Contribution of a genetic risk score to ethnic differences in fatty liver disease

Background and aims: Susceptibility to fatty liver disease (FLD) varies among individuals and between racial/ethnic groups. Several genetic variants influence FLD risk, but whether these variants explain racial/ethnic differences in FLD prevalence is unclear. We examined the contribution of genetic risk factors to racial/ethnic-specific differences in FLD. Methods: A case–control study comparing FLD patients (n = 1194) and population-based controls (n = 3120) was performed. Patient characteristics, FLD risk variants (PNPLA3-rs738409 + rs6006460, TM6SF2-rs58542926, HSD17B13-rs80182459 + rs72613567, MBOAT7/TMC4-rs641738, and GCKR-rs1260326) and a multi-locus genetic risk score (GRS) were examined. The odds of FLD for individuals with different risk factor burdens were determined. Results: Hispanics and Whites were over-represented (56% vs. 38% and 36% vs. 29% respectively) and Blacks under-represented (5% vs. 23%) among FLD patients, compared to the population from which controls were selected (p <.001). Among cases and controls, Blacks had a lower and Hispanics a greater, net number of risk alleles than Whites (p <.001). GRS was associated with increased odds of FLD (OR_Q5vsQ1 = 8.72 [95% CI = 5.97–13.0], p = 9.8 × 10⁻²⁸), with the association being stronger in Hispanics (OR_Q5vsQ1 = 14.8 [8.3–27.1]) than Blacks (OR_Q5vsQ1 = 3.7 [1.5–11.5], P-interaction = 0.002). After accounting for GRS, the odds of FLD between Hispanics and Whites did not differ significantly (OR = 1.06 [0.87–1.28], p =.58), whereas Blacks retained much lower odds of FLD (OR = 0.21, [0.15–0.30], p <.001). Conclusions: Blacks had a lower and Hispanics a greater FLD risk allele burden than Whites. These differences contributed to, but did not fully explain, racial/ethnic differences in FLD prevalence. Identification of additional factors protecting Blacks from FLD may provide new targets for prevention and treatment of FLD.