A Haplotype-Based Analysis of the PTPN22 Locus in Type 1 Diabetes

Abstract

A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoidspecific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P ‫؍‬ 7.9 ؋ 10 ؊5 ). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk.

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

“…These are Hipk1 and Bcl2l15, which have been demonstrated to be involved in apoptotic processes; the scaffolding protein Magi3, which participates in PTEN signaling; and the E3 ubiquitin-protein ligase Trim33, which negatively regulates TGF-b signaling. Of note, none of these 23 genes has been found to be associated with inflammatory and autoimmune conditions in humans (53,54). Because BCL2l15 has been reported to be in linkage disequilibrium with PTPN22 within the human syntenic region on chromosome 1, the coding region of this gene was sequenced in the parental strains.…”

Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients

“…rs689 (−23HphI variant, a surrogate for the subdivision of VNTR into class I [A] and III [T] alleles) and rs3842755, which also allows subdivision of class III into IIIA (C) and IIIB (A) alleles [29][30][31]. The SNP rs2476601 (also denoted 1858C/T) was genotyped in the PTPN22 gene [32,33]. Genotyping was performed by an allelic discrimination method (7900HT system; Applied Biosystems, Foster City, CA, USA).…”

PTPN22 Trp620 Explains the Association of Chromosome 1p13 With Type 1 Diabetes and Shows a Statistical Interaction With HLA Class II Genotypes

“…After correcting the most associated additional SNP, there was no evidence of any additional independent effects (minimum uncorrected P ϭ 0.00854 for rs735074 located in the flanking linkage disequilibrium block; corrected P ϭ 0.243), including the previously associated MAGI3 SNP rs1343125 (22) (uncorrected P ϭ 0.907), the Japaneseassociated SNP rs2488457 (25) (uncorrected P ϭ 0.866), and the rheumatoid arthritis-associated SNP rs3789604 (24) (uncorrected P ϭ 0.401) ( Table 1; Supplementary Table 2). We genotyped an additional five SNPs with TaqMan because they were not covered by either GWA scan: two SNPs (rs1310182 and rs2488458) associated with rheumatoid arthritis from Carlton et al (24), the rare nsSNP (ss73688585/K750N) associated with type 1 diabetes from Onengut-Gumuscu et al (23), and two SNPs (rs3789608 and ss73688608) found from our resequencing. Although we found evidence for associations between type 1 diabetes and rs1310182 (P ϭ 9.33 ϫ 10 Ϫ13 ), rs2488458 (P ϭ 3.46 ϫ 10 Ϫ34 ), and ss73688608 (P ϭ 1.80 ϫ 10 Ϫ7 ), these results were not independent of rs2476601/Arg620Trp (uncorrected P ϭ 0.840, 0.343, and 0.702, respectively).…”

“…Functional studies suggest that the Trp 620 allele has gain-offunction, immunosuppressive effects compared with the more common allele Arg 620 (19 -21). However, there have been attempts to assess whether there are other variants that confer risk of disease that are independent of rs2476601/ Trp 620 (22,23). One of the largest studies thus far to characterize disease association with PTPN22 resequenced the coding regions of the gene in 48 North American individuals and genotyped 37 SNPs in or near PTPN22 in up to 1,136 rheumatoid arthritis case subjects and 1,797 control subjects (set 1: 475 case subjects and 475 control subjects; set 2: 661 case subjects and 1,322 control subjects) (24).…”

“…Onengut-Gumuscu et al (23) resequenced the coding regions in 94 type 1 diabetic case subjects and genotyped 11 SNPs in 374 type 1 diabetic families. They identified a rare nsSNP K750N, which generates a premature stop codon, and presented some evidence of association with type 1 diabetes (P ϭ 0.026, minor allele frequency [MAF] ϭ 0.006).…”