Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital USA.
Division of Preventive Medicine, Brigham and Women's Hospital USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA USA.
Semin Arthritis Rheum. 2022 Aug;55:152036. doi: 10.1016/j.semarthrit.2022.152036. Epub 2022 May 28.
To examine genetic influence on the risk of elevations in liver function tests (AST and ALT) among patients using low-dose methotrexate (LD-MTX).
We examined data from the LD-MTX arm of a randomized double-blind placebo-controlled trial conducted among subjects without rheumatic disease. Genome wide association studies (GWAS) were performed in subjects of European ancestry to test the association between single nucleotide polymorphisms (SNPs) and the log transformed maximum values of AST, ALT, and dichotomized outcome with AST or ALT > 2 times upper limit of normal (ULN). The association between variants in MTX metabolism candidate genes and the outcomes was also tested. Furthermore, associations between a drug induced liver injury (DILI) weighted genetic risk score (wGRS) and the outcomes were tested, combining 10 SNPs and 11 classical HLA alleles associated with DILI.
In genome-wide genetic analyses among 1,429 subjects of European ancestry who were randomized to receive LD-MTX, two SNPs reached genome wide significance for association with log transformed maximum ALT. We observed associations between established candidate genes in MTX pharmacogenetics and log transformed maximum AST and ALT, as well as in dichotomized outcome with AST or ALT > 2 x ULN. There was no association between DILI wGRS or candidate variants and AST, ALT, or DILI response.
Modest evidence was observed that common variants affected AST and ALT levels in subjects of European ancestry on LD-MTX, but this genetic effect is not useful as a clinical predictor of MTX toxicity.
研究遗传因素对接受低剂量甲氨蝶呤（LD-MTX）治疗的患者肝功能试验（AST 和 ALT）升高风险的影响。
我们对一项无风湿性疾病受试者的随机双盲安慰剂对照试验的 LD-MTX 组数据进行了研究。在欧洲血统的受试者中进行了全基因组关联研究（GWAS），以检验单核苷酸多态性（SNP）与 AST、ALT 的最大对数转换值之间的关联，以及 AST 或 ALT>2 倍正常值上限（ULN）的二分结局。还检验了 MTX 代谢候选基因变异与结局之间的关联。此外，还检验了药物性肝损伤（DILI）加权遗传风险评分（wGRS）与结局之间的关联，该评分结合了与 DILI 相关的 10 个 SNP 和 11 个经典 HLA 等位基因。
在接受 LD-MTX 治疗的 1429 名欧洲血统随机分组的受试者中进行的全基因组遗传分析中，有两个 SNP 与 ALT 的最大对数转换值相关，达到了全基因组显著水平。我们观察到 MTX 药物遗传学中已确立的候选基因与 AST 和 ALT 的最大对数转换值以及 AST 或 ALT>2xULN 的二分结局之间存在关联。DILI wGRS 或候选变异与 AST、ALT 或 DILI 反应之间无关联。
观察到在接受 LD-MTX 治疗的欧洲血统受试者中，常见变异对 AST 和 ALT 水平有一定影响，但这种遗传效应不能作为 MTX 毒性的临床预测指标。
