A genome-first approach to mortality and metabolic phenotypes in p.Ala165Thr (rs2642438) heterozygotes and homozygotes.

BACKGROUND

A coding variant in (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive.

METHODS

Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank.

FINDINGS

p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of rs738409:G. In African-American and Black-British individuals, the allele frequency of p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of rs738409:G.

CONCLUSIONS

Together these data highlight as an important liver disease modifier that influences plasma lipids in an allele-dose-dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality calling for future studies exploring its therapeutic potential.

FUNDING

This study was funded by the German Research Foundation (DFG).