Alnylam Pharmaceuticals, Cambridge, MA, USA.
Regeneron Genetics Center, Tarrytown, NY, USA.
Nat Commun. 2021 Jul 27;12(1):4571. doi: 10.1038/s41467-021-24563-1.
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, 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.
了解肝细胞损伤的机制可能为肝脏疾病的治疗带来新的方法，对丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）血清活性的全基因组关联研究（GWAS）已被证明有助于研究肝脏生物学。在这里，我们报告了在英国生物银行的 411,048 名受试者中进行的 GWAS 与这两种酶相关的 100 个位点。罕见的错义变异 SLC30A10 Thr95Ile（rs188273166）与两种酶的最大升高相关，该关联在 DiscovEHR 研究中得到了复制。SLC30A10 将锰从肝脏排泄到胆管，罕见的纯合子功能丧失导致伴有肌张力障碍的高锰血症 1（HMNDYT1），其中包括肝硬化。与高锰血症的血液学症状一致，SLC30A10 Thr95Ile 携带者的红细胞比容增加，并且缺铁性贫血的风险增加。携带者也有更高的肝外胆管癌风险。这些结果表明，SLC30A10 中的遗传变异对比被诊断为 HMNDYT1 的患者影响更多的个体。
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