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DOI: 10.2337/db06-0225
© 2006 by the American Diabetes Association
A Haplotype-Based Analysis of the PTPN22 Locus in Type 1 Diabetes
1 Molecular Genetics Program, Benaroya Research Institute, Seattle, Washington
2 Department of Immunology, University of Washington School of Medicine, Seattle, Washington
3 Translational Research Program, Benaroya Research Institute, Seattle, Washington
Address correspondence and reprint requests to Patrick Concannon at Molecular Genetics Program, Benaroya Research Institute, 1201 Ninth Ave., Seattle, WA 98101-2795. E-mail: patcon{at}benaroyaresearch.org
Abbreviations:
CEPH, Centre d’Etude du Polymorphisme Humain; DHPLC, denaturing high-performance liquid chromatography; FBAT, family-based association test; IBD, identical-by-descent; SNP, single nucleotide polymorphism
A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific 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 x 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.
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