Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

Abstract

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (<i>PNPLA3</i>) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (<i>TM6SF2</i>) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (<i>PPARGC1A</i>) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (<i>ADCY3</i>) <i>(</i>rs713586), and insulin-like growth factor 1 (<i>IGF-1</i>) (rs1520220). In GLDI, <i>PNPLA3</i> I148M (<i>P</i> = 0.001) and <i>TM6SF2</i> E167K (<i>P</i> = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, <i>PNPLA3</i> I148M showed the same effect (<i>P</i> = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of <i>PNPLA3</i> and/or <i>TM6SF2</i> risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, <i>P</i> = 4 × 10^-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, <i>P</i> = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, <i>P</i> = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. <i>Conclusion:</i> The carriers of <i>PNPLA3</i> and/or <i>TM6SF2</i> variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (<i>Hepatology Communications</i> 2018;2:561-570).