J Med Genet 42:266-270 doi:10.1136/jmg.2004.026971
  • Letters to JMG

Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study

  1. H Qu1,
  2. M-C Tessier1,
  3. T J Hudson2,
  4. C Polychronakos1
  1. 1The McGill University Health Center (Montreal Children’s Hospital), Montréal, Quebec, Canada
  2. 2McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada
  1. Correspondence to:
 Dr C Polychronakos
 The McGill University Health Center (Montreal Children’s Hospital), 2300 Tupper, Montréal, Quebec H3H 1P3, Canada;

    Genetic susceptibility to the autoimmune B cell destruction that leads to Type 1 diabetes mellitus (T1D) is a complex trait.1 In recent years, many T1D associations have been reported, but only three (major histocompatibility complex, insulin, and cytotoxic T lymphocyte associated protein 4) have been confirmed in several independent studies.2,3 Independent confirmation is essential to eliminate artefacts of publication bias, multiple hypothesis testing, and, in findings of case–control studies, population stratification.4

    Bottini et al recently found, by a case–control design in two independent populations, a novel association of T1D with a single nucleotide polymorphism (SNP) that caused a R620W aminoacid substitution (dbSNP rs2476601) in the lymphoid protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene.5PTPN22 encodes LYP, a non-receptor tyrosine phosphatase involved in lymphocyte function.

    This paper leaves two potential questions unanswered. Firstly, results of case–control studies are potentially artefacts of population stratification, no matter how well matched are the two groups. Secondly, although Bottini et al show that the T allele encodes a protein unable to bind to its important Csk partner, and postulate this as a very attractive candidate mechanism for the genetic effect, they did not address the question of the haplotype structure of the locus and the possibility that the association is due to linkage disequilibrium (LD) with another variant. Here we present the results of a study that confirms this association in a design impervious to population stratification, and in a preliminary step towards addressing the second question, we define the LD block that encompasses the PTPN22-R620W SNP and present a computationally generated list of potentially functional SNPs within the block.



    Genomic DNA was obtained after informed consent from 588 nuclear families with at least one T1D affected child and two parents. The research ethics board of the Montreal Children’s …