Smyth Deborah J, Cooper Jason D, Howson Joanna M M, Walker Neil M, Plagnol Vincent, Stevens Helen, Clayton David G, Todd John A
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Diabetes. 2008 Jun;57(6):1730-7. doi: 10.2337/db07-1131. Epub 2008 Feb 27.
The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; nonreceptor type 22 (PTPN22) on chromosome 1p13 has been confirmed in type 1 diabetes and also in other autoimmune diseases, including rheumatoid arthritis and Graves' disease. Some studies have reported additional associated SNPs independent of rs2476601/Trp(620), suggesting that it may not be the sole causal variant in the region and that the relative risk of rs2476601/Trp(620) is greater in lower risk by HLA class II genotypes than in the highest risk class II risk category.
We resequenced PTPN22 and used these and other data to provide >150 SNPs to evaluate the association of the PTPN22 gene and its flanking chromosome region with type 1 diabetes in a minimum of 2,000 case subjects and 2,400 control subjects.
Due to linkage disequilibrium, we were unable to distinguish between rs2476601/Trp(620) (P = 2.11 x10(-87)) and rs6679677 (P = 3.21 x10(-87)), an intergenic SNP between the genes putative homeodomain transcription factor 1 and round spermatid basic protein 1. None of the previously reported disease-associated SNPs proved to be independent of rs2476601/Trp(620). We did not detect any interaction with age at diagnosis or sex. However, we found that rs2476601/Trp(620) has a higher relative risk in type 1 diabetic case subjects carrying lower risk HLA class II genotypes than in those carrying higher risk ones (P = 1.36 x 10(-4) in a test of interaction).
In our datasets, there was no evidence for allelic heterogeneity at the PTPN22 locus in type 1 diabetes, indicating that the SNP rs2476601/Trp(620) remains the best candidate in this chromosome region in European populations. The heterogeneity of rs2476601/Trp(620) disease risk by HLA class II genotype is consistent with previous studies, and the joint effect of the two loci is still greater in the high-risk group.
位于1p13染色体上的蛋白酪氨酸磷酸酶非受体型22（PTPN22）常见的1858C>T Arg620Trp（rs2476601）非同义单核苷酸多态性（SNP）与疾病的关联已在1型糖尿病以及包括类风湿性关节炎和格雷夫斯病在内的其他自身免疫性疾病中得到证实。一些研究报告了独立于rs2476601/Trp（620）的其他相关SNP，这表明它可能不是该区域唯一的致病变异，并且rs2476601/Trp（620）在HLA II类基因型风险较低的人群中的相对风险高于在最高风险的II类风险类别中的相对风险。
我们对PTPN22进行了重测序，并利用这些数据及其他数据提供了超过150个SNP，以评估PTPN22基因及其侧翼染色体区域与1型糖尿病在至少2000例病例和2400例对照中的关联性。
由于连锁不平衡，我们无法区分rs2476601/Trp（620）（P = 2.11×10^(-87)）和rs6679677（P = 3.21×10^(-87)），后者是假定的同源结构域转录因子1和圆形精子细胞碱性蛋白1基因之间的一个基因间SNP。先前报道的与疾病相关的SNP均未被证明独立于rs2476601/Trp（620）。我们未检测到与诊断时年龄或性别的任何相互作用。然而，我们发现rs2476601/Trp（620）在携带较低风险HLA II类基因型的1型糖尿病病例中的相对风险高于携带较高风险基因型的病例（相互作用检验中P = 1.36×10^(-4)）。
在我们的数据集中，没有证据表明1型糖尿病中PTPN22基因座存在等位基因异质性，这表明SNP rs2476601/Trp（620）仍是欧洲人群该染色体区域的最佳候选基因。rs2476601/Trp（620）疾病风险因HLA II类基因型而异，这与先前的研究一致，并且两个基因座的联合效应在高风险组中仍然更大。
