No association of the TLR2 gene Arg753Gln polymorphism with rheumatic heart disease and Behçet’s disease

Abstract

Behçet's disease (BD) is a multisystem inflammatory disorder of unknown etiology, and infections with different microorganisms including streptococci have been claimed as triggers of inflammatory attacks in BD pathogenesis. Toll-like receptor 2 (TLR2) has been known to recognize several microbial antigens including that of streptococci, and TLR2 gene Arg753Gln polymorphism has been reported to be strongly associated with acute rheumatic fever with an odds ratio of 100. This study aimed to investigate the TLR2 gene Arg753Gln polymorphism in a group of patients with BD and rheumatic heart disease (RHD) and to analyze the role of genotyping errors resulting from duplicated gene segments. The study group consisted of 211 patients with BD, 95 patients with RHD, and 94 matched Turkish healthy controls. Because of the duplicated exon 3 in 23-kb upstream of the TLR2 gene, genotyping for the Arg753Gln polymorphism with polymerase chain reaction-restriction fragment length polymorphism method was carried out using a new set of primers and PstI restriction enzyme. TLR2 gene Gln753 allele was observed in two of 211 (1.0%) patients with BD, five of 95 (5.3%) patients with RHD, and two of 94 (2.1%) healthy controls. All patients and controls were found to be heterozygous for Arg753Gln polymorphism, except one patient with BD, who was homozygous for Gln753. Although a slight increase of heterozygosity was noted in patients with RHD, no statistically significant difference was observed in the distribution of Arg753Gln polymorphism in BD and RHD compared to healthy controls. In conclusion, TLR2 gene Arg753Gln polymorphism is not associated with BD nor with RHD; and a duplicated region of the TLR2 exon 3 located 23-kb upstream of the polymorphic region may explain contradictory association findings described so far.

Investigations of genetic polymorphisms related to Behcet\s disease in Turkish population

“…TLR2 genine ait Arg753Gln ve Arg677Trp olmak üzere iki fonksiyonel polimorfizm tanımlanmıştır (65). Behçet hastalarının TLR tarafından algılanan streptokokus ve mikoplazma gibi infeksiyon ajanlarına yatkın olmasından yola çıkılarak TLR2 Arg753Gln polimorfizmi ile BH arasında ilişki olup olmadığı araştırılmış fakat herhangi anlamlı bir ilişki bulunamamıştır (66,67).…”

Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins

“…Probably the most investigated TLR2 polymorphism is the 2258GϾA polymorphism, which in studies performed with European populations has been reported to be associated with several important infections, such as Candida infections (20), severe bacterial infections (31), late-stage Lyme disease (46), acute rheumatic fever (6), urinary tract infections (51), tuberculosis (36), and autoinflammatory diseases such as Behcet disease (13) and familial Mediterranean fever (37). The TLR2 2258GϾA SNP was also reported to be involved in the development of arthritis and extraarticular features following infection with Salmonella en- terica serovar Enteritidis (57).…”

The Roles of Genetic Factors in Uveitis and Their Clinical Significance

“…111,118,119 Studies have also found associations between small ubiquitin-like modifier 4 (SUMO4) polymorphisms with Behçet disease 112,120 and C677T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene with ocular involvement in Behçet disease. 128 Researches have also investigated other candidate genes with function-based hypothesis, such as toll-like receptor 2 (TLR2), 129 protein tyrosine phosphatase non-receptor 22 (PTPN22), 130 endothelial nitric oxide synthase (eNOS), 131 and programmed cell death 1 (PD-1) genes. These included MEFV (the gene responsible for familial Mediterranean fever, FMF), 121 platelet glycoprotein receptor IIIA (GpIIIa) gene, 122 signal transducer and activator of transcription 3 (STAT3), 123 CD40, 124 IkappaBalpha, 125 cytotoxic T-lymphocyte antigen-4 (CTLA-4), 126 toll-like receptor-4 (TLR4), 127 and Fc receptor-like 3 gene (FCRL3).…”