versus generalized type of MG) andthe response to different therapeutic approaches complicatethe issue even further [10]

2 Genetic Approaches inAutoimmune Disorders

In contrast to Congenital Myasthenic Syndromes (CMS)which usually follow Mendelian principles of heredity anddo not entail an autoimmune component MG is a nonin-herited disease and like most autoimmune disorders it isconsidered to have a multifactorial underlying basis In factit is assumed that the pathogenesis of autoimmune diseases iscaused by a complex interaction between multiple genotypesof low penetrance and environmental factors includingpathogen exposure particularly Epstein-Barr virus [11ndash13]sex hormones [14] and lifestyle habits such as cigarettesmoking [15] Twin studies reviewed in [16] revealed thathigh concordance rates among monozygotic compared todizygotic twins observed in several autoimmune diseasesincluding MG are suggestive of a strong genetic componentHowever because of epistasis the individual effect of a genemay be masked or altered through its interaction with othergenes Moreover the genetic element seems to be restrainedand complicated as the disease-associated alleles of risk lociappear in healthy individuals as well

Over the past decade whole genome resequencing alongwith the rapid evolution of high throughput technologiesand statistical tools have provided novel insights in geneticstudies The development of a new prospect in geneticsgenome-wide association studies (GWAS) was crucial forthe identification of numerous loci involved in autoimmunediseases

The vast majority of genetic factors that have beenimplicated in autoimmune disease susceptibility are commonvariants predominantly single nucleotide polymorphisms(SNPs) rather than insertiondeletion polymorphisms ormicrosatellites SNPs are found quite frequently throughoutthe human genome while their impact on gene expression orproteinrsquos function is not always very noticeable

A genetic study has been traditionally implemented byeither linkage analysis or association analysis The latter isnowadays further diversified into candidate gene associationstudy and GWAS Linkage analysis allows inclusion of vastlydifferent subjects as it focuses on transmission patterns andnot on the residual pictureHowever it needswell-establishedpedigrees which is not an easy task in general and the lowrate of MG familial recurrence makes it even more difficultto construct On the other hand candidate gene associationstudy allows inclusion of completely unrelated subjects as itignores transmission patterns but it requires extreme cautionin grouping the test population in relevantly cohesive groupsin order to unveil association between genetic loci and thesyndromeunder study Also theremust be some a priori basisfor suspecting that the candidate genemay be correlated withthe disease

Being a combination of the former two approaches theTransmission-Disequilibrium Test (TDT) allows using thebase of case-control association studies to determine linkagethrough marker transmission in rather shallow family envi-ronments (ie with data collected or projected for as littleas two generations and sometimes with some links missing)[17] The GWAS is a step beyond as it is not the correlationwith a certain candidate locus that must be establishedor overruled but any association with any of the genomicmarkers irrespectively of physical distance is sought forSuch an endeavor is possible thanks to the existence and theconsiderable extent of linkage disequilibrium (LD) whichensures monoblock transmission through successive gener-ations of long chromosomal parts with polymorphic alleleslocated on them being ldquoin phaserdquo meaning that with novelmutagenesis excluded they are transmitted with identicalallelic status forming a haplotype Thus instead of millionsof markers one has just to check one marker per LD block atleast in theory

Convenient for detecting candidate loci without previousassumption as it may LD readily lowers the discriminationpotential of an association study and hence it impairs theaccurate location of the implicated site High-throughputanalysis alleviates this by increasing the number of markersinterrogated to more informative and discriminative levelsonce appropriate depth of analysis is ensured by assemblingadequate sample sizes All three genetic approaches establishby definition statistical correlations between candidate dis-ease loci and phenotypes but they do not produce causativerelationship especially in multifactorial diseases and syn-dromes where a combination of loci may produce an endresult unattainable by any of the constituents

In this review we attempted to incorporate all the recentdata of the international literature regarding the geneticassociations of MG generated mostly from candidate genestudies but also from the first GWAS conducted on MGpatients We focused mainly on studies published over thepast five years as previous studiesmdashbefore 2008mdashhave beencovered in a review by Giraud and coworkers [18]

3 Data Derived from the First GWAS inEOMG Patients

In 2012 the first GWAS for MG [19] was conducted throughan international collaboration of multiple centers that led tothe recruitment of 740MG cases After applying strict qualitycriteria to obtain the appropriate clustering of the samplesthe 649 patients whowere finally included in the study wereof North European descent and developed the disease earlywith age at onset gt10 years and lt40 years as they comprisea more homogeneous group suitable for genetic analysis Interms of thymic histological condition MG patients werediagnosed with thymus hyperplasia whereas a strong femalebias (829 of the overall MG group) was noticed As prob-ably expected the study detected the strongest associationin the Human Leukocyte Antigen (HLA) Class I locus(rs7750641) which after imputation and conditional analyses

BioMed Research International 3

of the broad HLA region led to the determination of HLA-Blowast08 allele as the main risk allele (Table 1) A higher degreeof association between the HLA-Blowast08 allele and EOMG wasrevealed when considering only the women Regarding theHLA-DRB1lowast0301 allele that had been previously associatedwith thymus hyperplasia-related MG [9] the modest signalobserved in the unconditioned analysis was clearly reducedwhen conditioning onHLA-B8 However two other alleles ofthe HLAClass II region DRB1lowast16 and DRB1lowast0701 conferreda positive and negative association respectively that reachedstatistically significant levels (Table 1) confirming previ-ous findings [9] This GWAS also verified the associationbetween MG with thymus hyperplasia and the rs2476601SNP in the PTPN22 locus (discussed below) which hasbeen reported in previous studies [20 21] In additiona novel association was established with TNFAIP3-inter-acting protein 1 (TNIP1) involved in the negative regulationof NF-120581Β [19] Applying imputation around the TNIP1 locusa strong association was demonstrated with the rs2233290SNP causing a proline to alanine substitution at position 151of the coding region [19]The fact that this variant does not liewithin any of the functional domains of the protein possiblyexplains the lack of association with TNFAIP3 which wasalso observed in a candidate gene study of Hellenic MGpopulation [22]

4 HLA Loci Susceptible to MG Occurrence

In the 1970s the HLA was the first identified genetic regionwith a significant role in predisposition of many autoimmunediseases However because of the large number of highlypolymorphic genes located at this region and related to theimmune function and because of the strong linkage disequi-librium across HLA the identification of the precise allelesassociated with disease susceptibility remains challenging

41 Thymoma-Related MG Thymomas are neoplasms ofthymic epithelial cells with sim30ndash45 of them associatedwith MG Except for the increased MG prevalence manyother autoimmune diseases also cooccur in patients withtumours of the thymus [33] Histologically thymomas areconsidered to be heterogeneous tumours According to theWorld Health Organization (WHO) thymomas are classifiedinto five histological types differentiated by their neoplastic(epithelial) and nonneoplastic (lymphocytes) componentproportions [34] These are types A AB B1 B2 and B3in order of increasing malignancy and they have all beenobserved in MG patients [35]

MG patients with thymoma comprise a distinct sub-set of the disease both pathologically and genetically Noreproducible HLA association has been reported in MG withthymoma

In 2001 a case-control study conducted by Garchon andcoworkers revealed no significant association of Class IIHLA-DRB1 locus in 106 French MG patients with thymoma[36] However histological data about thymoma subtypeswere not available which may partially explain the lack ofassociation

A subsequent study by the same research group com-prising 78 French MG patients with thymoma investigatedthe effect of Class I HLA-A locus to the occurrence ofparaneoplastic MG An increased frequency of HLA-Alowast25allele was found in the whole group of patients (Table 1)Considering only the subgroup of 27 MG patients witha B2 type thymoma the analysis demonstrated a negativeassociation of the HLA-Alowast02 allele (Table 1) indicating apotential protective role to the development of B2 thymoma[23]

Recently the Class II HLA-DQA1 and DQB1 genes wereassociated with thymoma-related MG in an Asian popula-tion Among the 102 northern Chinese MG patients whoconstituted a very heterogeneous study group 41 presentedwith thymoma with B2 type being the most prevalenthistological subgroup (51) A significant increase of HLA-DQA1lowast0401 and DQB1lowast0604 alleles was disclosed in MGpatients with thymoma (Table 1) compared to the oneswithout thymoma and to the control group [24]

Finally no association was observed in the case of 30Norwegian MG patients with thymoma who were genotypedfor HLA Class I and II loci [26]

42 Nonthymomatous MG The involvement of HLA-DRB1gene in MG occurrencemdashunder the perspective of itsheterogeneitymdashwas assessed through a large study including656 sporadic MG cases of Caucasian origin The groupof 192 MG patients with thymus hyperplasia presented asignificantly increased frequency of the DR3 allele and aconcurrent decrease of theDR7 allele frequency compared tothe 10235 healthy subjects (Table 1) [9] Moreover through arelative predispositional effect (RPE) analysis of DR allelesthe DR16 and DR9 alleles sequentially according to theirstrength were shown to be associated with susceptibility toMG and thymus hyperplasia (Table 1) [9] In order to achievea greater level of homogeneity the MG patients not beingdetected with any thymus anomalies were categorized by thepresence of ATAThe 59ATA-positive patients appeared to beassociated with the DR7 allele whilst a negative associationwas observed in the case of the DR3 allele (Table 1) revealinga reverse outcome from the one noticed in MG patientswith thymus hyperplasia and in ATA-negative patients whowere associated with DR3 (Table 1) as well [9] Additionallythis study investigated the transmission of the DR3 alleleusing the transmissiondisequilibrium test in 56 families thatconsisted of one offspring with MG and thymus hyper-plasia and one or two heterozygous parents This family-based association test determined the presence of geneticlinkage between the HLA-DR3 allele and MG with thymushyperplasia [9]

In the sequel study Garchon and coworkers reevaluatedthe contribution of the extended 81 HLA haplotype includ-ing Class I HLA-A1 and B8 loci and Class II HLA-DR3allele to the occurrence of MG with thymus hyperplasiaOverall 27 markers most of them microsatellites coveringthe entire region of HLA complex were genotyped Thefamily-based transmission disequilibrium test proved thedistorted transmission of a core part of the 81 haplotype


Table1HLA

allelesa

ssociatedwith

MGin

distinctsubgroup

softhe

diseasea

ndvario

usethn

icpo

pulations

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Thym

oma-relatedMG

mdashHLA

-AAlowast

25French

7826times10minus3

[23]

B2type

ofthym

oma

HLA

-AAlowast

02

French

27413times10minus4

[23]

mdashHLA

-DQA1

DQA1lowast04

01Northern

Chinese

4111times10minus2

[24]

mdashHLA

-DQB1

DQB1lowast

0604

Northern

Chinese

411times10minus3

[24]

Nonthymom

atousM

G

Thym

ushyperplasia

HLA

-DRB

1DR3

DR7

Ca

ucasian

192

lt1times10minus6

lt1times10minus6

[9]

Thym

ushyperplasia

HLA

-DRB

1DR16

Caucasian

192

11times10minus5

[9]

Thym

ushyperplasia

HLA

-DRB

1DR9

Caucasian

192

2times10minus3

[9]

ATA(+)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR7

Caucasian

591times10minus2b

[9]

ATA(minus)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR3

Caucasian

602times10minus4b

[9]

mdashHLA

-CClowast

0701

Swedish

438

102times10minus3

[25]

LOMGgt60

years

HLA

-DRB

1DRB

1lowast1501

Norwegian

9976times10minus5a

[26]

EOMGlt40

years

HLA

-BBlowast

08Norwegian

154

25times10minus13a

[26]

EOMGamp

MGwith

onset4

1ndash59

yearsamp

LOMG

HLA

-DRB

1DRB

1lowast1301

Norwegian

339

471times10minus4a

[26]

EOMG

HLA

-DRB

1DRB

1lowast08

DRB

1lowast09

NorthernHan

Chinese

527times10minus3

33times10minus2

[27]

LOMG

HLA

-DRB

1DRB

1lowast07

NorthernHan

Chinese

393times10minus2

[27]

OcularM

GHLA

-DRB

1DRB

1lowast09

DRB

1lowast12

NorthernHan

Chinese

34535times10minus5

2times10minus2

[27]

AChR

(+)

HLA

-DRB

1DRB

1lowast08

NorthernHan

Chinese

442times10minus2

[27]

AChR

(minus)

HLA

-DRB

1DRB

1lowast09

NorthernHan

Chinese

302times10minus3

[27]

mdashHLA

-BBlowast

08Saud

i109

34times10minus4a

[28]

mdashHLA

-BBlowast

50

Saud

i109

34times10minus3a

[28]

mdashHLA

-DQA1

DQA1lowast01012

Iranian

104

mdash[29]

mdashHLA

-DQB1

DQB1lowast

0502

Iranian

104

mdash[29]

Generalized

EOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n30

lt10minus3a

lt10minus3a

[30]

Generalized

LOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n18

13times10minus3a

lt10minus3a

[30]

Generalized

MGm

alep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n26

lt10minus3a

lt10minus3a

[30]


Table1Con

tinued

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Generalized

MGfe

malep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n22

lt10minus3a

16times10minus3a

[30]

EOMGwith

thym

ushyperplasia

HLA

-BBlowast

08North

European

649

287times10minus113a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast07

North

European

649

32times10minus8a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast16

North

European

649

13times10minus11a

[19]

MuSK-MG

mdashHLA

-DRB

1ampHLA

-DQB1

DR14-DQ5

haplotype

Dutch

2349times10minus5a

[31]

mdashHLA

-DQB1

DQB1lowast

0502

Italian

3773times10minus6a

[32]

HLA

-DRB

1DRB

1lowast16

Italian

3723times10minus9a

[32]

Negativea

ssociatio

nim

plying

aprotectiver

oleo

fthe

specifica

llelein

MG

a Adjustedaccordingto

Bonferroni

correctio

nform

ultip

lecomparis

ons

b 119875valuec

alculatio

nwas

basedon

thec

omparis

onbetweenAT

A(+)a

ndAT

A(minus)M

Gpatie

nts


in 46 cases This 12Mb segment mapped in the centralregion of the 81 haplotype between the BAT3 and C3-2-11markers encompasses the Class III and proximal Class I lociand constitutes the actual causative locus termed MYAS1[37] Furthermore a quantitative trait locus associated withanti-AChR autoantibody production is suggested to be sit-uated within the MYAS1 [37] Finally in the context of acase-control association study it was supported that the riskconferred by the 81 haplotype probably corresponds to anadditive genetic model [37]

More recent data derived from an association study of1472 SNPs covering the overall MHC region in a cohort of438MG cases from Sweden determined the Class I HLAlocus as the most susceptible in MG [25] More specif-ically the strongest association was detected in the caseof rs2523674 SNP mapped 35 kb downstream of the HLAcomplex protein 5 (HCP5) gene while the imputed HLA-Clowast0701 allele was also associated in an independent way(Table 1) [25] Although this study scrutinized a large set ofgenetic variants across the vast MHC region it disregardedthe heterogeneous clinical and biological profiles of thedisease that could lead to distinct HLA association signals

In order to assess this heterogeneity a case-control associ-ation study in the Norwegian population examined the HLA-A -B -C and -DRB1 loci in well-defined subgroups of MGpatients sorted by the age at onset (Early-onset lt 40 yearsLate-onset gt 60 years and intermediate group = 41ndash59 years)and the histology of the thymus (thymoma or nonthymoma)The greatest association of LOMG (gt60 years as determinedin this study) was with the DRB1lowast15 01 allele (Table 1) whilethe DR7 allele showed a modest association which ceased tobe significant in the case of MG patients with ATA and age atonset over the 40 years [26] In the group of EOMG patientsthe previously demonstrated association with the HLA-Alowast01-Blowast08 -Clowast07 and -DRB1lowast0301 alleles was also confirmedin this study and further conditional analysis revealed thatHLA-Blowast08 was the responsible allele for the strongest risk toMGsusceptibility detected for this haplotype (Table 1) [26] Anegative associationwith theDRB1lowast13 01 allele was observedin both EOMG and LOMG patients (Table 1) suggesting itsprotective role in MG [26]

Another study of HLA-DRB1 locus in a northern HanChinese cohort of MG patients showed a significantlyincreased frequency of DRB1lowast09 allele in EOMGpatients anda corresponding raise of DRB1lowast07 allele frequency in LOMG(Table 1) [27] The DRB1lowast09 was also associated with thenegative to anti-AChR antibodies subgroup but the strongestassociation of this allele was uncovered in the case of MGpatients with the ocular type of the disease (Table 1) [27]It is worth mentioning that unlike Caucasian populationsno statistically significant differences were observed in thefrequency of DRB1lowast03 allele in this study

In Saudi MG patients DNA typing of HLA Class I and IIloci revealed a robust association only with the Blowast08 alleledetected mostly in the female and early-onset disease part ofthe study group [28] In addition HLA-Blowast08 and -DRB1lowast03alleles were shown to be in linkage disequilibrium thusforming a haplotype from which the A1 locus appeared tobe unexpectedly excluded [28] The HLA-DQB1 locus did

not show any correlation with MG in Saudi patients but ina study encompassing Iranian patients HLA-DQA1lowast01012and DQB1lowast0502 alleles were positively associated with MG(Table 1) [29]

The contribution of HLA-DQ and DR loci to MG pre-disposition was also assessed in 48 Tunisian patients withgeneralized MG and almost half of them being seroneg-ative to anti-AChR antibodies (2048) The DRB1lowast03 andDQB1lowast02 alleles were significantly more prevalent in theEOMG patients while the LOMG patients were associatedwith the DRB1lowast04 and DQB1lowast0302 alleles (Table 1) [30]When comparing the allele frequencies according to genderthe resultswere the opposite ofwhatwould be expected as theEOMG-associated DRB1lowast03 and DQB1lowast02 alleles presentedin a significantly increased frequency in male patients andtheDRB1lowast04 andDQB1lowast0302 alleles in women (Table 1) [30]This contradiction could be in part due to the limited numberof MG patients participating in the study

43 MuSK-MG MuSK-MG is a separate clinical entity withdiscrete clinical features and patterns of weakness comparedto AChR-MG In MuSK-MG no abnormalities have beenreported in the histology of the thymus [38]

The HLA-DR14-DQ5 haplotype was strongly associatedwith MuSK-MG in 23 white Dutch patients (Table 1) whilethe B8-DR3 haplotype which has been consistently asso-ciated with early-onset AChR-MG showed no significantdifference [31]

Another study comprising 37 Italian MuSK-MGpatients demonstrated strong association with DQB1lowast0502and DRB1lowast16 alleles (Table 1) [32] Since the molecularDQB1lowast0502 allele corresponds to the serologic DQ5 theseresults confirm the association of MuSK-MG with DQ5established by the above-mentioned study

All statistically significant HLA associations with MGgenerated from the above-mentioned studies are summa-rized in Table 1

5 Non-HLA Related Loci Associated withMG Predisposition

51 Protein Tyrosine Phosphatase Nonreceptor Type 22(PTPN22) A General Autoimmunity Risk Factor PTPN22located on 1p133ndashp131 chromosomal region encodes fora cytoplasmic tyrosine phosphatase which is specificallyexpressed in lymphoid cells Structurally PTPN22 con-sists of two functional domains the N-terminal catalytic-dephosphorylation domain and the C-terminal bindingdomain that mediates its interaction with the SH3 domain ofthe intracellular C-src tyrosine kinase (CSK) [39] Throughthe complex with CSK PTPN22 functions as a molecule-regulator of the TCR signalling pathway leading to the sup-pression of T-cell response [40]Themissense SNP rs2476601(1858CgtT) which leads to an arginine to tryptophan sub-stitution (R620W) has been reproducibly associated withmultiple autoimmune diseases MG included as reviewedin [41] As a matter of fact a meta-analysis conductedrecently on the association of rs2476601 with a plethora


of autoimmune diseases established the correlation of thisvariant with rheumatoid arthritis MG lupus type I diabetesand several other diseases but not with a cluster of diseasesaffecting the skin the gastrointestinal tract or immuneprivileged areas such as psoriasis Crohnrsquos disease multiplesclerosis and so forth [42] Recent data derived from thestudy by Zhang et al indicated an impairment of 620Wvariant stability in the protein level caused by an increaseddegradation rate compared to the wild-type 620R protein[43]

Following the study of the French MG population [21]recent data have confirmed the correlation of R620W toMG susceptibility in other Northern European populationsas well A case-control study in a large cohort of SwedishCaucasian MG patients revealed that the minor T alleleshowed the greatest association with the subgroup of MGwith thymus hyperplasia and anti-AChR antibodies (Table 2)[20] The same study evidenced a significant increase ofIL-2 producing cells after stimulation of PBMC with thehuman AChR protein in patients with the T allele Thisobservation is inconsistent with the results of decreased IL-2levels demonstrated by Vang and coworkers in patients withtype I autoimmune diabetes carrying the 620W allele [44]

An association study of the R620W variant in Hungarianand German MG patients proved that the PTPN22 1858Tallele was associated with MG predisposition only in thesubgroup of nonthymoma patients with detectable ATA(Table 2) [45] leading to conflicting conclusions comparedto the French MG study in which the association wasestablished in the exactly opposite case of non-thymomapatients lacking ATA [21]

Another study inGermanCaucasianMGpatients was thefirst to uncover a strong association between +1858T geno-types and thymoma-related MG (Table 2) [46] A statisticallysignificant associationwas reportedwith EOMG subjects too(Table 2) It is worth mentioning that the intratumorous IL-2expression levels were found to be reduced in patients bearingthe +1858T allele [46]

In discordance with the above studies determinationof rs2476601 allele frequencies in a large Italian group ofMG patients showed no statistically significant differencesbetween patients and healthy controls [47] Instead thers2488457 SNPwhich resides in thePTPN22 promoter region(-1123GgtC) appeared to be associated withMG characterizedby low titer anti-AChR antibodies (Table 2) [47]This absenceof association between MG predisposition and +1858T allelemight be in accordance with the decreased allele frequencyobserved in the general population of the southern Europeancountries compared to the northern and eastern part of thecontinent [48]

A meta-analysis of the four above studies performedon allele frequencies of the PTPN22 rs2476601 verified theassociation of the T allele with nonthymomatous MG [47]The statistical power of association was significantly reducedwhen the results from the Italian group were added to themeta-analysis data [47]

An overview of the results derived from the geneticassociation studies for PTPN22 is presented in Table 2

52 Association of Other Non-HLA Loci with MG Susceptibil-ity To begin with one of the most important associations isthat of the rs16862847 SNP located at the promoter regionof the CHRNA1mdashencoding the alpha-subunit of the muscleAChR pentameric channelmdashwhich has been constantly asso-ciated with MG as discussed in detail in [18]

The (cytotoxic T lymphocyte-associated 4) CTLA-4CD152 membrane receptor exerts its impact as suppressor ofactivated T-cells via binding to B7 costimulatory moleculeson antigen-presenting cells In the absence of a trigger non-stimulated peripheral T lymphocytes express an alternativetranscript which encodes a soluble form of CD152 (sCD152)[49] In addition to previous studies reporting a probableassociation between the +49AG coding variant and thesubset of thymoma-related MG [50 51] the involvement ofSNPs located at the promoter region ofCTLA-4 has also beenevaluated Two SNPs at positions -1772TC and -1661AGupstream of CTLA-4 were shown to be associated with MGin a group of 165MG patients of Swedish origin [52] Becauseof their location within regulatory elementsmdashthe NF-1 andcEBP binding sitesmdashthese polymorphisms plausibly have aneffect on gene transcription or even splicing as implied bythe increased levels of sCD152 in -1772TC heterozygote MGpatients [52]

Given the indisputable role of glycobiology in immu-nity and inflammation galectinsmdashmembers of the glycan-binding protein familymdashwere considered as good candi-dates in the investigation of genetic factors predisposingto autoimmunity Galectins are soluble proteins containinga carbohydrate recognition domain with high affinity toN-acetyllactosamine oligosaccharides [53] They mediate abroad spectrum of immunomodulatory activities both intra-cellular and extracellular including induction of apoptosisnegative regulation of T-cell response cell adhesion and pre-mRNA splicing [54] The rs2737713 polymorphism whichleads to a phenylalanine to tyrosine substitution (F19Y)in the LGALS8 locus encoding galectin-8 appeared to bemoderately associated with MG [55] A previous study of thesame research group examined two SNPs in the 51015840 upstreamsequence of the galectin-1 gene (LGALS1) along with twoSNPs in regulatory regions of the interleukin receptor 2120573 gene(IL2R120573) which resides in the 22q13 chromosomal regiontoo A strong association was identified between MG andthe haplotype formed by SNPs rs4820293 and rs743777 ofLGALS1 and IL2R120573 respectively but functional studies didnot verify an impact of rs4820293-different genotypes ongene expression [56]

Another cytokine receptor this time interleukin-4 recep-tor alpha (IL4R120572) was examined in a cohort of HungarianMG patients recruited from the NEPSYBANK (HungarianNeurological and Psychiatric Biobank) [57] as occurred inthe two above-mentioned studies In this survey three mis-sense variants in the IL4R120572 (I75V S503P and Q576R) whichare thought to disrupt the signal transduction of interleukin-4 (IL-4) were selected A statistically significant associationwas observed only in the case of I75V polymorphism andparticularly when the 75V allele existed in homozygosity[58]


Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG

mdash34times10minus4

ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts

mdashlt1times10minus5

[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols


Interleukin-10 (IL-10) is an anti-inflammatory cytokinewhich exerts its function by downregulating TH1-mediatedresponses whereas it constitutes a proliferation and differ-entiation factor for activated B cells [59] Three SNPs atpositions -1082 (AG) -819 (TC) and -592 (AC) in the 51015840flanking sequence of IL-10 determine the formation of threehaplotypes (GCC ACC and ATA) that are implicated inIL-10 production levels in vitro [60] A study conductedon the Norwegian population proved the association of thelow expression-related genotypes ACCACC and ATAATAwith the subgroups of ATA-positive and EOMG patientsrespectively [61] However in the Hellenic population theGCCGCC genotype conferring for high IL-10 levels showeda statistical trend of association when the EOMG and LOMGsubsets were compared [22]

Foxp3 is a transcription factor member of the fork-headwinged-helix family with a specific role in the functionof CD4+CD25+ T regulatory cells A marked reduction inTreg immunosuppressive activity in vitro has been identifiedin MG patients accompanied by a decrease in FOXP3expression [62] A recent study in Han Chinese MG casesattempted to assess the contribution of two SNPs rs3761548(minus3279AC) and rs2280883 (IVS9+459AG) in the FOXP3gene to MG susceptibility Statistically significant differ-ences in the genotype distribution of the intronic variantwere observed between patients and controls uncoveringa potential protective role of the IVS9+459G allele to thedevelopment of MG [63] No association was evidenced inthe case of rs3761548 even after stratification of the subjectsaccording to age at onset gender histology of the thymus andclinical classification [63]

6 Genetic Loci Not Associated with MG

The studies resulting in no statistically significant associationare minimally published This fact although unconstructiveas it denies clues for more promising direction of furtherresearch might be a justified policy since better selectedpopulation groups and enhanced correlation protocols mightlead to positive future findings Briefly in the last five yearsInterferonRegulatory Factor 5 (IRF5) [22]TNF120572-induced pro-tein 3 (TNFAIP3) [22] IL10 [22] Stromal Cell Derived Factor-1 (SDF1) [64] Programmed Death-1 (PD-1) [65] OestrogenReceptor Alpha (OR120572) [66] Class II Transactivator (CIITA)[67] and Protein Tyrosine Phosphatase Receptor type C(PTPRC) also designated as CD45 [68] have been tested andtemporarily rejected The list of nonassociated loci becomesmore extensive if previous studies discussed elsewhere [18]are taken into account

7 Conclusion

The purely autoimmune nature of MG entails the fact thatcomplex pathogenetic mechanisms cause the deregulationof normal immune function so that an immune responsetargeting the MG-related autoantigens would develop As itwas expected numerous studies have verified quite strongassociations with various HLA alleles depending largely on

the traits of the study group Moreover a series of non-HLAloci were shown to be implicated enriching our understand-ing of the multifaceted autoimmune procedures and thusunraveling the specific role of these genes in immunologicalpathways Most of these risk loci have been repeatedlyassociated with several autoimmune diseases indicating theexistence of common underlying pathogenesis in autoimmu-nity Thus MG-associated loci might exert their implicationthrough upregulation of the immune response inhibitionof immunosuppressive mechanisms or impairment of thedelicate procedure of regulating the discrimination betweenautologous and heterologous molecular conformations viaprocesses such as the immune tolerance

It is obvious that nowadays the majority of associationstudies use preferentially SNPs as genetic markers since theirfrequency in the genome is much higher and they are locatedat many more sites of interest than microsatellites In factas displayed above association studies focus on SNPs thatreside not only in exons but also in regulatory regions suchas cis-elements (promoters and operators) and splicing sitesFurthermore being easier andmore robust to genotype SNPsare automation friendly allowing formassive interrogation inmultiple candidate genes format and also in truly genomicscale studies as it is the case in GWAS However thefuture of genetic analysis in autoimmune diseases and itscorresponding applications in treatment healthcare andpopulation studies lie in the rapid progress of next generationsequencing platforms which in the very next years will attainthe sequencing of whole exome transcriptome or genome ina low-cost and accurate manner

Acknowledgments

This study has been cofinanced by (a) the European Union(European Social FundmdashESF) and Greek national fundsthrough the Operational Program ldquoEducation and LifelongLearningrdquo of the National Strategic Reference Framework(NSRF) Research Funding Program Thales Investing inknowledge society through the European Social Fund (b)the FP-7 Research Potential ProgramRegpot SEEDRUG ofUniversity of Patras (Grant no EU FP7 REGPOT) CT-2011-285950

References

[1] A M Gomez J van den Broeck K Vrolix et al ldquoAntibodyeffector mechanisms in myasthenia gravismdashpathogenesis at theneuromuscular junctionrdquo Autoimmunity vol 43 no 5-6 pp353ndash370 2010

[2] JM LindstromM E Seybold V A Lennon et al ldquoAntibody toacetylcholine receptor inmyasthenia gravis Prevalence clinicalcorrelates and diagnostic valuerdquo Neurology vol 26 no 11 pp1054ndash1059 1976

[3] W Hoch J McConville S Helms J Newsom-Davis A MelmsandAVincent ldquoAuto-antibodies to the receptor tyrosine kinaseMuSK in patients with myasthenia gravis without acetylcholinereceptor antibodiesrdquoNature Medicine vol 7 no 3 pp 365ndash3682001


[4] A Pevzner B Schoser K Peters et al ldquoAnti-LRP4 autoantibod-ies in AChR- and MuSK-antibody-negative myasthenia gravisrdquoJournal of Neurology vol 259 no 3 pp 427ndash435 2011

[5] B Zhang J S Tzartos M Belimezi et al ldquoAutoantibod-ies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravisrdquo Archives of Neurology vol 69no 4 pp 445ndash451 2012

[6] S J Tzartos A Kokla S L Walgrave and B M Conti-Tronconi ldquoLocalization of the main immunogenic region ofhuman muscle acetylcholine receptor to residues 67ndash76 of the120572 subunitrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 85 no 9 pp 2899ndash2908 1988

[7] S J Tzartos T Barkas M T Cung et al ldquoAnatomy ofthe antigenic structure of a large membrane autoantigen themuscle-type nicotinic acetylcholine receptorrdquo ImmunologicalReviews vol 163 pp 89ndash120 1998

[8] M N Meriggioli and D B Sanders ldquoAutoimmune myastheniagravis emerging clinical and biological heterogeneityrdquo TheLancet Neurology vol 8 no 5 pp 475ndash490 2009

[9] M Giraud G Beaurain A M Yamamoto et al ldquoLinkage ofHLA tomyasthenia gravis and genetic heterogeneity dependingon anti-titin antibodiesrdquoNeurology vol 57 no 9 pp 1555ndash15602001

[10] J J G M Verschuuren J Palace and N Erik Gilhus ldquoClinicalaspects of myasthenia explainedrdquo Autoimmunity vol 43 no 5-6 pp 344ndash352 2010

[11] J A James B R Neas K L Moser T Hall G R BrunerA L Sestak et al ldquoSystemic lupus erythematosus in adults isassociated with previous Epstein-Barr virus exposurerdquoArthritisamp Rheumatism vol 44 no 5 pp 1122ndash1126 2001

[12] N Balandraud J B Meynard I Auger et al ldquoEpstein-Barrvirus load in the peripheral blood of patients with rheumatoidarthritis accurate quantification using real-time polymerasechain reactionrdquoArthritis ampRheumatism vol 48 no 5 pp 1223ndash1228 2003

[13] A Ascherio K L Munger E T Lennette et al ldquoEpstein-Barrvirus antibodies and risk of multiple sclerosis a prospectivestudyrdquo Journal of the AmericanMedical Association vol 286 no24 pp 3083ndash3088 2001

[14] K H Costenbader D FeskanichM J Stampfer and EW Karl-son ldquoReproductive andmenopausal factors and risk of systemiclupus erythematosus in womenrdquo Arthritis amp Rheumatism vol56 no 4 pp 1251ndash1262 2007

[15] E W Karlson S C Chang J Cui et al ldquoGene-environmentinteraction between HLA-DRB1 shared epitope and heavycigarette smoking in predicting incident rheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 69 no 1 pp 54ndash60 2010

[16] D P Bogdanos D S Smyk E I Rigopoulou et al ldquoTwin studiesin autoimmune disease genetics gender and environmentrdquoJournal of Autoimmunity vol 38 no 2-3 pp J156ndashJ169 2012

[17] R S Spielman R E McGinnis and W J Ewens ldquoTransmis-sion test for linkage disequilibrium the insulin gene regionand insulin-dependent diabetes mellitus (IDDM)rdquo AmericanJournal of Human Genetics vol 52 no 3 pp 506ndash516 1993

[18] MGiraud C Vandiedonck andH J Garchon ldquoGenetic factorsin autoimmune myasthenia gravisrdquo Annals of the New YorkAcademy of Sciences vol 1132 pp 180ndash192 2008

[19] P K Gregersen R Kosoy A T Lee et al ldquoRisk for myastheniagravis maps to a 151 ProrarrAla change in TNIP1 and to human

leukocyte antigen-Blowast08rdquo Annals of Neurology vol 72 no 6 pp927ndash935 2012

[20] A K Lefvert Y Zhao R Ramanujam S Yu R Pirskanenand L Hammarstrom ldquoPTPN22 R620W promotes productionof anti-AChR autoantibodies and IL-2 in myasthenia gravisrdquoJournal of Neuroimmunology vol 197 no 2 pp 110ndash113 2008

[21] C Vandiedonck C Capdevielle M Giraud et al ldquoAssocia-tion of the PTPN22lowastR620W polymorphism with autoimmunemyasthenia gravisrdquo Annals of Neurology vol 59 no 2 pp 404ndash407 2006

[22] Z Zagoriti M Georgitsi O Giannakopoulou et al ldquoGeneticsof myasthenia gravis a case-control association study in theHellenic populationrdquo Clinical and Developmental Immunologyvol 2012 Article ID 484919 7 pages 2012

[23] C Vandiedonck C Raffoux B Eymard et al ldquoAssociationof HLA-A in autoimmune myasthenia gravis with thymomardquoJournal of Neuroimmunology vol 210 no 1-2 pp 120ndash123 2009

[24] H Yang J Hao X Peng et al ldquoThe association of HLA-DQA1lowast0401 and DQB1lowast0604 with thymomatous myastheniagravis inNorthern Chinese patientsrdquo Journal of the NeurologicalSciences vol 312 no 1-2 pp 57ndash61 2012

[25] J D Rioux P Goyette T J Vyse et al ldquoMapping of multiplesusceptibility variants within the MHC region for 7 immune-mediated diseasesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 106 no 44 pp18680ndash18685 2009

[26] A H Maniaol A Elsais A Lorentzen et al ldquoLate onsetmyasthenia gravis is associated with HLA DRB1lowast1501 in theNorwegian populationrdquo PLoS ONE vol 7 no 5 Article IDe36603 2012

[27] Y C Xie Y Qu L Sun et al ldquoAssociation between HLA-DRB1and myasthenia gravis in a Northern Han Chinese populationrdquoJournal of Clinical Neuroscience vol 18 no 11 pp 1524ndash15272011

[28] A H Hajeer F A Sawidan S Bohlega et al ldquoHLA class iand class II polymorphisms in Saudi patients with myastheniagravisrdquo International Journal of Immunogenetics vol 36 no 3pp 169ndash172 2009

[29] G A Yousefipour Z Salami and S Farjadian ldquoAssociation ofHLA-DQA1lowast01012 and DQB1lowast0502 with myasthenia gravis inSouthern Iranian patientsrdquo Iranian Journal of Immunology vol6 no 2 pp 99ndash102 2009

[30] N Fekih-Mrissa S Klai J Zaouali N Gritli and R MrissaldquoAssociation of HLA-DRDQ polymorphism with myastheniagravis in Tunisian patientsrdquo Clinical Neurology and Neuro-surgery vol 115 no 1 pp 32ndash36 2013

[31] E H Niks J B M Kuks B O Roep et al ldquoStrong associationof MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5rdquo Neurology vol 66 no 11 pp 1772ndash1774 2006

[32] E Bartoccioni F Scuderi A Augugliaro et al ldquoHLA class IIallele analysis in MuSK-positive myasthenia gravis suggests arole for DQ5rdquo Neurology vol 72 no 2 pp 195ndash197 2009

[33] A Marx N Willcox M I Leite et al ldquoThymoma and parane-oplastic myasthenia gravisrdquo Autoimmunity vol 43 no 5-6 pp413ndash427 2010

[34] R P Hasserjian P Strobel and A Marx ldquoPathology of thymictumorsrdquo Seminars in Thoracic and Cardiovascular Surgery vol17 no 1 pp 2ndash11 2005


[35] P Strobel A Bauer B Puppe et al ldquoTumor recurrence andsurvival in patients treated for thymomas and thymic squamouscell carcinomas a retrospective analysisrdquo Journal of ClinicalOncology vol 22 no 8 pp 1501ndash1509 2004


[37] C Vandiedonck G Beaurain M Giraud et al ldquoPleiotropiceffects of the 81 HLA haplotype in patients with autoimmunemyasthemia gravis and thymus hyperplasiardquo Proceedings of theNational Academy of Sciences of the United States of Americavol 101 no 43 pp 15464ndash15469 2004

[38] M I Leite P Scrobel M Jones et al ldquoFewer thymic changes inMuSK antibody-positive than inMuSK antibody-negativeMGrdquoAnnals of Neurology vol 57 no 3 pp 444ndash448 2005

[39] I Rhee and A Veillette ldquoProtein tyrosine phosphatases inlymphocyte activation and autoimmunityrdquoNature Immunologyvol 13 no 5 pp 439ndash447 2012

[40] G L Burn L Svensson C Sanchez-Blanco M Saini and A PCope ldquoWhy is PTPN22 a good candidate susceptibility gene forautoimmune diseaserdquo FEBS Letters vol 585 no 23 pp 3689ndash3698 2011

[41] P K Gregersen and L M Olsson ldquoRecent advances in thegenetics of autoimmune diseaserdquo Annual Review of Immunol-ogy vol 27 pp 363ndash391 2009

[42] J Zheng S Ibrahim F Petersen and X Yu ldquoMeta-analysisreveals an association of PTPN22 C1858T with autoimmunediseases which depends on the localization of the affectedtissuerdquo Genes and Immunity vol 13 no 8 pp 641ndash652 2012

[43] J Zhang N Zahir Q Jiang et al ldquoThe autoimmune diseaseg-associated PTPN22 variant promotes calpain-mediated LypPep degradation associated with lymphocyte and dendritic cellhyperresponsivenessrdquo Nature Genetics vol 43 no 9 pp 902ndash907 2011

[44] TVangMCongiaMDMacis et al ldquoAutoimmune-associatedlymphoid tyrosine phosphatase is a gain-of-function variantrdquoNature Genetics vol 37 no 12 pp 1317ndash1319 2005

[45] B Greve P Hoffmann Z Illes et al ldquoThe autoimmunity-relatedpolymorphism PTPN22 1858CT is associated with anti-titinantibody-positive myasthenia gravisrdquoHuman Immunology vol70 no 7 pp 540ndash542 2009

[46] W Y Chuang P Strobel D Belharazem et al ldquoThe PTPN22gain-of-function 1858T(+) genotypes correlate with low IL-2expression in thymomas and predispose to myasthenia gravisrdquoGenes and Immunity vol 10 no 8 pp 667ndash672 2009

[47] C Provenzano R Ricciardi F Scuderi et al ldquoPTPN22 andmyasthenia gravis replication in an Italian population andmeta-analysis of literature datardquo Neuromuscular Disorders vol22 no 2 pp 131ndash138 2012

[48] P K Gregersen H S Lee F Batliwalla and A B BegovichldquoPTPN22 setting thresholds for autoimmunityrdquo Seminars inImmunology vol 18 no 4 pp 214ndash223 2006

[49] G Magistrelli P Jeannin N Herbault et al ldquoA soluble form ofCTLA-4 generated by alternative splicing is expressed by non-stimulated human T cellsrdquo European Journal of Immunologyvol 29 no 11 pp 3596ndash3602 1999

[50] X B Wang M Kakoulidou Q Qiu et al ldquoCDS1 and promotersingle nucleotide polymorphisms of theCTLA-4 gene in human

myasthenia gravisrdquoGenes and Immunity vol 3 no 1 pp 46ndash492002

[51] WY Chuang P Scrobel R Gold et al ldquoACTLA4high genotypeis associated with myasthenia gravis in thymoma patientsrdquoAnnals of Neurology vol 58 no 4 pp 644ndash648 2005

[52] X B Wang R Pirskanen R Giscombe and A K LefvertldquoTwo SNPs in the promoter region of the CTLA-4 gene affectbinding of transcription factors and are associated with humanmyasthenia gravisrdquo Journal of Internal Medicine vol 263 no 1pp 61ndash69 2008

[53] F T Liu and G A Rabinovich ldquoGalectins regulators of acuteand chronic inflammationrdquo Annals of the New York Academy ofSciences vol 1183 pp 158ndash182 2010

[54] F T Liu R Y Yang and D K Hsu ldquoGalectins in acute andchronic inflammationrdquo Annals of the New York Academy ofSciences vol 1253 no 1 pp 80ndash91 2012

[55] Z Pal P Antal S K Srivastava et al ldquoNon-synonymous singlenucleotide polymorphisms in genes for immunoregulatorygalectins association of galectin-8 (F19Y) occurrence withautoimmune diseases in a Caucasian populationrdquo Biochimica etBiophysica Acta vol 1820 no 10 pp 1512ndash1518 2012

[56] Z Pal P Antal A Millinghoffer et al ldquoA novel galectin-1 and interleukin 2 receptor 120573 haplotype is associated withautoimmune myasthenia gravisrdquo Journal of Neuroimmunologyvol 229 no 1-2 pp 107ndash111 2010

[57] M J Molnar and P Bencsik ldquoEstablishing a neurological-psychiatric biobank banking informatics ethicsrdquo CellularImmunology vol 244 no 2 pp 101ndash104 2006

[58] Z Pal Z Varga A Semsei et al ldquoInterleukin-4 receptoralpha polymorphisms in autoimmune myasthenia gravis in aCaucasian populationrdquo Human Immunology vol 73 no 2 pp193ndash195 2012

[59] K W Moore R de Waal Malefyt R L Coffman andA OrsquoGarra ldquoInterleukin-10 and the interleukin-10 receptorrdquoAnnual Review of Immunology vol 19 pp 683ndash765 2001

[60] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[61] E H Alseth H L Nakkestad J Aarseth N E Gilhus andG OSkeie ldquoInterleukin-10 promoter polymorphisms in myastheniagravisrdquo Journal of Neuroimmunology vol 210 no 1-2 pp 63ndash662009

[62] M Thiruppathi J Rowin Q Li Jiang J R Sheng B S Prab-hakar and M N Meriggioli ldquoFunctional defect in regulatory Tcells in myasthenia gravisrdquo Annals of the New York Academy ofSciences vol 1274 pp 68ndash76 2012

[63] J Zhang Y Chen G Jia et al ldquoFOXP3 -3279 and IVS9+459polymorphisms are associated with genetic susceptibility tomyasthenia gravisrdquo Neuroscience Letters vol 534 pp 274ndash2782013

[64] G A Yousefipour M R Haghshenas S Yahyazadeh and NErfani ldquoStromal cell derived factor-1 genetic variation at locus801 in patients with myasthenia gravisrdquo Iranian Journal ofImmunology vol 8 no 2 pp 90ndash95 2011

[65] P Sakthivel R Ramanujam X BWang R Pirskanen andA KLefvert ldquoProgrammed death-1 from gene to protein in autoim-mune human myasthenia gravisrdquo Journal of Neuroimmunologyvol 193 no 1-2 pp 149ndash155 2008


[66] Z Pal A Gal V Remenyi A Tordai and M J MolnarldquoOestrogen receptor alpha gene intronic polymorphisms andautoimmune myasthenia gravis in Caucasian womenrdquo Neuro-muscular Disorders vol 19 no 12 pp 822ndash824 2009

[67] R Ramanujam Y Zhao R Pirskanen and L HammarstromldquoLack of association of the CIITAmdash168ArarrG promoter SNPwith myasthenia gravis and its role in autoimmunityrdquo BMCMedical Genetics vol 11 no 1 article 147 2010

[68] R Ramanujam R Pirskanen and L Hammarstrom ldquoTheCD45 77CG allele is not associated with myasthenia gravismdasha reassessment of the potential role of CD45 in autoimmunityrdquoBMC Research Notes vol 3 article 292 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Clinically the extent and the severity of the symptoms theprogression rate (ocular versus generalized type of MG) andthe response to different therapeutic approaches complicatethe issue even further [10]

2 Genetic Approaches inAutoimmune Disorders

In contrast to Congenital Myasthenic Syndromes (CMS)which usually follow Mendelian principles of heredity anddo not entail an autoimmune component MG is a nonin-herited disease and like most autoimmune disorders it isconsidered to have a multifactorial underlying basis In factit is assumed that the pathogenesis of autoimmune diseases iscaused by a complex interaction between multiple genotypesof low penetrance and environmental factors includingpathogen exposure particularly Epstein-Barr virus [11ndash13]sex hormones [14] and lifestyle habits such as cigarettesmoking [15] Twin studies reviewed in [16] revealed thathigh concordance rates among monozygotic compared todizygotic twins observed in several autoimmune diseasesincluding MG are suggestive of a strong genetic componentHowever because of epistasis the individual effect of a genemay be masked or altered through its interaction with othergenes Moreover the genetic element seems to be restrainedand complicated as the disease-associated alleles of risk lociappear in healthy individuals as well

Over the past decade whole genome resequencing alongwith the rapid evolution of high throughput technologiesand statistical tools have provided novel insights in geneticstudies The development of a new prospect in geneticsgenome-wide association studies (GWAS) was crucial forthe identification of numerous loci involved in autoimmunediseases

The vast majority of genetic factors that have beenimplicated in autoimmune disease susceptibility are commonvariants predominantly single nucleotide polymorphisms(SNPs) rather than insertiondeletion polymorphisms ormicrosatellites SNPs are found quite frequently throughoutthe human genome while their impact on gene expression orproteinrsquos function is not always very noticeable

A genetic study has been traditionally implemented byeither linkage analysis or association analysis The latter isnowadays further diversified into candidate gene associationstudy and GWAS Linkage analysis allows inclusion of vastlydifferent subjects as it focuses on transmission patterns andnot on the residual pictureHowever it needswell-establishedpedigrees which is not an easy task in general and the lowrate of MG familial recurrence makes it even more difficultto construct On the other hand candidate gene associationstudy allows inclusion of completely unrelated subjects as itignores transmission patterns but it requires extreme cautionin grouping the test population in relevantly cohesive groupsin order to unveil association between genetic loci and thesyndromeunder study Also theremust be some a priori basisfor suspecting that the candidate genemay be correlated withthe disease

Being a combination of the former two approaches theTransmission-Disequilibrium Test (TDT) allows using thebase of case-control association studies to determine linkagethrough marker transmission in rather shallow family envi-ronments (ie with data collected or projected for as littleas two generations and sometimes with some links missing)[17] The GWAS is a step beyond as it is not the correlationwith a certain candidate locus that must be establishedor overruled but any association with any of the genomicmarkers irrespectively of physical distance is sought forSuch an endeavor is possible thanks to the existence and theconsiderable extent of linkage disequilibrium (LD) whichensures monoblock transmission through successive gener-ations of long chromosomal parts with polymorphic alleleslocated on them being ldquoin phaserdquo meaning that with novelmutagenesis excluded they are transmitted with identicalallelic status forming a haplotype Thus instead of millionsof markers one has just to check one marker per LD block atleast in theory

Convenient for detecting candidate loci without previousassumption as it may LD readily lowers the discriminationpotential of an association study and hence it impairs theaccurate location of the implicated site High-throughputanalysis alleviates this by increasing the number of markersinterrogated to more informative and discriminative levelsonce appropriate depth of analysis is ensured by assemblingadequate sample sizes All three genetic approaches establishby definition statistical correlations between candidate dis-ease loci and phenotypes but they do not produce causativerelationship especially in multifactorial diseases and syn-dromes where a combination of loci may produce an endresult unattainable by any of the constituents

In this review we attempted to incorporate all the recentdata of the international literature regarding the geneticassociations of MG generated mostly from candidate genestudies but also from the first GWAS conducted on MGpatients We focused mainly on studies published over thepast five years as previous studiesmdashbefore 2008mdashhave beencovered in a review by Giraud and coworkers [18]

3 Data Derived from the First GWAS inEOMG Patients

In 2012 the first GWAS for MG [19] was conducted throughan international collaboration of multiple centers that led tothe recruitment of 740MG cases After applying strict qualitycriteria to obtain the appropriate clustering of the samplesthe 649 patients whowere finally included in the study wereof North European descent and developed the disease earlywith age at onset gt10 years and lt40 years as they comprisea more homogeneous group suitable for genetic analysis Interms of thymic histological condition MG patients werediagnosed with thymus hyperplasia whereas a strong femalebias (829 of the overall MG group) was noticed As prob-ably expected the study detected the strongest associationin the Human Leukocyte Antigen (HLA) Class I locus(rs7750641) which after imputation and conditional analyses














Table1HLA

allelesa

ssociatedwith

MGin

distinctsubgroup

softhe

diseasea

ndvario

usethn

icpo

pulations

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Thym

oma-relatedMG

mdashHLA

-AAlowast

25French

7826times10minus3

[23]

B2type

ofthym

oma

HLA

-AAlowast

02

French

27413times10minus4

[23]

mdashHLA

-DQA1

DQA1lowast04

01Northern

Chinese

4111times10minus2

[24]

mdashHLA

-DQB1

DQB1lowast

0604

Northern

Chinese

411times10minus3

[24]

Nonthymom

atousM

G

Thym

ushyperplasia

HLA

-DRB

1DR3

DR7

Ca

ucasian

192

lt1times10minus6

lt1times10minus6

[9]

Thym

ushyperplasia

HLA

-DRB

1DR16

Caucasian

192

11times10minus5

[9]

Thym

ushyperplasia

HLA

-DRB

1DR9

Caucasian

192

2times10minus3

[9]

ATA(+)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR7

Caucasian

591times10minus2b

[9]

ATA(minus)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR3

Caucasian

602times10minus4b

[9]

mdashHLA

-CClowast

0701

Swedish

438

102times10minus3

[25]

LOMGgt60

years

HLA

-DRB

1DRB

1lowast1501

Norwegian

9976times10minus5a

[26]

EOMGlt40

years

HLA

-BBlowast

08Norwegian

154

25times10minus13a

[26]

EOMGamp

MGwith

onset4

1ndash59

yearsamp

LOMG

HLA

-DRB

1DRB

1lowast1301

Norwegian

339

471times10minus4a

[26]

EOMG

HLA

-DRB

1DRB

1lowast08

DRB

1lowast09

NorthernHan

Chinese

527times10minus3

33times10minus2

[27]

LOMG

HLA

-DRB

1DRB

1lowast07

NorthernHan

Chinese

393times10minus2

[27]

OcularM

GHLA

-DRB

1DRB

1lowast09

DRB

1lowast12

NorthernHan

Chinese

34535times10minus5

2times10minus2

[27]

AChR

(+)

HLA

-DRB

1DRB

1lowast08

NorthernHan

Chinese

442times10minus2

[27]

AChR

(minus)

HLA

-DRB

1DRB

1lowast09

NorthernHan

Chinese

302times10minus3

[27]

mdashHLA

-BBlowast

08Saud

i109

34times10minus4a

[28]

mdashHLA

-BBlowast

50

Saud

i109

34times10minus3a

[28]

mdashHLA

-DQA1

DQA1lowast01012

Iranian

104

mdash[29]

mdashHLA

-DQB1

DQB1lowast

0502

Iranian

104

mdash[29]

Generalized

EOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n30

lt10minus3a

lt10minus3a

[30]

Generalized

LOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n18

13times10minus3a

lt10minus3a

[30]

Generalized

MGm

alep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n26

lt10minus3a

lt10minus3a

[30]


Table1Con

tinued

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Generalized

MGfe

malep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n22

lt10minus3a

16times10minus3a

[30]

EOMGwith

thym

ushyperplasia

HLA

-BBlowast

08North

European

649

287times10minus113a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast07

North

European

649

32times10minus8a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast16

North

European

649

13times10minus11a

[19]

MuSK-MG

mdashHLA

-DRB

1ampHLA

-DQB1

DR14-DQ5

haplotype

Dutch

2349times10minus5a

[31]

mdashHLA

-DQB1

DQB1lowast

0502

Italian

3773times10minus6a

[32]

HLA

-DRB

1DRB

1lowast16

Italian

3723times10minus9a

[32]

Negativea

ssociatio

nim

plying

aprotectiver

oleo

fthe

specifica

llelein

MG


Bonferroni

correctio

nform

ultip

lecomparis

ons

b 119875valuec

alculatio

nwas

basedon

thec

omparis

onbetweenAT

A(+)a

ndAT

A(minus)M

Gpatie

nts




























Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Table1HLA

allelesa

ssociatedwith

MGin

distinctsubgroup

softhe

diseasea

ndvario

usethn

icpo

pulations

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Thym

oma-relatedMG

mdashHLA

-AAlowast

25French

7826times10minus3

[23]

B2type

ofthym

oma

HLA

-AAlowast

02

French

27413times10minus4

[23]

mdashHLA

-DQA1

DQA1lowast04

01Northern

Chinese

4111times10minus2

[24]

mdashHLA

-DQB1

DQB1lowast

0604

Northern

Chinese

411times10minus3

[24]

Nonthymom

atousM

G

Thym

ushyperplasia

HLA

-DRB

1DR3

DR7

Ca

ucasian

192

lt1times10minus6

lt1times10minus6

[9]

Thym

ushyperplasia

HLA

-DRB

1DR16

Caucasian

192

11times10minus5

[9]

Thym

ushyperplasia

HLA

-DRB

1DR9

Caucasian

192

2times10minus3

[9]

ATA(+)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR7

Caucasian

591times10minus2b

[9]

ATA(minus)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR3

Caucasian

602times10minus4b

[9]

mdashHLA

-CClowast

0701

Swedish

438

102times10minus3

[25]

LOMGgt60

years

HLA

-DRB

1DRB

1lowast1501

Norwegian

9976times10minus5a

[26]

EOMGlt40

years

HLA

-BBlowast

08Norwegian

154

25times10minus13a

[26]

EOMGamp

MGwith

onset4

1ndash59

yearsamp

LOMG

HLA

-DRB

1DRB

1lowast1301

Norwegian

339

471times10minus4a

[26]

EOMG

HLA

-DRB

1DRB

1lowast08

DRB

1lowast09

NorthernHan

Chinese

527times10minus3

33times10minus2

[27]

LOMG

HLA

-DRB

1DRB

1lowast07

NorthernHan

Chinese

393times10minus2

[27]

OcularM

GHLA

-DRB

1DRB

1lowast09

DRB

1lowast12

NorthernHan

Chinese

34535times10minus5

2times10minus2

[27]

AChR

(+)

HLA

-DRB

1DRB

1lowast08

NorthernHan

Chinese

442times10minus2

[27]

AChR

(minus)

HLA

-DRB

1DRB

1lowast09

NorthernHan

Chinese

302times10minus3

[27]

mdashHLA

-BBlowast

08Saud

i109

34times10minus4a

[28]

mdashHLA

-BBlowast

50

Saud

i109

34times10minus3a

[28]

mdashHLA

-DQA1

DQA1lowast01012

Iranian

104

mdash[29]

mdashHLA

-DQB1

DQB1lowast

0502

Iranian

104

mdash[29]

Generalized

EOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n30

lt10minus3a

lt10minus3a

[30]

Generalized

LOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n18

13times10minus3a

lt10minus3a

[30]

Generalized

MGm

alep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n26

lt10minus3a

lt10minus3a

[30]


Table1Con

tinued

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Generalized

MGfe

malep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n22

lt10minus3a

16times10minus3a

[30]

EOMGwith

thym

ushyperplasia

HLA

-BBlowast

08North

European

649

287times10minus113a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast07

North

European

649

32times10minus8a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast16

North

European

649

13times10minus11a

[19]

MuSK-MG

mdashHLA

-DRB

1ampHLA

-DQB1

DR14-DQ5

haplotype

Dutch

2349times10minus5a

[31]

mdashHLA

-DQB1

DQB1lowast

0502

Italian

3773times10minus6a

[32]

HLA

-DRB

1DRB

1lowast16

Italian

3723times10minus9a

[32]

Negativea

ssociatio

nim

plying

aprotectiver

oleo

fthe

specifica

llelein

MG


Bonferroni

correctio

nform

ultip

lecomparis

ons

b 119875valuec

alculatio

nwas

basedon

thec

omparis

onbetweenAT

A(+)a

ndAT

A(minus)M

Gpatie

nts




























Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1HLA

allelesa

ssociatedwith

MGin

distinctsubgroup

softhe

diseasea

ndvario

usethn

icpo

pulations

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Thym

oma-relatedMG

mdashHLA

-AAlowast

25French

7826times10minus3

[23]

B2type

ofthym

oma

HLA

-AAlowast

02

French

27413times10minus4

[23]

mdashHLA

-DQA1

DQA1lowast04

01Northern

Chinese

4111times10minus2

[24]

mdashHLA

-DQB1

DQB1lowast

0604

Northern

Chinese

411times10minus3

[24]

Nonthymom

atousM

G

Thym

ushyperplasia

HLA

-DRB

1DR3

DR7

Ca

ucasian

192

lt1times10minus6

lt1times10minus6

[9]

Thym

ushyperplasia

HLA

-DRB

1DR16

Caucasian

192

11times10minus5

[9]

Thym

ushyperplasia

HLA

-DRB

1DR9

Caucasian

192

2times10minus3

[9]

ATA(+)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR7

Caucasian

591times10minus2b

[9]

ATA(minus)w

ithno

thym

icabno

rmalities

HLA

-DRB

1DR3

Caucasian

602times10minus4b

[9]

mdashHLA

-CClowast

0701

Swedish

438

102times10minus3

[25]

LOMGgt60

years

HLA

-DRB

1DRB

1lowast1501

Norwegian

9976times10minus5a

[26]

EOMGlt40

years

HLA

-BBlowast

08Norwegian

154

25times10minus13a

[26]

EOMGamp

MGwith

onset4

1ndash59

yearsamp

LOMG

HLA

-DRB

1DRB

1lowast1301

Norwegian

339

471times10minus4a

[26]

EOMG

HLA

-DRB

1DRB

1lowast08

DRB

1lowast09

NorthernHan

Chinese

527times10minus3

33times10minus2

[27]

LOMG

HLA

-DRB

1DRB

1lowast07

NorthernHan

Chinese

393times10minus2

[27]

OcularM

GHLA

-DRB

1DRB

1lowast09

DRB

1lowast12

NorthernHan

Chinese

34535times10minus5

2times10minus2

[27]

AChR

(+)

HLA

-DRB

1DRB

1lowast08

NorthernHan

Chinese

442times10minus2

[27]

AChR

(minus)

HLA

-DRB

1DRB

1lowast09

NorthernHan

Chinese

302times10minus3

[27]

mdashHLA

-BBlowast

08Saud

i109

34times10minus4a

[28]

mdashHLA

-BBlowast

50

Saud

i109

34times10minus3a

[28]

mdashHLA

-DQA1

DQA1lowast01012

Iranian

104

mdash[29]

mdashHLA

-DQB1

DQB1lowast

0502

Iranian

104

mdash[29]

Generalized

EOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n30

lt10minus3a

lt10minus3a

[30]

Generalized

LOMG

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n18

13times10minus3a

lt10minus3a

[30]

Generalized

MGm

alep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast03

DQB1lowast

02Tu

nisia

n26

lt10minus3a

lt10minus3a

[30]


Table1Con

tinued

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Generalized

MGfe

malep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n22

lt10minus3a

16times10minus3a

[30]

EOMGwith

thym

ushyperplasia

HLA

-BBlowast

08North

European

649

287times10minus113a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast07

North

European

649

32times10minus8a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast16

North

European

649

13times10minus11a

[19]

MuSK-MG

mdashHLA

-DRB

1ampHLA

-DQB1

DR14-DQ5

haplotype

Dutch

2349times10minus5a

[31]

mdashHLA

-DQB1

DQB1lowast

0502

Italian

3773times10minus6a

[32]

HLA

-DRB

1DRB

1lowast16

Italian

3723times10minus9a

[32]

Negativea

ssociatio

nim

plying

aprotectiver

oleo

fthe

specifica

llelein

MG


Bonferroni

correctio

nform

ultip

lecomparis

ons

b 119875valuec

alculatio

nwas

basedon

thec

omparis

onbetweenAT

A(+)a

ndAT

A(minus)M

Gpatie

nts




























Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Con

tinued

MGsubgroup

HLA

locus

HLA

alleleor

serologicaltype

Ethn

icgrou

por

descent

Num

bero

fcases

119875value

Reference

Generalized

MGfe

malep

atients

HLA

-DRB

1ampHLA

-DQB1

DRB

1lowast04

DQB1lowast

0302

Tunisia

n22

lt10minus3a

16times10minus3a

[30]

EOMGwith

thym

ushyperplasia

HLA

-BBlowast

08North

European

649

287times10minus113a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast07

North

European

649

32times10minus8a

[19]

EOMGwith

thym

ushyperplasia

HLA

-DRB

1DRB

1lowast16

North

European

649

13times10minus11a

[19]

MuSK-MG

mdashHLA

-DRB

1ampHLA

-DQB1

DR14-DQ5

haplotype

Dutch

2349times10minus5a

[31]

mdashHLA

-DQB1

DQB1lowast

0502

Italian

3773times10minus6a

[32]

HLA

-DRB

1DRB

1lowast16

Italian

3723times10minus9a

[32]

Negativea

ssociatio

nim

plying

aprotectiver

oleo

fthe

specifica

llelein

MG


Bonferroni

correctio

nform

ultip

lecomparis

ons

b 119875valuec

alculatio

nwas

basedon

thec

omparis

onbetweenAT

A(+)a

ndAT

A(minus)M

Gpatie

nts




























Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2As

sociationof

PTPN

22rs2476601and

rs2488457SN

Pswith

distinctMGsubgroup

sin

sixdifferent

popu

latio

ns

SNPAs

sociated

allele

Ethn

icgrou

por

descent

MGsubgroup

Num

bero

fcases

119875value

Reference

rs24766011

858T

North

European

EOMGwith

thym

ushyperplasia

649

82times10minus10a

[19]

French

Non

thym

omaamp

ATA(minus)

293

59times10minus4

[21]

Non

thym

omaamp

ATA(+)

97NS

Thym

oma

80NS

Swedish

Caucasian

Allpatie

nts

409

27times10minus4

[20]

Thym

ushyperplasia

142

14times10minus4

AChR

(+)

350

49times10minus4

Thym

ushyperplasia

ampAC

hR(+)

128

66times10minus5

German

ampHun

garia

n

Allno

nthymom

aMGpatie

nts

208

NS

[45]

Non

thym

omaamp

ATA(+)

507times10minus3a

Non

thym

omaamp

ATA(minus)

152

NS

AChR

(+)

164

lt005

Thym

oma

33NS

German

Caucasian

Thym

oma

7928times10minus3

[46]

EOMG


ItalianCa

ucasian

AllMGpatie

nts

356

NSb

[47]

EOMG

117NSb

AChR

(+)

252

NSb

MuSK(+)

72NSb

Thym

oma

56NSb

Non

thym

oma

300

NSb

Meta-analysisof

the[20214546]

AllMGpatie

nts


[47]

Non

thym

oma


AChR

(+)


Thym

oma

mdashNS

rs2488457-1123C

ItalianCa

ucasian

AChR

(+)w

ithlowtiterle10nM

500019

[47]


Bonferroni

correctio

nform

ultip

letesting

b 119875

values

werec

alculated

basedon

geno

type

frequ

encies

betweenpatie

ntsa

ndcontrols






7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















7 Conclusion




Acknowledgments


References















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Recent Advances in Genetic Predisposition ...downloads.hindawi.com/journals/bmri/2013/404053.pdf · Recent Advances in Genetic Predisposition of Myasthenia Gravis ZoiZagoriti,