Presenter of 1 Presentation
GENETIC RISK OF FATTY LIVER DISEASE AND MORTALITY IN THE GENERAL POPULATION
Abstract
Background and Aims
Fatty liver disease associates with increased mortality. This study aims to use genetic variants implicated in fatty liver disease to assess if fatty liver disease per se causes increased mortality.
Methods
We included participants from two prospective studies of the general Danish population, the Copenhagen City Heart Study and the Copenhagen General Population Study, totaling n=110,913. All participants were genotyped for six variants with known effects on fatty liver disease: PNPLA3 rs738409, TM6SF2 rs58542926, HSD17B13 rs72613567, MBOAT7 rs641738, MTARC1 rs2642438, and GCKR rs1260326. Hazard ratios were calculated using Cox-regression.
Results
During a median follow-up of 9.5 years, 16,119 individuals died, hereof 201 due to liver-related causes, 1,736 to ischemic heart disease (IHD), and 4,973 to extrahepatic cancer. The variants at PNPLA3, HSD17B13, TM6SF2, and MBOAT7 (but not those at MTARC1 and GCKR) associated with liver-related mortality with per-allele hazard ratios of 1.3 to 1.6 (p-values<0.06). The strongest effect was seen for the PNPLA3-variant, for which homozygous carriers had a three-fold higher risk of liver-related death compared to non-carriers. A genetic risk score comprised of the variants at PNPLA3, TM6SF2 and HSD17B13 was associated with stepwise increased liver-related mortality, with a maximum hazard ratio of 13 (95% CI: 3.8-48) for those with 5 or 6 versus 0 risk-increasing alleles (Figure, bottom, p-trend=9x10E-7). The fatty liver disease variants, individually or combined, did not associate with IHD-related, extrahepatic cancer-related, or all-cause mortality (Figure, top).
Conclusions
Genetic risk of fatty liver disease associated with liver-related but not IHD-related, extrahepatic cancer-related or overall mortality in the general population.
