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. 2010 Aug;42(8):698-702.
doi: 10.1038/ng.625. Epub 2010 Jul 11.

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Elaine F Remmers  1 , Fulya Cosan, Yohei Kirino, Michael J Ombrello, Neslihan Abaci, Colleen Satorius, Julie M Le, Barbara Yang, Benjamin D Korman, Aris Cakiris, Oznur Aglar, Zeliha Emrence, Hulya Azakli, Duran Ustek, Ilknur Tugal-Tutkun, Gulsen Akman-Demir, Wei Chen, Christopher I Amos, Michael B Dizon, Afet Akdag Kose, Gulsevim Azizlerli, Burak Erer, Oliver J Brand, Virginia G Kaklamani, Phaedon Kaklamanis, Eldad Ben-Chetrit, Miles Stanford, Farida Fortune, Marwen Ghabra, William E R Ollier, Young-Hun Cho, Dongsik Bang, John O'Shea, Graham R Wallace, Massimo Gadina, Daniel L Kastner, Ahmet Gül
Affiliations

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Elaine F Remmers et al. Nat Genet. 2010 Aug.

Abstract

Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

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Figures

Figure 1
Figure 1
Behçet's disease genome-wide association results. The –log10 P values (allelic Chi-squared test) for association of 311,459 autosomal SNPs in 1215 BD cases and 1278 controls from Turkey are shown segregated by chromosome and sorted by genomic position.
Figure 2
Figure 2
Analysis of associations within the MHC. The 292 SNPs from the MHC region with allelic Chi-squared P < 0.0001 are shown before (blue symbols) and after (red symbols) conditioning for HLA-B51. Blue symbols represent -log10 P (allelic Chi-squared test). Red symbols represent –log10 regressor P-values of the same markers from a logistic regression analysis with HLA-B51 specified as a covariate. The green horizontal line at –log10P = 7.301 corresponds to the genome-wide significance threshold of 5 × 10-8. The locations of HLA genes are shown above the association graph.
Figure 3
Figure 3
Fine-mapping of the IL10 and IL23R/IL12RB2 regions. Regional association plot and linkage disequilibrium structure of the disease-associated regions surrounding (a) IL10 and (b) IL23R/IL12RB2 showing SNPs genotyped in the genome-wide analysis (blue) and fine-mapping analysis (green). The LD structure of the same regions are shown with red filled squares linking pairs of markers indicating the intensity of LD by intensity of fill, D’= 1 (intense red) to D’ = 0 (no fill). In (a) the pink circles represent rs1518111 and the yellow circles represent rs3024505, which is associated with IBD and SLE. In (b) the pink circles represent rs924080 and the yellow circles represent the IL23R coding variants associated with other seronegative diseases.
Figure 3
Figure 3
Fine-mapping of the IL10 and IL23R/IL12RB2 regions. Regional association plot and linkage disequilibrium structure of the disease-associated regions surrounding (a) IL10 and (b) IL23R/IL12RB2 showing SNPs genotyped in the genome-wide analysis (blue) and fine-mapping analysis (green). The LD structure of the same regions are shown with red filled squares linking pairs of markers indicating the intensity of LD by intensity of fill, D’= 1 (intense red) to D’ = 0 (no fill). In (a) the pink circles represent rs1518111 and the yellow circles represent rs3024505, which is associated with IBD and SLE. In (b) the pink circles represent rs924080 and the yellow circles represent the IL23R coding variants associated with other seronegative diseases.
Figure 4
Figure 4
Expression analysis of IL10. (a) Allelic imbalance detected by real time PCR of the IL10 SNP, rs1518111 (A is the BD-associated allele), in pre-mRNA from purified monocytes from healthy, rs1518111 heterozygous blood donors (n=8, p<0.01). The error bar represents the standard deviation. (b) IL-10 production by peripheral blood mononuclear cells isolated from healthy Turkish blood donors measured 24 hr after stimulation with LPS, relative to rs1518111 genotype. (c) IL-10 production by CD14+ monocytes isolated from ethnically diverse, healthy American blood donors measured 24 hr after stimulation with MDP + PAM3Cys, relative to rs1518111 genotype. In (b) and (c) the horizontal lines indicate the medians.
Figure 4
Figure 4
Expression analysis of IL10. (a) Allelic imbalance detected by real time PCR of the IL10 SNP, rs1518111 (A is the BD-associated allele), in pre-mRNA from purified monocytes from healthy, rs1518111 heterozygous blood donors (n=8, p<0.01). The error bar represents the standard deviation. (b) IL-10 production by peripheral blood mononuclear cells isolated from healthy Turkish blood donors measured 24 hr after stimulation with LPS, relative to rs1518111 genotype. (c) IL-10 production by CD14+ monocytes isolated from ethnically diverse, healthy American blood donors measured 24 hr after stimulation with MDP + PAM3Cys, relative to rs1518111 genotype. In (b) and (c) the horizontal lines indicate the medians.
Figure 4
Figure 4
Expression analysis of IL10. (a) Allelic imbalance detected by real time PCR of the IL10 SNP, rs1518111 (A is the BD-associated allele), in pre-mRNA from purified monocytes from healthy, rs1518111 heterozygous blood donors (n=8, p<0.01). The error bar represents the standard deviation. (b) IL-10 production by peripheral blood mononuclear cells isolated from healthy Turkish blood donors measured 24 hr after stimulation with LPS, relative to rs1518111 genotype. (c) IL-10 production by CD14+ monocytes isolated from ethnically diverse, healthy American blood donors measured 24 hr after stimulation with MDP + PAM3Cys, relative to rs1518111 genotype. In (b) and (c) the horizontal lines indicate the medians.
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