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

Stefan Stender; Julia Kozlitina; Børge G. Nordestgaard; Anne Tybjærg-Hansen; Helen H. Hobbs; Jonathan C. Cohen

doi:10.1038/ng.3855

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

Stefan Stender, Julia Kozlitina, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Helen H. Hobbs^*, Jonathan C. Cohen

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

131 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	49
Udgave nummer	6
Sider (fra-til)	842-847
Antal sider	6
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3855
Status	Udgivet - jun. 2017

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10.1038/ng.3855

http://europepmc.org/articles/pmc5562020?pdf=render

Citationsformater

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AU - Stender, Stefan

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AU - Tybjærg-Hansen, Anne

AU - Hobbs, Helen H.

AU - Cohen, Jonathan C.

PY - 2017/6

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N2 - 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.

AB - 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.

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

Abstract

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