Barbara Davis Center for Childhood Diabetes, University of Colorado-Denver, Aurora, CO 80045-6511, USA.
Genes Immun. 2009 Dec;10 Suppl 1(Suppl 1):S21-6. doi: 10.1038/gene.2009.87.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is the third major locus affecting risk of type I diabetes (T1D), after HLA-DR/DQ and INS. The most associated single-nucleotide polymorphism (SNP), rs2476601, has a C->T variant and results in an arginine (R) to tryptophan (W) amino acid change at position 620. To assess whether this, or other specific variants, are responsible for T1D risk, the Type I Diabetes Genetics Consortium analyzed 28 PTPN22 SNPs in 2295 affected sib-pair (ASP) families. Transmission Disequilibrium Test analyses of haplotypes revealed that all three haplotypes with a T allele at rs2476601 were overtransmitted to affected children, and two of these three haplotypes showed statistically significant overtransmission (P=0.003 to P=5.9E-12). Another haplotype had decreased transmission to affected children (P=3.5E-05). All haplotypes containing the rs2476601 T allele were identical for all SNPs across PTPN22 and only varied at centromeric SNPs. When considering rs2476601 'C' founder chromosomes, a second haplotype (AGGGGC) centromeric of PTPN22 in the C1orf178 region was associated with protection from T1D (odds ratio=0.81, P=0.0005). This novel finding requires replication in independent populations. We conclude the major association of PTPN22 with T1D is likely due to the recognized non-synonymous SNP rs2476601 (R620W).
蛋白酪氨酸磷酸酶非受体型 22（PTPN22）是继 HLA-DR/DQ 和 INS 之后影响 1 型糖尿病（T1D）风险的第三个主要基因座。最相关的单核苷酸多态性（SNP）rs2476601 具有 C->T 变体，导致位置 620 的精氨酸（R）到色氨酸（W）氨基酸变化。为了评估这种或其他特定变体是否导致 T1D 风险，1 型糖尿病遗传学联合会在 2295 个受影响的同胞对（ASP）家族中分析了 28 个 PTPN22 SNP。单倍型传递不平衡测试分析表明，rs2476601 处具有 T 等位基因的所有三种单倍型均传递给受影响的孩子，其中两种单倍型显示出统计学上显著的传递过度（P=0.003 至 P=5.9E-12）。另一种单倍型向受影响的孩子传递减少（P=3.5E-05）。所有包含 rs2476601 T 等位基因的单倍型在 PTPN22 上的所有 SNP 都是相同的，仅在着丝粒 SNP 处有所不同。当考虑 rs2476601“C”创始染色体时，第二个单倍型（AGGGGC）位于 PTPN22 内的 C1orf178 区域的着丝粒附近，与 T1D 保护相关（比值比=0.81，P=0.0005）。这一新发现需要在独立人群中复制。我们得出结论，PTPN22 与 T1D 的主要关联可能归因于公认的非 synonymous SNP rs2476601（R620W）。
