Genome‐wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals

Abstract

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome‐wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome‐wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome‐wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST‐associated variants on liver disease, the weighted burden of significant BMI‐modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.

Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17‐beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms

“…This has subsequently been replicated in multiple genome‐wide analyses that also implicate these variants in levels of serum aminotransferases and liver disease in adults. [ 12 , 13 , 14 ] HSD17B13 has subsequently been validated in multiple cohorts of adults, [ 6 , 16 , 17 , 33 , 56 , 57 , 58 ] and although a small group of children were included in the original replication cohort where this variant was identified, [ 10 ] features specific to pediatric NAFLD histology were not described in detail. Similarly, the histologic features associated with the variant in MTARC1 had not been described in children until now.…”

“…More recently, strong human genetic evidence has identified two protective variants at genome‐wide significance in adults: rs72613567T>TA in hydroxysteroid 17‐beta dehydrogenase 13 ( HSD17B13 ) [ 10 ] and p.Ala165Thr in mitochondrial amidoxime reducing component 1 ( MTARC1 , rs2642438G>A). [ 11 , 12 , 13 , 14 , 15 ]…”

Multiomics study of nonalcoholic fatty liver disease

“…America 1,8,9 . Several sequence variants have been associated with liver enzymes [10][11][12] , cirrhosis 13 and NAFLD [14][15][16] , including missense variants in PNPLA3 (ref. 17 ), TM6SF2 (ref.…”

The clinically relevant MTARC1 p.Ala165Thr variant impacts neither the fold nor active site architecture of the human mARC1 protein

“…A protective effect of the mARC1 p.Ala165Thr variant against liver disease and changes to lipid metabolism were first published in 2020 by Emdin et al . (Emdin et al ., 2020, Emdin et al ., 2021) and has since been confirmed by the work of other groups in additional studies (Luukkonen et al ., 2020, Mann et al ., 2020, Parisinos et al ., 2020, Gao et al ., 2021, Ghodsian et al ., 2021, Janik et al ., 2021). It has consequently been suggested, that mARC1 could present a target for future NALFD or NASH therapies (Bianco et al ., 2021).…”