Article | Published:

Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci

Nature Genetics volume 49, pages 842847 (2017) | Download Citation

Abstract

Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene–environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis. We found no evidence of strong interaction between adiposity and sequence variants influencing other adiposity-associated traits. These results indicate that adiposity augments genetic risk of NAFLD at multiple loci that confer susceptibility to hepatic steatosis through diverse metabolic mechanisms.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

  2. 2.

    Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

  3. 3.

    et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

  4. 4.

    et al. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat. Genet. 47, 1114–1120 (2015).

  5. 5.

    , , & The mystery of missing heritability: Genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA 109, 1193–1198 (2012).

  6. 6.

    Variance components models for gene–environment interaction in twin analysis. Twin Res. 5, 554–571 (2002).

  7. 7.

    Twins and the mystery of missing heritability: the contribution of gene–environment interactions. J. Intern. Med. 272, 440–448 (2012).

  8. 8.

    et al. Missing heritability of common diseases and treatments outside the protein-coding exome. Hum. Genet. 133, 1199–1215 (2014).

  9. 9.

    , & Genomics and drug response. N. Engl. J. Med. 364, 1144–1153 (2011).

  10. 10.

    et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

  11. 11.

    et al. Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes. Cancer Epidemiol. Biomarkers Prev. 23, 2829–2839 (2014).

  12. 12.

    , & The importance of gene–environment interactions in human obesity. Clin. Sci. (Lond.) 130, 1571–1597 (2016).

  13. 13.

    & Gene–environment interaction. Annu. Rev. Psychol. 65, 41–70 (2014).

  14. 14.

    , , & Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980).

  15. 15.

    et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

  16. 16.

    et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).

  17. 17.

    et al. Hepatic de novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J. Clin. Endocrinol. Metab. 100, E1125–E1132 (2015).

  18. 18.

    et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).

  19. 19.

    et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).

  20. 20.

    in Introduction to Quantitative Genetics 1st edn. 292–301 (Ronald Press Company, 1960).

  21. 21.

    Effect modification and the limits of biological inference from epidemiologic data. J. Clin. Epidemiol. 44, 221–232 (1991).

  22. 22.

    , , & Behavior of QQ-plots and genomic control in studies of gene–environment interaction. PLoS One 6, e19416 (2011).

  23. 23.

    & Pathophysiology guided treatment of nonalcoholic steatohepatitis. J. Gastroenterol. Hepatol. 27 (suppl. 2), 58–64 (2012).

  24. 24.

    , & Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).

  25. 25.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

  26. 26.

    et al. The MBOAT7TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).

  27. 27.

    et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108–118 (2015).

  28. 28.

    et al. Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55, 114–122 (2012).

  29. 29.

    et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc. Natl. Acad. Sci. USA 107, 7892–7897 (2010).

  30. 30.

    et al. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes 60, 3110–3120 (2011).

  31. 31.

    , , , & Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J. Biol. Chem. 291, 10659–10676 (2016).

  32. 32.

    et al. PNPLA3 gene–by–visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: the NHLBI family heart study. Int. J. Obes. (Lond.) 37, 432–438 (2013).

  33. 33.

    , & Nonalcoholic fatty liver disease and low-carbohydrate diets. Annu. Rev. Nutr. 29, 365–379 (2009).

  34. 34.

    et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am. J. Clin. Nutr. 92, 1522–1527 (2010).

  35. 35.

    et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124–131 (2011).

  36. 36.

    et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520–528 (2008).

  37. 37.

    et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131–1138 (2011).

  38. 38.

    et al. Association of the I148M/PNPLA3 variant with elevated alanine transaminase levels in normal-weight and overweight/obese Mexican children. Gene 520, 185–188 (2013).

  39. 39.

    et al. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One 6, e27933 (2011).

  40. 40.

    , , , & Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. Br. Med. J. 340, c1240 (2010).

  41. 41.

    , , , & Variant in PNPLA3 is associated with alcoholic liver disease. Nat. Genet. 42, 21–23 (2010).

  42. 42.

    et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  43. 43.

    et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).

  44. 44.

    et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

  45. 45.

    Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am. J. Hum. Genet. 14, 353–362 (1962).

  46. 46.

    , & Patatin-like phospholipase domain–containing 3 and the pathogenesis and progression of pediatric nonalcoholic fatty liver disease. Hepatology 52, 1189–1192 (2010).

  47. 47.

    et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462–E468 (2005).

  48. 48.

    , , & The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J. Am. Coll. Cardiol. 63, 2121–2128 (2014).

  49. 49.

    et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473–1480 (2004).

  50. 50.

    et al. Data quality of administratively collected hospital discharge data for liver cirrhosis epidemiology. J. Med. Syst. 21, 11–20 (1997).

  51. 51.

    , , , & A robust example of collider bias in a genetic association study. Am. J. Hum. Genet. 98, 392–393 (2016).

  52. 52.

    , & A review of instrumental variable estimators for Mendelian randomization. Stat. Methods Med. Res. (2015).

Download references

Acknowledgements

This work was supported by grants from the US National Institutes of Health (NIH) (PO1 HL20948 and RO1 DK090066 to H.H.H. and J.C.C. and UL1TR001105 to H.H.H.) and The Danish Council for Independent Research, Medical Sciences (Sapere Aude 4004-00398 to S.S.). The Copenhagen cohort is supported by the Danish Council for Independent Research, the Research Fund at Rigshospitalet, Copenhagen University Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund, Ingeborg and Leo Dannin's Grant, Henry Hansen and Wife's Grant, and a grant from the Odd Fellow Order (to A.T.-H.).

Author information

Affiliations

  1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Stefan Stender
    •  & Helen H Hobbs
  2. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Stefan Stender
    • , Julia Kozlitina
    •  & Helen H Hobbs
  3. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Stefan Stender
    •  & Anne Tybjærg-Hansen
  4. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

    • Børge G Nordestgaard
  5. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.

    • Børge G Nordestgaard
    •  & Anne Tybjærg-Hansen
  6. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

    • Børge G Nordestgaard
    •  & Anne Tybjærg-Hansen
  7. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Helen H Hobbs
  8. The Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Jonathan C Cohen

Authors

  1. Search for Stefan Stender in:

  2. Search for Julia Kozlitina in:

  3. Search for Børge G Nordestgaard in:

  4. Search for Anne Tybjærg-Hansen in:

  5. Search for Helen H Hobbs in:

  6. Search for Jonathan C Cohen in:

Contributions

S.S.: study concept and design, analysis and interpretation of data, drafting of the manuscript, statistical analysis, and critical revision of the manuscript. J.K.: analysis and interpretation of data, statistical analysis, and critical revision of the manuscript. A.T.-H. and B.G.N.: acquisition of data and critical revision of the manuscript. H.H.H.: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, acquisition of data, and study supervision. J.C.C.: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, acquisition of data, and study supervision.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Helen H Hobbs or Jonathan C Cohen.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Tables 1–6.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3855

Further reading