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

ABSTRACT 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.

Download full-text


Available from: Juan-Manuel Anaya, Sep 28, 2015
32 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1(∗)03:01 (OR: 4.04; 95%CI: 1.41-11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1(∗)04:05 (OR: 4.64; 95%CI: 2.14-10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1(∗)04:01 (OR: 3.86; 95%CI: 2.32-6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1(∗)06:02 and DRB1(∗)15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1(∗)06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.
    04/2012; 2012(2):569728. DOI:10.1155/2012/569728
  • Source
    • "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, "
    [Show abstract] [Hide abstract]
    ABSTRACT: The single nucleotide polymorphism (SNP) rs6822844 within the KIAA1109-TENR-IL2-IL21 gene cluster has been associated with rheumatoid arthritis (RA). Other variants within this cluster, including rs17388568 that is not in linkage disequilibrium (LD) with rs6822844, and rs907715 that is in moderate LD with rs6822844 and rs17388568, have been associated with a number of autoimmune phenotypes, including type 1 diabetes (T1D). Here we aimed to: one, confirm at a genome-wide level of significance association of rs6822844 with RA and, two, evaluate whether or not there were effects independent of rs6822844 on RA at the KIAA1109-TENR-IL2-IL21 locus. A total of 842 Australasian RA patients and 1,115 controls of European Caucasian ancestry were genotyped for rs6822844, rs17388568 and rs907715. Meta-analysis of these data with published and publicly-available data was conducted using STATA. No statistically significant evidence for association was observed in the Australasian sample set for rs6822844 (odds ratio (OR)=0.95 (0.80 to 1.12), P=0.54), or rs17388568 (OR=1.03 (0.90 to 1.19), P=0.65) or rs907715 (OR=0.98 (0.86 to 1.12), P=0.69). When combined in a meta-analysis using data from a total of 9,772 cases and 10,909 controls there was a genome-wide level of significance supporting association of rs6822844 with RA (OR=0.86 (0.82 to 0.91), P=8.8x10(-8), P=2.1x10(-8) including North American Rheumatoid Arthritis Consortium data). Meta-analysis of rs17388568, using a total of 6,585 cases and 7,528 controls, revealed no significant association with RA (OR=1.03, (0.98 to 1.09); P=0.22) and meta-analysis of rs907715 using a total of 2,689 cases and 4,045 controls revealed a trend towards association (OR=0.93 (0.87 to 1.00), P=0.07). However, this trend was not independent of the association at rs6822844. The KIAA1109-TENR-IL2-IL21 gene cluster, that encodes an interleukin (IL-21) that plays an important role in Th17 cell biology, is the 20th locus for which there is a genome-wide (P<or=5x10(-8)) level of support for association with RA. As for most other autoimmune diseases, with the notable exception of T1D, rs6822844 is the dominant association in the locus. The KIAA1109-TENR-IL2-IL21 locus also confers susceptibility to other autoimmune phenotypes with a heterogeneous pattern of association.
    Arthritis research & therapy 06/2010; 12(3):R116. DOI:10.1186/ar3053 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To summarize recent findings on new pathogenic mechanisms of interaction between genetic and environmental factors and between innate and adaptive immunity in primary Sjögren's syndrome and to reconcile pathogenesis and treatment by focusing on the crucial pathogenic steps that could be targeted by emerging therapies. Regarding genetic predisposition, the functional relevance of IRF5 and STAT4 gene polymorphisms in the activation of type I interferon pathways has been demonstrated. It has also been shown that the isolated stimulation of innate immunity in mice can result in dryness, which precedes lymphocytic infiltrates in salivary glands. In animal models, possible environmental triggers of the disease, such as oestrogen deficiency and/or infection by Epstein-Barr virus, can lead to innate immune followed by autoimmune epithelitis. The IFN-BAFF-B lymphocyte pathogenic axis is, therefore, targeted by numerous drugs currently in evaluation. The development of consensus disease activity scores and patient-related outcomes might help to initiate new controlled trials. The first positive randomized controlled trial with rituximab has been recently published. Hopefully, persistent and joint efforts by many teams to improve the knowledge on the pathogenesis of the disease may allow identification of new therapeutic targets in Sjögren's syndrome.
    Current opinion in rheumatology 09/2010; 22(5):471-7. DOI:10.1097/BOR.0b013e32833c36c5 · 4.89 Impact Factor
Show more