ORIGINAL ARTICLE

APOE and LRPAP1 gene polymorphism and riskof Parkinson’s disease

Neeraj Kumar Singh • Basu Dev Banerjee •

Kiran Bala • Mitrabasu • Aldrin Anthony Dung Dung •

Neelam Chhillar

Received: 19 July 2013 / Accepted: 21 January 2014

� Springer-Verlag Italia 2014

Abstract Epidemiologic findings suggest that lipids and

alteration in lipid metabolizing protein/gene may contrib-

ute to the development of neurodegenerative disorders. The

aim of the current study was to determine the serum lipid

levels and genetic variation in two lipid metabolizing

genes, low-density lipoprotein receptor-related protein-

associated protein (LRPAP1) and apolipoprotein E (APOE)

gene in Parkinson’s disease (PD). Based on well-defined

inclusion and exclusion criteria, this study included 70

patients with PD and 100 age-matched controls. LRPAP1

and APOE gene polymorphism were analyzed by poly-

merase chain reaction and restriction fragment length

polymorphism, respectively. Fasting serum lipid levels

were determined using an autoanalyser. The logistic

regression analysis showed that high levels of serum cho-

lesterol [odds ratio (OR) = 1.101, 95 % confidence inter-

val (CI95%) = 1.067–1.135], LRPAP1 I allelic variant

alone (OR = 2.766, CI95% = 1.137–6.752) and in combi-

nation with APOE e4 allelic variant (OR = 4.187,

CI95% = 1.621–10.82) were significantly associated with

increase in PD risk. Apart from that, the high levels of LDL

cholesterol appears to have a protective role (OR = 0.931,

CI95% = 0.897–0.966) against PD. The LRPAP1 I allelic

variant may be considered a candidate gene for PD, pre-

dominantly in patients having the APOE e4 allelic variant.

Keywords Neurodegenerative disease � Parkinson’s

disease � APOE e4 allele � LRPAP1 I allele �Cholesterol � LDL cholesterol

Introduction

Parkinson’s disease (PD) is the second most common

neurodegenerative disorder after Alzheimer’s disease (AD)

with a prevalence rate of 1–2 % in people over the age of

50 years. It is characterized by debilitating symptoms of

tremor, rigidity and bradykinesia. Some of the clinical,

neurochemical, and pathologic features are the same in PD

and AD [1]. Patients with PD may frequently develop

dementia. Moreover, patients with AD often develop Par-

kinsonism [2]. Both PD and AD are characterized by

neuronal death and protein deposition of a-synuclein and

b-amyloid, respectively [3].

Apolipoprotein E (APOE) gene polymorphism is an

important determinant for the development of various

neurodegenerative and cardiovascular disorders. The e4

allele of APOE gene is a risk factor, whereas e2 allele of

APOE gene is protective for AD [4, 5]. The role of APOE

gene in PD has been investigated in several studies but

conflicting results have been observed [6–11]. Generally,

APOE e4 allele has been associated with high levels of

serum cholesterol and low-density lipoprotein cholesterol

(LDL cholesterol), whereas e2 allele has been associated

N. K. Singh � N. Chhillar (&)

Department of Neurochemistry, Institute of Human Behaviour

and Allied Sciences, Dilshad Garden, Delhi 110095, India

e-mail: nlmchhillar@yahoo.co.in

B. D. Banerjee

Environmental Biochemistry Laboratory, Department

of Biochemistry, University College of Medical Science

and GTB Hospital, Dilshad Garden, Delhi 110095, India

K. Bala � A. A. Dung Dung

Department of Neurology, Institute of Human Behaviour

and Allied Sciences, Dilshad Garden, Delhi 110095, India

Mitrabasu

Health Centre, Institute of Nuclear Medicine and Allied

Sciences, DRDO, Timarpur, Delhi 110054, India

123

Neurol Sci

DOI 10.1007/s10072-014-1651-6

with low levels of serum cholesterol and LDL cholesterol

[12, 13]. Huang et al. [14] have reported the association of

lower serum LDL cholesterol level with PD patients. These

findings suggest that altered lipid metabolism and abnor-

malities in genes/proteins of the lipid metabolic pathway

may contribute to PD risk.

Apolipoprotein E (APOE) participates in the clearance of

lipids through low-density lipoprotein receptor (LDLR) and

LDL receptor-related protein (LRP) in human brain. LDL

receptor-related protein-associated protein1 (LRPAP1)

might function as a chaperone protein to nascent LRP during

its intracellular transport. Any mutational/functional

abnormality in LRPAP1 may lead to a reduced amount of

mature LRP which may alter the clearance of lipids [15].

Koob et al. [16] showed that change in cholesterol compo-

sition alters the level of a-synuclein in vitro. So far, there are

no studies which indicate the role of LRPAP1 in PD but a few

studies have shown that I allele of LRPAP1 gene was

significantly associated with other diseases like gallstone

disease [17, 18] and AD [19, 20]. A study performed by

Pandey et al. [21] reported that the frequency of DD geno-

type and D allele of LRPAP1 were high in various dementias.

Keeping this in view, the present study was undertaken

to further examine the role of serum lipid levels and

polymorphism of the lipid metabolizing genes (i.e., APOE

and LRPAP1) in PD.

Materials and methods

Study population and design

A total of 170 subjects (PD = 70 and control = 100),

belonging to the state of Delhi and other surrounding states

of North India were enrolled for the study. The sample size

was calculated using PS software, version 3.0.14

(a = 0.05, b = 0.20 and power = 0.80). The study pro-

tocol and informed consent form were reviewed and

approved by Institutional Ethics Committee. Patients in age

group of 50–85 years with complaints of bradykinesia,

resting tremor, rigidity, and postural reflex impairment

were examined by neurologist in the out-patient Depart-

ment of Neurology, Institute of Human Behaviour and

Allied Sciences, Delhi, India during February 2010 to June

2012. These patients were assessed by the United Kingdom

Parkinson’s Disease Society Brain Bank clinical diagnostic

criteria for PD. Magnetic resonance imaging (MRI)/com-

puted tomography (CT)/positron emission tomography

(PET) was done to support the clinical diagnosis of PD.

Additional inclusion criteria, score of [23 on the mini-

mental state examination (MMSE) and a Clinical Dementia

Rating (CDR) score of B0.5 were used to rule out any

impairment in memory or dementia. The control group

comprised age, sex and geographically matched volunteers.

Subjects were excluded in both case and control groups if

there was no consent for participation in the study, history

of cerebral stroke, epilepsy, head trauma, other concomi-

tant disease potentially associated with PD, moderate to

severe depressive episode, familial history of any kind of

cognitive/behavioral abnormality and chronic intake of

drugs affecting lipid profile and cognitive processes.

Nutritional deficiency, metabolic abnormalities and central

nervous system infections were ruled out.

APOE genotyping

Genomic DNA was isolated using peripheral blood by salt-

ing-out method. The fourth exon of APOE gene which

encodes amino acid residues 112 and 158 was amplified on

Bio-Rad iQ5 cycler using the specific primers 50-ACAG

AATTCGCCCCGGCCTGGTACAC-30 and 50-TAAGCTT

GGCACGGCTGTCCAAGGA-30 [5]. PCR reaction mixture

(20.0 ll) containing 19 high-fidelity master mix (0.04U/ll

DNA polymerase, 1.5 mM MgCl2, 200 lM dNTPs), 7.5 %

dimethyl sulfoxide (DMSO), 10 ng of genomic DNA and

0.5 lM of each primer were used. PCR profile consisted of a

1 min hold at 98 �C followed by 35 cycles of 98 �C (30 s),

65 �C (30 s.) and 72 �C (30 s) and final extension 72 �C for

3 min. PCR product (244 bp) was digested with 10 units of

Hha1 and run on 12 % polyacrylamide gel followed by the

ethidium bromide staining. The fragments obtained from the

restriction digestion were compared with known molecular

weight marker. The e3e3 genotype contained 91, 48, 38 and

35 bp fragment; the e3e4 genotype contained 91, 72, 48, 38

and 35 bp fragment; the e3e2 genotype contained 91, 83, 48,

38 and 35 bp fragment; the e4e2 genotype contained 91, 83,

72, 48 and 38 bp fragments. Except for 38 bp common

fragment other two common fragments (18 and 16 bp) were

too small to be detected.

LRPAP1 Genotyping

The primers 50-GGTGTTTCTGGACACAAAGGA-30 and

50-AGTGTGCGTGGAGCCTATG-30 were used for

amplification [21]. PCR reaction mixture containing 19

high-fidelity master mix (0.04 U/ll DNA polymerase,

1.5 mM MgCl2, 200 lM dNTPs), 10 ng of genomic DNA

and 0.25 lM of each primer in 20.0 ll volume was used.

PCR protocol consisted of a 1 min hold at 98 �C followed

by 35 cycles of 98 �C (30 s), 64 �C (30 s) and 72 �C (30 s)

and final extension 72 �C for 3 min. This polymorphism

arises due to 37 bp insertions in intron 5 which was

detected by 2 % agarose gel electrophoresis. The DD

genotype contained 185 bp fragment; the DI genotypes

contained 222 and 185 bp fragments; the II genotypes

contained 222 bp fragment.

Neurol Sci

123

Estimation of lipids

Serum lipids, i.e., cholesterol, triglycerides, high density

lipoprotein cholesterol (HDL cholesterol) and LDL cho-

lesterol were estimated in sample collected after overnight

fasting using commercially available kit manufactured by

Centronic GmbH, Germany by using autoanalyser (XL-300

from Transasia).

Statistical analysis

The statistical analysis was carried out using SPSS ver. 17.0.

Mean ± standard deviations were calculated to describe the

quantitative data, whereas percentages were calculated to

describe qualitative data. The distribution of demographic

characteristics for cases and controls were compared by v2

tests. The genotypes and allelic distributions were calculated

by 2 9 2 contingency tables. Independent sample t test was

used for comparing mean of normally distributed continuous

variables. The risk factor was estimated using logistic

regression analysis, with demographical profile, serum

cholesterol, LDL cholesterol, presence/absence of APOE e4

and LRPAP1 I allelic variants as predictor variables for PD

verses controls’ status. All tests were two tailed and p \ 0.05

was considered as significant for result interpretation.

Results

The demographic profiles of PD and control are presented

in Table 1. A Mann–Whitney U test revealed no significant

difference in the age of PD patients and controls

(U = 3,140.50, w = 5,625.50, z = -1.141, p = 0.254).

The frequency of PD patients with smoking habit was

significantly low as compared to the controls (28.57 vs.

46.0 %, p = 0.022).

The gel pictures of APOE and LRPAP1 gene poly-

morphism are shown in Figs. 1 and 2, respectively. The

genotypes and allelic frequency of APOE and LRPAP1-

gene are shown in Table 2. APOE e4 allele frequency was

significantly high (v2 = 5.6, p = 0.017) in PD as com-

pared to controls. Among the APOE genotypes, e3e4

showed a strong significant association (v2 = 6.26,

p = 0.012) with PD patients as compared to controls. The

frequency of I allele and DI genotype was significantly

high in PD patients as compared to controls (v2 = 10.66,

p = 0.001 and v2 = 9.23, p = 0.002, respectively).

Table 2 also indicates that the LRPAP1 I allelic variant

alone (v2 = 4.7, p = 0.030) as well as with combination of

APOE e4 allelic variant (OR = 10.128, p = 0.001) was

significantly associated with increase in PD risk.

The independent sample t test results show that the

mean levels of serum cholesterol and LDL cholesterol were

Table 1 Sociodemographic characteristics of Parkinson’s disease

(PD) and controls

Characteristic Controls

(n = 100)

PD (n = 70) v2 p value

Age (years) 59.71 ± 8.114 58.01 ± 8.623 0.254

Sex

Male 61 (61.0) 38 (54.28) 0.763 0.382

Female 39 (39.0) 32 (45.71)

Habitat

Urban 64 (64.0) 46 (65.71) 0.053 0.818

Rural 36 (36.0) 24 (34.28)

Dietary habit

Vegetarian 49 (49.0) 40 (57.14) 1.095 0.295

Non-vegetarian 51 (51.0) 30 (42.86)

Smoking habit

Currently yes 46 (46.0) 20 (28.57) 5.266 0.022*

Never smoked 54 (54.0) 50 (71.43)

Alcohol habit

Currently yes 37 (37.0) 22 (31.43) 0.564 0.453

Never intake 63 (63.0) 48 (68.57)

Mean ± SD, Figure in parentheses indicate percentage and *

p \ 0.05 (by Pearson v2 test)

Fig. 1 Polyacrylamide gel picture shows the APOE gene polymor-

phism. e3e3 genotype in lane 1, 4 and 7. e3e4 genotype in lane 2 and

6. e3e2 genotype in lane 3. e4e2 in lane 5. DNA ladder in lane M

Fig. 2 Agarose gel picture shows the LRPAP1 gene polymorphism.

DD genotype in lane 2, 4, 5 and 8. DI genotype in lane 3 and 6. II

genotype in lane 7. DNA ladder in lane 1

Neurol Sci

123

significantly high in PD patients as compared to controls

(Table 3). Distributions of serum lipid levels according to

smoking status and presence/absence of e4 and I allele are

shown in Table 3. The significantly elevated levels of

serum cholesterol were not affected by smoking habit and

presence/absence of the APOE e4 and LRPAP1 I allelic

variants. However, the LDL cholesterol levels were

affected by presence/absence of the APOE e4 and LRPAP1

I allelic variants. Logistic regression was performed to

assess the impact of number of factors on the likelihood of

increase in PD risk (Table 4).

Discussion

To the best of our knowledge this is the first study to

investigate the role of LRPAP1 gene in PD. No significant

difference was found between demographical profile such

as age, sex, habitat, dietary and alcohol habit. We found

significantly low frequency of PD cases with smoking habit

as compared to the controls (p \ 0.05) which is in accor-

dance with other studies showing consistently low risk of

PD among cigarette smokers [22, 23]. It has also been

observed that nicotine or other component of cigarette

Table 2 Distribution of APOE

and LRPAP1 genotypes and

allelic variants in Parkinson’s

disease (PD) and controls

Figure in parentheses indicate

frequency

– Not present, ND not done

* p \ 0.01

� p \ 0.05

Alleles/genotypes Controls

(n = 100)

PD

(n = 70)

Odds ratio (OR) 95 % CI for OR p value

Lower Upper

e3 173 (0.87) 111 (0.79)

e4 15 (0.08) 22 (0.16) 2.286 1.137 4.595 0.017�

e2 12 (0.06) 7 (0.05) 0.909 0.347 2.379 0.841

e3e3 74 (0.74) 42 (0.60)

e3e4 14 (0.14) 21 (0.30) 2.643 1.217 5.737 0.012�

e3e2 11 (0.11) 6 (0.09) 0.961 0.331 2.786 0.920

e4e4 – –

e4e2 1 (0.01) 1 (0.01) ND

e2e2 – –

D 176 (0.88) 104 (0.74)

I 24 (0.12) 36 (0.26) 2.538 1.435 4.491 0.001*

DD 78 (0.78) 38 (0.54)

DI 20 (0.20) 28 (0.40) 2.874 1.438 5.744 0.002*

II 2 (0.02) 4 (0.06) ND

Without e4 and I allele 72 (0.72) 33 (0.47)

With e4 and I allele 9 (0.09) 17 (0.24) 4.121 1.663 10.207 0.001*

e4 allele without I allele 6 (0.06) 5 (0.07) ND

I allele without e4 allele 13 (0.13) 15 (0.21) 2.517 1.076 5.886 0.030�

Table 3 Serum lipid levels

according to the smoking status

and presence/absence of e4 and

I allele in Parkinson’s disease

(PD) and controls

Mean ± SD

* p \ 0.001

� p \ 0.01} p \ 0.05

Variables Groups N Cholesterol Triglycerides HDL

cholesterol

LDL

cholesterol

All subject Control 100 124.12 ± 31.13 159.63 ± 49.92 47.19 ± 9.10 72.45 ± 24.67

PD 70 168.17 ± 41.0* 159.32 ± 67.97 46.76 ± 10.24 88.53 ± 33.57*

Currently

smoking

Control 46 124.87 ± 33.99 156.76 ± 39.89 47.61 ± 9.30 72.70 ± 27.01

PD 20 162.30 ± 32.37* 171.55 ± 78.16 42.70 ± 7.29 86.55 ± 26.27�

Never smoked Control 54 123.48 ± 28.76 162.07 ± 57.36 46.83 ± 9.01 72.24 ± 22.75

PD 50 170.52 ± 44.05* 154.44 ± 63.66 48.38 ± 10.84 89.32 ± 36.29�

Without e4 and

I allele

Control 72 133.26 ± 23.48 152.47 ± 43.08 46.50 ± 8.82 63.34 ± 17.77

PD 33 140.03 ± 21.19* 153.12 ± 80.49 46.75 ± 12.31 62.36 ± 18.03

With e4 and I

allele

Control 09 165.66 ± 32.84 192.11 ± 65.75 44.44 ± 6.87 113.77 ± 14.77

PD 17 201.70 ± 31.76} 162.0 ± 56.86 43.64 ± 5.32 126.17 ± 20.36

e4 allele

without I

allele

Control 06 164.66 ± 20.71 171.0 ± 24.20 49.0 ± 6.03 111.83 ± 10.43

PD 05 205.40 ± 18.0� 223.60 ± 54.41 56.20 ± 10.94 104.60 ± 4.77

I allele without

e4 allele

Control 13 136.76 ± 28.89 171.53 ± 69.01 52.07 ± 11.90 76.07 ± 19.87

PD 15 179.66 ± 46.30� 148.53 ± 41.49 47.13 ± 7.71 98.06 ± 28.38}

Neurol Sci

123

lowers the risk of PD via unknown mechanisms [22–24].

Furthermore, Hong et al. [25] also showed that nicotine and

hydroquinone inhibit a-synuclein fibrillation.

The APOE gene is polymorphic with three common

alleles, e2, e3 and e4. The e4 allele is less effective than the

e3 and e2 alleles to mediate neuronal repair, remodeling,

and protection [26]. The univariate analysis of our study

showed that PD patients are more than twofold at risk when

having at least one copy of APOE e4 allele. Several studies

have investigated the role of APOE in PD but conflicting

results have been observed [6–11]. We have also observed

that PD patients are more than twofold at risk when having

at least one copy of LRPAP1 I allele. The polymorphic I

allele arises due to insertion of 37 base pair in intron 5.

There are no data in the literature about the association

between LRPAP1 gene polymorphism and risk of PD. The

univariate analysis also showed that synergistically the

LRPAP1 I allele along with APOE e4 allele was found to

be more susceptible (nearly fourfold) in PD rather than

their individual effect. The APOE and LRPAP1 genes play

an important role in the lipid metabolism. Any mutational/

functional abnormality in these genes may lead to an

alteration in cerebral lipid metabolism which may be linked

to neurodegenerative disease because maintenance of lipid

homeostasis is necessary for normal neuronal function.

Few findings showed that alteration in cerebral lipid

metabolism may be linked to PD [27, 28].

PD being multifactorial disease, APOE and LRPAP1

genotyping could be considered for its clinical diagnosis.

However, as in Table 3, the presence of e4 allele (n = 15)

and I allele (n = 22) in healthy subjects whereas its

absence in diagnosed PD subjects (n = 48 and n = 38,

respectively) indicated that some other factors were also

associated with risk of developing PD. Among the other

factors, levels of serum cholesterol, LDL cholesterol and

smoking status in the present study indicate that they may

participate independently to risk of PD.

The present study observed significantly high levels of

serum cholesterol and LDL cholesterol in PD patients as

compared to controls. A study of Hu et al. [29] indicated

that high serum cholesterol may increase PD risk. Inter-

estingly, Koob et al. [16] showed that change in cholesterol

composition using cholesterol lowering agents reduces the

level of a-synuclein in vitro. Our study has also pointed out

the influence of smoking status and presence/absence of

APOE e4 and LRPAP1 I allelic variants on serum lipid

levels. The significant high levels of serum cholesterol and

LDL cholesterol remain unchanged with smoking status.

The present study observed significantly high levels of

serum cholesterol in diagnosed PD patients (n = 33) who

were neither carrying e4 allele nor I allele (Table 3).

Several studies have shown that APOE allelic variants (e3,

e2 and e4) were associated with variation of serum cho-

lesterol and LDL cholesterol levels [30–32].

We used logistic regression analysis to assess the impact

of number of factors on prediction of risk for PD. Apart

from the association between the LRPAP1 I allelic variant

and risk of PD which was independent of the presence of

the APOE e4 allelic variant, we found an increase in the

risk of PD (OR = 4.187) in those patients who carried both

LRPAP1 I and APOE e4 allelic variants. The logistic

regression result also shows that beside LRPAP1 I and

APOE e4 allelic variants, higher levels of serum choles-

terol were significantly associated with increase in PD risk,

recording an odds ratio of 1.101. This indicates that for an

additional 1 unit (mg/l) increment of serum cholesterol

levels, chances of developing PD in our population will be

1.101. Moreover, LDL cholesterol even appears to have a

Table 4 Risk factor for

Parkinson’s disease

* p \ 0.001

� p \ 0.01} p \ 0.05a Variable(s) entered on step 1:

Age, sex, habitat, dietary habit,

smoking habit, alcohol habit,

cholesterol, LDL cholesterol,

presence/absence of e4 and I

allele

B SE Wald df Sig. OR 95 % CI for OR

Lower Upper

Step 1a

Age -0.048 0.030 2.511 1 0.113 0.953 0.898 1.012

Sex (1) 0.334 0.341 0.957 1 0.328 1.396 0.715 2.723

Habitat (1) -0.689 0.480 2.065 1 0.151 0.502 0.196 1.285

Dietary habit (1) -041 0.459 0.008 1 0.929 0.960 0.391 2.359

Smoking habit (1) 0.679 0.387 3.066 1 0.080 1.971 0.922 4.212

Alcohol habit (1) 0.099 0.503 0.039 1 0.844 1.104 0.412 2.962

Cholesterol 0.096 0.016 36.817 1 0.000* 1.101 1.067 1.135

LDL cholesterol -0.072 0.019 14.214 1 0.000* 0.931 0.897 0.966

Without e4 and I allele 11.717 3 0.008

With e4 and I allele (1) 1.432 0.484 8.745 1 0.003� 4.187 1.621 10.817

e4 allele without I allele (2) 0.753 0.669 1.265 1 0.261 2.123 0.572 7.885

I allele without e4 allele (3) 1.017 0.455 4.994 1 0.025} 2.766 1.133 6.752

Constant -6.046 2.044 8.748 1 0.003 0.002

Neurol Sci

123

protective role (OR = 0.931) against PD. At this stage, we

are unable to interpret the protective role of increased LDL

cholesterol levels in PD. The protective role of LDL cho-

lesterol can be studied in more details by prospective

studies with a larger sample size to further understand the

mechanisms involved. However, a study supports the

hypothesis that low LDL cholesterol is associated with an

increased risk of PD [33] and Tikhonoff et al. [34] sug-

gested that low levels of LDL cholesterol may not be good

for the elderly. In addition, a study suggested that the

concept of ‘‘LDL is bad cholesterol’’ is a simplistic and

scientifically untenable hypothesis [35].

Although the univariate analysis of our study showed

that PD patients are more than twofold at risk when having

at least one copy of APOE e4 allele, however, no associ-

ation was found in multivariate analysis. This disparity

may be due to the other confounding factors and/or small

sample size of the current cohort. The small sample size is

a limitation of our study and a replication study with large

sample size would certainly be justified.

In conclusion, the result obtained from this study clearly

indicates that LRPAP1 I allelic variant might be considered

a candidate gene for PD and suggests that it could be a

dynamic risk factor in patients having the APOE e4 allelic

variant. Moreover, the high serum cholesterol levels were

independently associated with risk of PD. Apart from that

the LDL cholesterol appears to have a protective role

against PD. The data of this study may be considered for

study design and analysis in future studies for the etiology

of PD keeping in view the environmental factors.

Acknowledgments One of the authors (Neeraj Kumar Singh) is

thankful to Indian Council of Medical Research (ICMR), New Delhi,

for providing Senior Research Fellowship support to undertake this

study.

Conflict of interest The authors declare that there are no conflicts

of interest with respect to the authorship and/or publication of this

article.

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