Dataset Information

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

ABSTRACT: Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

SUBMITTER: Ward LD

PROVIDER: S-EPMC8316433 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

Ward Lucas D LD Tu Ho-Chou HC Quenneville Chelsea B CB Tsour Shira S Flynn-Carroll Alexander O AO Parker Margaret M MM Deaton Aimee M AM Haslett Patrick A J PAJ Lotta Luca A LA Verweij Niek N Ferreira Manuel A R MAR Baras Aris A Hinkle Gregory G Nioi Paul P

Nature communications 20210727 1

Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, ...[more]

PMID: 34315874

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Project description:BackgroundLiver fibrosis is a necessary stage for various chronic liver diseases to develop into cirrhosis. The detection of serum markers of liver fibrosis is a commonly used method for early screening of liver fibrosis, mainly including type IV collagen (IVC), hyaluronic acid (HA), laminin (LN), and type III procollagen (PCIII). However, the high cost of the instrument and the slow detection speed are not conducive to mass screening and detection of the population. In this study, the widely used biochemical platform was used to jointly detect the liver fibrosis marker IVC and aspartate aminotransferase (AST) and alanine aminotransferase (ALT), We investigated the feasibility of serum IVC combined with the AST and ALT ratio (AST/ALT ratio) as a marker for liver fibrosis.MethodsA total of 81 patients with liver disease by clinical liver biopsy comprised the study group, and 50 healthy people who underwent physical examination in the study period were selected as the control group. Serum IVC, AST and ALT levels were detected by biochemical testing, AST/ALT ratio was calculated, and four serum markers of liver fibrosis (IVC, HA, LN, and PCIII) were measured by chemiluminescence. Moreover, imaging by color Doppler ultrasound (B-ultrasound) was performed for statistical analysis.Results(I) Serum IVC and the AST/ALT ratio were significantly higher in the study group than in the control group (P<0.05). (II) The sensitivity of serum IVC combined with AST/ALT ratio detected biochemically and the four markers of liver fibrosis detected by chemiluminescence in the diagnosis of liver cirrhosis was 95.83%, 97.92%, without significant difference, but the specificity and accuracy of IVC + AST/ALT ratio in the diagnosis of liver cirrhosis were significantly higher (94.00%, 94.90%). (III) The detection rate of serum IVC + AST/ALT ratio for the diagnosis of early liver fibrosis was significantly higher than with imaging examination (45.45% vs. 21.21%).ConclusionsSerum IVC + AST/ALT ratio determined by biochemical analysis has high diagnostic accuracy in the diagnosis of liver fibrosis and liver cirrhosis, and is worthy of clinical application and promotion.

Dataset Information

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

Publications

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

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