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Background: Genes involved in the regulation of immune responses, such as Toll-like receptor 4 (TLR4) and CD14, show genetic variations with potential functional implications. Because atherosclerosis is an inflammatory process apparently modulated by chronic infections, we studied the effect of single nucleotide polymorphisms (SNPs) in TLR4 and CD14 on the extent of clinically relevant atherosclerosis in patients with peripheral arterial disease (PAD). Methods: Using an in-house–developed polymerase chain reaction–based restriction length polymorphism assay, we determined the genotype, allele frequency, and carrier traits of the TLR4 +896 A>G and the CD14 −260 C>T SNPs in 607 white Dutch patients with PAD. The extent of clinically relevant atherosclerosis was determined on the basis of the number of vascular territories involved, ie, coronary, cerebral, aortic, and peripheral. Results: A total of 55% of the patients had PAD only. Approximately one third of the patients had two and 11% had three vascular territories affected by clinically relevant atherosclerosis. The TLR4 +866 G allele frequency was 11%, and the CD14 −260 T allele frequency was approximately 74%. Among PAD patients, TLR4 +896 G allele carriership was univariantly associated with extensive (more than two vascular territories affected) atherosclerotic disease (odds ratio, 2.22; P = .020; χ2 test), whereas CD14 −260 C>T carriership/homozygosity was not. Trend analysis showed that the TLR4 +866 G allele frequency increased with the number of vascular territories affected by clinically relevant atherosclerosis (P trend, .0074). In a multivariate logistic regression analysis including cardiovascular risk factors and TLR4 and CD14 SNPs, only the interaction variable “TLR4 +896 G allele carriership/CD14 −260 TT genotype” survived as an independent predictor of extensive atherosclerotic disease (P = .031; odds ratio, 4.2; 95% confidence interval, 1.1-15.4). Conclusions: The carrier trait TLR4 G allele/CD14 TT genotype, rather than each SNP individually, is associated with the extent of clinically relevant atherosclerotic disease. Considering the importance of immune responses in atherogenesis and the genetic variation of immune regulatory genes, our data provide an explanation for interindividual differences in susceptibility to atherosclerosis and demonstrate the need to take a wider approach in analyzing relevant carrier traits instead of individual polymorphisms in relation to atherosclerosis. [Copyright &y& Elsevier]

The recent identification of the CARD15/NOD2 gene as a susceptibility locus for Crohn's disease represents an important step in the immunopathogenesis of inflammatory bowel disease. The gene explains about 20% of the genetic susceptibility CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. The three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations, with regional variation across Europe. In non-Caucasian populations Crohn's disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2. Genotype-phenotype analyses demonstrated an association of these mutations with ileum-specific disease and an increased incidence of the fibrostenotic phenotype. Although CARD15 variants do not predict response to the TNF alpha monoclonal antibodies, there are no data available on the possible influence of CARD15 mutations on response to other drugs. Screening for CARD15 mutations in order to identify high-risk individuals or to introduce an individualized disease management is therefore currently not recommended.

We have previously shown that female outbred CF-1 mice are susceptible to prolonged genital tract infection with the oculogenital serovars (D-K) of Chlamydia trachomatis, and that partial homotypic and heterotypic protection against reinfection is induced. To understand the possible role of inherent T-helper 1 (Th1)/Th2 polarity bias on both the course of infection and the level of acquired immunity induced by infection, 2 immunologically different and well-characterized inbred strains of mice, BALB/c and C57BL/6, were studied in this model. Groups of mice were inoculated intravaginally with C. trachomatis serovar D (Ct D) and monitored by culture to determine the duration of initial infection. Two months later, mice were reinfected, and monitored along with age- and condition-matched control groups. Plasma and vaginal secretions were collected for serologic analysis and specific delayed-type hypersensitivity was assessed by footpad swelling. Initial infection in C57BL/6 mice was comparable in duration to outbred CF-1 mice (median duration 42 versus 43.5 days), while BALB/c mice had a shorter median duration of initial infection (12 days). All strains had significantly shorter durations of infection following reinfection. BALB/c mice shed 4-10 times more inclusion-forming units (IFU) than both C57BL/6 and CF-1 mice on sample days during the first week of infection and all strains shed less IFU during reinfection. C57BL/6 and BALB/c mice had significantly lower anti-Ct D immunoglobulin G titers in both plasma and vaginal secretions than CF-1 mice following resolution of infection; the frequency of immunoglobulin A seropositive vaginal secretions was less in both inbred strains, being significantly less in the case of C57BL/6 mice. Qualitative analysis of the antigen specificity and isotype composition revealed differences among the mouse strains. All 3 strains had detectable levels of specific footpad swelling on day 14 of infection, whereas only BALB/c mice showed a significant response at 70 days post-infection. Significant differences between 2 strains of mice that differ in Th1/Th2 polarity bias were observed in: 1) the duration of infection; 2) the level of bacterial shedding during infection; and 3) the quantitative and qualitative cellular and humoral responses made in response to female genital tract infection with a human oculogenital isolate of C. trachomatis. In addition, a similar and significant level of partial acquired immunity to reinfection was observed in both strains, suggesting that inherent Th1/Th2 polarity bias present upon initial infection does not prevent the development of a protective immune response within the genital tract during infection with an oculogenital isolate of C. trachomatis.