Hughes L B, Beasley T M, Patel H, Tiwari H K, Morgan S L, Baggott J E, Saag K G, McNicholl J, Moreland L W, Alarcón G S, Bridges S L
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 415 Lyons-Harrison Research Building, Birmingham, AL 35294-0007, USA.
Ann Rheum Dis. 2006 Sep;65(9):1213-8. doi: 10.1136/ard.2005.046797. Epub 2006 Jan 26.
The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis.
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.
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.
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.
: 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.
抗叶酸药物甲氨蝶呤（MTX）常用于治疗类风湿关节炎。
确定类风湿关节炎非洲裔美国人和高加索人以及对照人群中，亚甲基四氢叶酸还原酶（MTHFR）基因5个常见编码单核苷酸多态性（SNP）的等位基因频率，以评估这些种族或民族群体之间等位基因频率是否存在差异，以及这些SNP是否对MTX的疗效或毒性有不同影响。
对之前参与两项前瞻性临床试验之一的223例（193例高加索人和30例非洲裔美国人）类风湿关节炎患者MTHFR编码区的677、1298及另外3个SNP的等位基因频率进行了特征分析，并将基因型与MTX的疗效和毒性进行关联分析。另外308例参与观察性研究的类风湿关节炎患者，一组主要为高加索人，另一组为非洲裔美国人，以及103例正常对照（53例非洲裔美国人和50例高加索人）用于分析这些SNP及其相关单倍型的等位基因频率。
5个SNP中的3个以及高加索人和非洲裔美国人之间的单倍型频率存在显著差异。类风湿关节炎患者与同种族或民族对照人群的等位基因频率相似。在患有类风湿关节炎的非洲裔美国人中，rs4846051C、677T和1298C等位基因频率分别为0.33、0.11和0.13。在患有类风湿关节炎的高加索人中，这些等位基因频率分别为0.08（与患有类风湿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以28个关节疾病活动评分相对于基线值的平均变化衡量的MTX反应之间无关联。在高加索人中，1298A（主要）等位基因与MTX相关不良事件显著增加相关，具有隐性遗传效应特征（比值比15.86，95%置信区间1.51至167.01；p = 0.021），证实了既往报道。在非洲裔美国人中，MTX毒性评分与rs4846051C等位基因以及包含该等位基因的单倍型之间存在关联，但在高加索人中无此关联。
这些结果虽为初步结果，但凸显了常见MTHFR SNP频率的种族或民族差异。MTHFR 1298A和rs4846051C等位基因分别与高加索人和非洲裔美国人的MTX相关不良事件相关，但这些发现应在更大规模研究中得到重复验证。rs4846051 SNP在非洲裔美国人中比在高加索人中更为常见，在未来关于基因混合的研究中也可被证明是一个有用的祖先信息标记。
