Polymorphisms in the Tumor Necrosis Factor/Lipopolysaccharides Pathway in Crohn Disease in the Jewish Ashkenazi Population

Abstract

Tumor necrosis factor (TNF)-alpha plays a role in the inflammatory process in Crohn disease, a disease with an apparent polygenic basis. We investigated whether polymorphisms in multiple genes involved in the lipopolysaccharide-TNF inflammatory pathway are independently associated with Crohn disease in the Jewish Ashkenazi population. Polymorphisms in CD14, Toll-like receptor 4 (TLR4), and TNF-alpha were studied. In addition, we investigated polymorphisms in the TNF-alpha converting enzyme (TACE) gene, which to date has not been studied for an association with Crohn disease. To examine whether TLR4 Asp299Gly, CD14-260C/T, TNF-1031T/C, TNF-863C/A, TNF-857C/T, TACE-172C/T, and TACE-154C/A polymorphisms are associated with Crohn disease in the Ashkenazi Jewish population, we analyzed families with at least 1 child with Crohn disease for association with these mutations using a family-based association test (transmission disequilibrium test) for analysis. The allelic frequency in the patient population of TLR4 G allele was 8.0%, CD14 T allele was 51.3%, TNF-1031C was 18.8%, TNF-863A was 14.2%, TNF-857T was 25.2%, TACE172T was 20.7%, and TACE154A was 24.5%. The transmission disequilibrium test transmitted:untransmitted (T:U) result for TLR4G was T:U = 32:20, for CD14T was T:U = 103:88, for TNF-1031C was T:U = 48:56, for TNF-863A was T:U = 39:42, for TNF-857T was T:U = 63:62, for TACE-172C/T was T:U = 48:59, and for TACE-154C/A was T:U = 52:55. No statistically significant associations were observed. The transmission disequilibrium test did not demonstrate preferential transmission of these variants in Jewish Ashkenazi patients with Crohn disease. These results suggest that these polymorphisms in the TNF/lipopolysaccharide pathway play little or no role in susceptibility to Crohn disease in the Jewish Ashkenazi population.