The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study

Objectives: Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation. Methods: We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using similar to 2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits. Results: Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47 x 10(-9) <= CMA-p <= 4.29 x 10(-10)) as compared with the suggestive significance of marginal tests (4.11 x 10(-5) <= GWA-p <= 2.34 x 10(-6)). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p = 4.88 x 10(-10)) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p = 5.74 x 10(-6), ALT:p = 3.71 x 10(-6)). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p <= 3.3 x 10(-7)). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans. Conclusions: CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease. (C) 2013 Elsevier Ireland Ltd. All rights reserved.