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Idiosyncratic DILI: It’s in the Genome

Idiosyncratic DILI: It’s in the Genome. Matthew R. Nelson Why DILI Idiosyncrasy? The Immune System and Beyond Silver Spring, MD March 14, 2012. Many factors may influence iDILI risk. Genetics. Disease. Age. Other Meds. Dose. Diet. Environment. Compliance.

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Idiosyncratic DILI: It’s in the Genome

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  1. Idiosyncratic DILI: It’s in the Genome Matthew R. Nelson Why DILI Idiosyncrasy? The Immune System and Beyond Silver Spring, MD March 14, 2012

  2. Many factors may influence iDILI risk Genetics Disease Age Other Meds Dose Diet Environment Compliance Image from Ramachandran R and Kakar, (2009) J ClinPathol 62:481-492

  3. The age-old question Env Genes

  4. 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?

  5. From Daly et al. (2009) Nat. Genet. 41:816-9

  6. 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

  7. DILI genetic risk factors

  8. The genetic effects that we knowDisease-related associations in NHGRI GWAS Catalog From http://www.genome.gov/gwastudies

  9. The genetic effects that we knowPharmacogenetic effects

  10. We are largely limited to discovering major iDILIrisk factors α = 5×10-8, N Cases = Controls, log-additive OR N = 100K 10K 1K 100

  11. HeritabilityThe genetic contribution to phenotypic variation • Narrow-sense heritability • Broad-sense heritability *From Hill et al. 2008, PLoS Genet. 4:e10000008 via Zuket al. 2012, PNAS, 109:1193 Heritability (H2)*

  12. Estimating heritability via familial resemblance H2 = 2( rMZ ― rDZ ) Broad sense! rMZ and rDZ are the phenotypic correlations between MZ and DZ twin pairs

  13. Estimating heritability viafamilial resemblance h2 = b From Visscher et al., Nat Rev Genet (2008) 9:255-66 http://powerofthegene.com/joomla/index.php/genetic-inheritance/recessive

  14. 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

  15. Examples of variance explained by genetics From Yang et al. (2011) Nat Genet 43:519-27

  16. iDILI heritability estimates (Visscher) From Casey Overby and Yufeng Shen, in preparation

  17. 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

  18. 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 drugs • Some drugs probably don’t have major common genetic risk factors • Heritability 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 DILI • However, in most instances, non-genetic factors are important

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