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Multicenter Study
. 2017 Jun;49(6):842-847.
doi: 10.1038/ng.3855. Epub 2017 Apr 24.

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

Stefan Stender  1   2   3 , Julia Kozlitina  2 , Børge G Nordestgaard  4   5   6 , Anne Tybjærg-Hansen  3   5   6 , Helen H Hobbs  1   2   7 , Jonathan C Cohen  8
Affiliations
Multicenter Study

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

Stefan Stender et al. Nat Genet. 2017 Jun.

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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Conflict of interest statement

Conflicts of interest

None of the authors had potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Hepatic triglyceride content by body mass index and PNPLA3 I148M genotype in the Dallas Heart Study. Hepatic triglyceride content was measured by magnetic resonance spectroscopy. Circles and error bars depict medians and interquartile ranges of HTGC. The HTGC-increasing effect of the 148M-allele was amplified by increasing adiposity (p-interaction I148M × BMI on HTGC=4×10−5). The dashed line marks the 95th percentile of HTGC in the general population. Abbreviations: HTGC, hepatic triglyceride content.
Fig. 2
Fig. 2
Hepatic triglyceride content by body mass index and GCKR P446L and TM6SF2 E167K genotypes in the Dallas Heart Study. Circles and error bars depict medians and interquartile ranges of HTGC. The dashed line marks the 95th percentile of HTGC in the general population. Abbreviations: HTGC, hepatic triglyceride content.
Fig. 3
Fig. 3
Serum levels of alanine aminotransferase by body mass index and PNPLA3 I148M genotype in the Dallas Heart Study, the Dallas Biobank, and the Copenhagen cohort. Circles and error bars depict medians and interquartile ranges of ALT. The ALT-increasing effect of the 148M-allele was amplified by increasing adiposity (p-interaction I148M × BMI on ALT <0.001 in all three cohorts). Abbreviations: ALT, alanine aminotransferase.
Fig. 4
Fig. 4
Risk of cirrhosis by body mass index and PNPLA3 I148M genotype in the Copenhagen cohort. Circles and error bars depict odds ratios and 95% confidence intervals. The II-genotype acted as the reference group within each BMI-group. The risk-increasing effect of the 148M-allele was amplified by increasing adiposity (p-interaction I148M × BMI on risk of cirrhosis=0.026).
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Comment in

References

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