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 for this work

Department of Clinical Medicine

131 Citations (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.

Original language	English
Journal	Nature Genetics
Volume	49
Issue number	6
Pages (from-to)	842-847
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3855
Publication status	Published - Jun 2017

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title = "Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci",

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.",

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T1 - Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci

AU - Stender, Stefan

AU - Kozlitina, Julia

AU - Nordestgaard, Børge G.

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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JO - Nature Genetics

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

Abstract

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