Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis
Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis
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DOI：
10.1136/ard.2005.046797
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发表时间：
2006-09-01
影响因子：
27.4
通讯作者：
Bridges, S. L., Jr.
中科院分区：
文献类型：
--
作者：
Hughes, L. B.;Beasley, T. M.;Bridges, S. L., Jr.
背景资料：抗叶酸药物甲氨蝶呤（MTX）是治疗类风湿关节炎的常用药物。目的：为了确定非洲人亚甲基四氢叶酸还原酶（MTHFR）基因中5个常见编码单核苷酸多态性（SNP）的等位基因频率，美国人和高加索人类风湿性关节炎患者和对照组，以评估这些种族或种族组之间等位基因频率是否存在差异，以及这些SNP是否差异性地影响MTX的疗效或毒性。方法：在MTHFR编码区的677，1298和3个额外的SNPs在223例（193名白人和30名非洲裔美国人）类风湿性关节炎患者，以前参加了两个前瞻性临床试验之一的等位基因频率进行了表征，基因型与MTX的疗效和毒性。另外308名类风湿关节炎患者参加了观察性研究，一组主要是白人，另一组是非洲裔美国人，以及103名正常对照（53名非洲裔美国人和50名高加索人）被用来计算这些SNP及其相关单倍型的等位基因频率。在高加索人和非裔美国人之间的五个SNPs中的三个和单倍型频率中观察到显著不同的等位基因频率。等位基因频率在类风湿性关节炎患者和相同种族或民族的对照组之间相似。rs 4846051 C、677 T和1298 C等位基因在非裔美国人类风湿性关节炎患者中的频率分别为0.33、0.11和0.13。在患有类风湿性关节炎的白种人中，这些等位基因频率分别为0.08（与患有类风湿性关节炎的非洲裔美国人相比，p < 0.001）、0.30（p = 0.002）和0.34（p < 0.001）。SNP等位基因或单倍型与甲氨蝶呤治疗反应之间无相关性，通过28个关节疾病活动性评分较基线值的平均变化来衡量。在白种人中，1298 A（主要）等位基因与MTX相关不良事件的隐性遗传效应特征显著增加相关（比值比15.86，95%置信区间1.51至167.01; p = 0.021），证实了先前的报告。MTX毒性评分与rs 4846051 C等位基因和包含该等位基因的单倍型在非裔美国人中存在相关性，但在Caucasians.Conclusions：这些结果虽然是初步的，但突出了常见MTHFR SNPs频率的种族或民族差异。MTHFR 1298 A和rs 4846051 C等位基因分别与白种人和非裔美国人中的MTX相关不良事件相关，但这些发现应在更大规模的研究中重复。rs 4846051 SNP在非裔美国人中远比在高加索人中更常见，也可以被证明是未来遗传混合物研究中有用的祖先信息标记。
Background: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis.Objective: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX.Methods: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes.Results: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African- Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African- Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p < 0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p < 0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African- Americans, but not in Caucasians.Conclusions : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African- Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African- Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.