A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes

Summary Background A coding variant in MTARC1 (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 MTARC1 p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank. Findings MTARC1 p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower low-density lipoprotein cholesterol (LDL-C), lower ApoB, lower high-density lipoprotein cholesterol (HDL-C), lower ApoA-I, and higher insulin growth factor 1 (IGF-1). Per each minor allele, the risk of non-alcoholic fatty liver disease (NAFLD) was reduced by ∼15%. The alanine aminotransferase (ALT)-lowering and NAFLD-protective effect of MTARC1 p.Ala165Thr was amplified by obesity, diabetes mellitus, and presence of PNPLA3 rs738409:G. In African American and Black British individuals, the allele frequency of MTARC1 p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, MTARC1 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, although 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 PNPLA3 rs738409:G. Conclusions Together, these data highlight MTARC1 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).