PTPN22R620W minor allele is a genetic risk factor for giant cell arteritis

Abstract

Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an ‘archetypal non-HLA autoimmunity gene’. The minor allele of a functional PTPN22 single nucleotide polymorphism (rs2476601, R620W), which disrupts an interaction motif in the protein, was originally reported to be associated with biopsy-proven GCA in Spanish patients, with supporting data from three replicate Northern European studies. Recently, this observation was extended with additional patients and controls, and studies encompassing European, Scandinavian, UK and American patients. The aim of our study was to determine the association between PTPN22 rs2476601 (R620W) and biopsy-proven GCA in an Australian case cohort.

The Contribution of PTPN22 to Rheumatic Disease

“…PTPN22 association was equal in patients with the anti–proteinase 3 serotype and those with the antimyeloperoxidase serotype. Although an initial study showed a lack of association, several later studies have documented and replicated a significant association of 1858T with biopsy‐proven giant cell arteritis (GCA) with an odds ratio of 1.62 (95% confidence interval 1.29–2.04). These findings have been replicated in Spanish, Scandinavian, British, American, and Australian patient samples.…”

“…These findings have been replicated in Spanish, Scandinavian, British, American, and Australian patient samples. There was no difference in risk between patients with and those without polymyalgia rheumatica or visual ischemic manifestations (). In contrast, PTPN22 was not associated with Takayasu arteritis, Behçet's disease, or IgA vasculitis ().…”

New insights into the pathogenesis of giant cell arteritis

“…Differently from MHC class II alleles, only a weak association has been demonstrated with MHC class I alleles such as HLA-A*31, HLA-B*8, HLA-B*15, HLA-Cw3, HLA-Cw6 and MHC class I polypeptide-related sequence A (MICA) [24]. Outside the HLA region, the most significant loci included the protein tyrosine phosphatase non-receptor type 22 (PTPN22) [31] and the leucine rich repeat containing 32 (LRRC32) [31]. More recently, Carmona et al published a GWAS demonstrating that PLG and P4HA2 are risk genes at the genome-wide level of significance.…”

The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism and Susceptibility to Autoimmune Diseases

“…Though Lester et al [267] could not find any significant difference in the distribution of alleles and genotypes of PTPN22 C1858T polymorphism between patients and control groups, they suggested that there is a significant association between the minor allele of PTPN22 C1858T polymorphism and GCA.…”