In this study, one of the largest genetic studies of GPA to date, we investigated the comparability of genetic risk factors of GPA with other autoimmune diseases by examining single-marker associations as well as composite genetic risk scores of previously identified autoimmune disease susceptibility loci.
In single marker analyses, we confirmed an association of GPA with genetic variation in CTLA4
. The 2 SNPs in this gene found to be associated with GPA in this study, rs3087243 and rs231735, have been previously associated with RA and T1D (39
). rs3087243 does not appear to be significantly linked to previously identified GPA-associated CTLA4
polymorphisms rs5742909 (−319C/T) or rs231775 (+49A/G), with r2
<0.1, but rs231735 shows moderate linkage with rs231775 (r2
). These findings suggest that CTLA4
may harbor multiple genetic variants contributing to disease risk. rs3087243 has been suggested to influence CTLA4
mRNA stability, since it is located ~300 bp downstream from the major 3′ poly-A tail, while rs231735 is located ~40 kb upstream of CTLA4
and does not have a known functional effect. The PTPN22
polymorphism that showed some evidence of association in this study, rs2476601, has been previously associated with GPA (28
) and with multiple other autoimmune diseases (13
). This non-synonymous polymorphism induces an amino acid change from arginine to tryptophan at codon 620, and is thought to increase its degradation leading to lymphocyte hyper-responsiveness (69
Our findings also suggest that the risk of GPA and RA share a common genetic background, which was not observed for CD, SLE, T1D, or UC. This finding is supported by a previous epidemiologic study showing an increase in RA among offspring of patients with GPA (30
). This finding is not intuitive, since the pulmonary and renal manifestations of GPA are not common in RA, and inflammatory arthritis, the hallmark of RA, is not present in all patients with GPA and is rarely destructive. Having a similar genetic background implies that the two diseases may share similar pathogenic mechanisms, and the shared association with alleles in CTLA4
suggests that this mechanism involves the threshold for activation or deactivation of autoreactive T cells.
The major strength of this analysis is the relatively large sample size represented by the meta-analysis when compared to other candidate gene studies for GPA, which improved statistical power to test a relative large number of candidate genes. However, this study still had limited power to detect associations of modest effect sizes, and thus, there may be additional associations that have not been identified. Another strength is that careful adjustment for population stratification was performed, which is not always accounted for in candidate gene studies. Finally, not all of the associated loci for these autoimmune diseases were genotyped. Therefore, other loci may be shared between GPA and SLE, T1D, CD, and/or UC, and the genetic background for these diseases may be more similar to GPA than what was found in this study.
Further delineation of the genetic contribution to risk of GPA will likely require a combination of GWAS studies and an ongoing hypothesis-driven search for rare variants (such as null alleles in A1AT/SERPINA) that would be missed by such screens. A prediction of the current study might be that outside of HLA-DPB1, CTLA4, and perhaps a few other polymorphisms associated with multiple autoimmune diseases, most genes found to predispose to GPA will reflect the unique pathophysiology of this disease rather than more generic disruption of immune homeostasis.