During the past year we have performed a more in-depth analysis of our Turkish Behcet's disease case control collection to identify novel disease-associated loci. The genomic data including 311,459 markers in 1,278 patients with Behcet's disease and 1,215 healthy controls from Turkey were used to impute genotypes of over 5.9 million markers using the 1000 Genomes Phase 3 multiethnic panel. 13 novel loci with at least suggestive associations (P<5 x 10e-6) were directly genotyped in a replication cohort of 769 patients and 601 healthy controls from Turkey. A risk allele of rs1869947 in TLR2-RNF175 showed strong association in both cohorts and meta-analysis revealed genome-wide association (P=8.01 x 10e-9, OR 1.64, 95 percent CI 1.38-1.94). Zymosan (TLR-2 ligand)-stimulated peripheral blood mononuclear cells homozygous for the risk allele of rs1869947 produced more tumor necrosis factor (TNF) protein than cells from protective allele homozygotes (P=0.025). Association of the Behcet's disease-associated TLR2 allele with increased TNF production in response to a TLR-2 ligand suggests that an innate immune response to microbial products contributes to Behcet's disease. These findings help explain combined contributions of genetic and environmental risk factors to Behcet's disease pathogenesis. A manuscript describing these findings is currently in preparation.
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