Confirmation of an Association Between rs6822844 at the IL2-IL21 Region and Multiple Autoimmune Diseases

Oklahoma Medical Research Foundation, Oklahoma City, OK73104, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 02/2010; 62(2):323-9. DOI: 10.1002/art.27222
Source: PubMed


Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies.
We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies.
We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (F(ST) = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P(meta) = 3.61 x 10(-6)), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (P(meta) = 3.48 x 10(-12)), type 1 DM (P(meta) = 5.33 x 10(-5)), and CD (P(meta) = 5.30 x 10(-3)). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; P(meta) = 2.61 x 10(-25), odds ratio 0.73 [95% confidence interval 0.69-0.78]).
Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

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    • "For instance, ITGAM and its variant (rs1143679, Arg77His) are associated with SLE and systemic sclerosis (SSc) [62]. Another example is the association of rs6822844 in the IL2-IL21 region with SLE, T1D, and SS in non-European populations [24]. "
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    • "A similar protective effect was also observed in the NARAC GWAS for rs6822844 (OR = 0.84, P = 0.011), with combined evidence for association with RA of P = 2.1 × 10-8 when combined with our meta-analysis P- value. Our analysis used the same European Caucasian RA sample sets recently meta-analysed by Maita et al. [29], with the addition of the WTCCC, Barton et al. [12], Australasian and NARAC [3] data. Meta-analysis of the T1D-associated SNP rs17385868 (Figure 2) on the other hand, did not reveal any significant association between the minor allele of rs17388568 and RA (OR = 1.03, "
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