Idiosyncratic DILI: It’s in the Genome
Matthew R. Nelson
Why DILI Idiosyncrasy? The Immune System and BeyondSilver Spring, MD March 14, 2012
Many factors may influence iDILI risk
Environment
GeneticsAge
Dose
Compliance
Diet
Disease
OtherMeds
Image from Ramachandran R and Kakar, (2009) J Clin Pathol 62:481-492
The age-old question
Genes Env
Questions
What do we know about the contribution of genetics to iDILI risk?
How does what we know inform what we can learn and the studies needed?
Can we estimate the genetic contribution to iDILI?
From Daly et al. (2009) Nat. Genet. 41:816-9 5
Combined DILIN/iSAEC cross-drug analysis783 cases, 3001 controls
Key findings
– No major cross-drug risk factors– STAT4 associated with hepatocellular DILI
(OR = 1.4, p = 1.5×10-5)
From Urban et al., submitted
DILI genetic risk factors
Drug Genetic Risk Factor
Prevalence Risk Allele Freq. Rel. Risk Convincing risk factorsCross drug <0.001 STAT4 rs7574865 0.24 1.4Ximelagatran 0.08 HLA-DRB1*07:01 0.08 4Augmentin <0.001 HLA-DRB1*15:01 0.15 4
HLA-A*02:01 0.27 3PTPN22 R620W 0.12 2
Lapatinib 0.09 HLA-DRB1*07:01 0.08 9Lumiracoxib 0.013 HLA-DRB1*15:01 0.15 13Ticlopidine <0.001 HLA-A*33:03 0.14 36Flucloxacillin <0.001 HLA-B*57:01 0.04 81
Hyperbilirubinemia risk factorsPazopanib 0.12 UGT1A1*28 0.3 13Tranilast 0.12 UGT1A1*28 0.3 48
Unconfirmed/suspect risk factorsIsoniazid CYP2E1*1 & NAT2
GSTM1 & GSTT1 NullTroglitazone GSTM1 & GSTT1 NullDiclofenac UGT2B7*2
ABCC2 C-24TIL4 C-590AIL10 C-627A
Tacrine IL6
The genetic effects that we knowDisease-related associations in NHGRI GWAS Catalog
From http://www.genome.gov/gwastudies
The genetic effects that we knowPharmacogenetic effects
We are largely limited to discovering major iDILI risk factors
1001K10K100KN =
α = 5×10-8, N Cases = Controls, log-additive OR
HeritabilityThe genetic contribution to phenotypic variation
Narrow-sense heritability
Broad-sense heritability
P
A
VVh 2
P
IDA
VVVVH
2
Birth weightBMI, age 20-29BMI, age 30-39
Height (clinically measured)Age at menarche
Age at menopauseMale baldness
Alanine aminotransferaseAspartate aminotransferase
ApoEInsulin concentration
Total cholesterolTriglycerides
Diastolic blood pressureSystolic blood pressure
Alcohol consumptionCloninger: Harm avoidance
Cloninger: PersistenceVoting behavior
Major depressive disorder
Hay feverLiability to asthma
Osteoarthritis in womenSusceptibility to Migraine
0 10 20 30 40 50 60 70 80 90 100
Heritability (H2)**From Hill et al. 2008, PLoS Genet. 4:e10000008via Zuk et al. 2012, PNAS, 109:1193
Estimating heritability via familial resemblance
rMZ and rDZ are the phenotypic correlations between MZ and DZ twin pairs
H2 = 2( rMZ ― rDZ )
Broad sense!
Estimating heritability viafamilial resemblance
From Visscher et al., Nat Rev Genet (2008) 9:255-66http://powerofthegene.com/joomla/index.php/genetic-inheritance/recessive
h2 = b
Estimating heritability in population samples with genome-wide data
×
Use the genomic estimates of genetic relatedness to derive an estimate of heritability (h2) from the joint genotypic and phenotypic resemblance.
From Yang et al. (2010) Nat Genet 42:565-71
Examples of variance explained by genetics
Trait N h2 (%)Visscherh2 (s.e., %) GWAS (%)
Height 11,576 80-90 42 (3.0) ~10BMI 11,558 42-80 16 (2.9) ~1.5vWF 6,641 66-75 25 (5.1) ~13QTi 6,567 37-60 17 (5.2) ~7
From Yang et al. (2011) Nat Genet 43:519-27
iDILI heritability estimates (Visscher)
From Casey Overby and Yufeng Shen, in preparation
Opportunities in iSAEC phase 2
iSAEC DILI consortium (IDILIC) expanding case collection
– Range of case recruitment strategies
–Academic networks
–HMOs
–Hospital-based EHRs
– >2,000 DILI cases
– Multi-ethnic
–Includes Chinese centers
Drug-specific sample sizes to identify major risk factors
Large overall sample to dip further into more modest cross-drug risk factors
Drug/ClassPhase I Cases
Phase I & 2 Cases
Other 52 725Co-amoxiclav 176 448Flucloxacillin 75 219
TB 29 202Thiopurine 6 128
Zileuton 71 71Statin 8 81
Diclofenac 27 74Ibuprofen etc. 44 55
Nimesulide 15 47Nitrofurantoin 6 36
Total 509 2,086
Conclusions
Several drug-specific risk factors known
–Largely limited to adaptive and innate immune response–ADME-related associations tenuous
They do not explain all of the DILI risk for their respective drugsSome drugs probably don’t have major common genetic risk factorsHeritability due to common variants for Augmentin and flucloxacillin
appears modest (25-35%)
–Rare variants may be responsible for some additional fraction of the risk
Genetic risk factors are important at least for some forms of DILI
–May be necessary for true DILIHowever, in most instances, non-genetic factors are important