Background/Purpose: The genetic association between HLA-B51 and Behcet’s disease is well established. However, localizing this genetic effect and exploring additional susceptibility loci within the HLA has been limited by the complexity and the strong linkage disequilibrium in this region. Herein, we provide evidence for multiple independent genetic effects within the HLA region in Behcet’s disease, using two independent and ethnically divergent cohorts.
Methods: A total of 503 Turkish patients and 504 controls, and 144 Italian patients and 1270 controls were genotyped across 8,572 SNPs in the HLA extended region (Chr6: 28,889kb-33,000kb, HG19) using a custom platform (Immunochip). After applying quality control and tests for autosomal heterozygosity, identity by descent, and population stratification by principal component analysis, 467 Turkish patients and 472 controls, and 127 Italian patients and 1266 controls were included in the final analysis. Additional variants from the 1000 Genomes Project were imputed in both cohorts using Impute 2 with a combined reference panel of 1,092 individuals. Meta-analysis was then performed among 24,834 markers conserved between the two cohorts and genetic analysis performed. Next, logistic regression and pairwise conditional analysis was performed to identify independent effects among the associations detected.
Results: Three independent genetic association effects were detected between the HLA region and Behcet’s disease (r2<0.30). The most significant association was with rs116799036 (meta-analysis: OR= 3.88, P= 9.42×10-50; Turkish: OR= 3.74, P= 5.75×10-33; Italian: OR= 4.14, P= 4.93×10-23) which is located approximately 24kb upstream of HLA-B and 18kb upstream of MICA. A second independent genetic association tagged by rs12525170 located within PSORS1C1 (meta-analysis: OR= 3.01, P= 3.01×10-26; Turkish: OR= 2.90, P= 1.35×10-17; Italian: OR= 3.22, P= 4.51×10-12), and a third tagged by rs114854070 located ~1.4kb upstream of HLA-F-AS1 (meta-analysis: OR= 1.95, P= 7.84X10-14; Turkish: OR= 1.97, P= 2.34×10-9; Italian: OR= 1.91, P= 3.74×10-6) were also detected. Each of these three genetic associations in the HLA region maintained significance after controlling for the effects of the other two using regression analysis, in both cohorts independently and in the meta-analysis. This was confirmed using pairwise conditional analysis.
Conclusion: Multiple independent genetic associations are observed in the HLA region for Behcet’s disease. While the most significant association resides upstream of HLA-B and MICA genes, two genetic associations in PSORS1C1 and in HLA-F-AS1 appear to be independent.
Disclosure:
T. Hughes,
None;
A. Adler,
None;
P. S. Coit,
None;
V. Yilmaz,
None;
K. Aksu,
None;
N. Duzgun,
None;
G. Keser,
None;
A. Cefle,
None;
A. Yazici,
None;
A. Ergen,
None;
E. Alpsoy,
None;
C. Salvarani,
None;
B. Casali,
None;
I. Koetter,
None;
J. Gutierrez-Achury,
None;
C. Wijmenga,
None;
H. Direskeneli,
None;
G. Saruhan-Direskeneli,
None;
A. H. Sawalha,
None.
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/dense-genotyping-imputation-and-regression-analysis-identifies-multiple-independent-genetic-susceptibility-loci-within-the-hla-region-in-behcets-disease/