CD14 Polymorphisms Research Articles

Genetic polymorphisms in cytokine and adhesion molecule genes in coronary artery disease.

Both inflammation and genetics play an important role in the pathogenesis of atherosclerosis and coronary artery disease. Epidemiological studies have investigated the association between coronary artery disease (CAD) and gene polymorphisms of the inflammatory molecules tumor necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta-1 and beta-2, interleukin (IL)-1 and its receptor antagonist (IL-1ra), CD14 (the receptor for lipopolysaccharide), P- and E-selectins, and platelet endothelial cell adhesion molecule (PECAM)-1. Current evidence suggests that the TNF polymorphisms explored so far are not linked to CAD. The majority of studies conducted showed no significant association between TGFbeta-1 and coronary atherosclerosis, but the data currently available are somewhat controversial. Some polymorphisms may increase the risk of myocardial infarction (MI) within specific ethnic groups or in certain populations. The association between the IL-1 system and atherosclerosis is complex and may vary as a result of a number of factors, such as stage of disease, clinical phenotype, and possibly population characteristics. The E-selectin gene (SELE) Arg128, 98T, and Phe554 alleles may increase the risk of atherosclerosis, but not necessarily the risk of MI. This association seems to be more pronounced in younger patients. The PECAM1 Leu125Val and Ser563Asn polymorphisms may increase the risk of atherosclerosis but not necessarily of MI. This association may be especially important in patients with a low risk for developing atherosclerosis. Current data indicate that screening for CD14-260C/T genotypes is unlikely to be a useful tool for risk assessment and it remains unclear whether CD14 polymorphisms significantly increase the risk of MI. The associations between candidate gene polymorphisms and CAD are complex as a consequence of pleiotropy, variations with age, selection due to the high lethality of the disease, and interactions with other genes and environmental factors. Nonetheless, although the current data is preliminary and partly conflicting, it does provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of CAD.

Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections.

Human toll-like receptor 4 (hTLR4) and CD14 are known to be components of the lipopolysaccharide receptor complex. Our study investigated the association between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphism(s) with outcome in an intensive care unit (ICU) population at risk for sepsis. By use of a polymerase chain reaction-based restriction fragment-length polymorphism analysis technique, the hTLR4 gene was altered in 14 (18%) of 77 ICU patients (all positive for systemic inflammatory response syndrome) and in 5 (13%) of 39 volunteers. There was a significantly higher incidence of gram-negative infection among patients with the mutations (11 [79%] of 14), compared with that in the wild-type population (11 [17%] of 63; P=.004). No association between CD14 polymorphism(s) and the incidence of infection or outcome was observed. These findings indicate that hTLR4 mutations are associated with an increased incidence of gram-negative infections in critically ill patients in a surgical setting.

The -260 C-->T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients.

CD14, expressed on the cell surface of monocytes and hepatic Kupffer cells, interacts with Gram-positive and Gram-negative bacteria. Upon CD14 stimulation, these cells respond with the enhanced release of cytokines involved in the pathophysiology of sepsis. The purpose of this study was to evaluate whether the genotype distribution of the -260 C-->T promoter polymorphism of the CD14 gene is associated with the development of severe sepsis in trauma patients. Fifty-eight severely injured blunt trauma patients with an injury severity score of 16 or more and without pre-existing chronic diseases. Genotyping for the single nucleotide exchange polymorphism of the CD14 gene was performed by means of a real-time polymerase chain reaction with fluorescence-labeled hybridization probes. Diagnosis of severe sepsis was based on the criteria of the ACCP/SCCM criteria. Fourteen out of the 58 patients (24.6%) developed a trauma-related severe sepsis. The overall allele frequency was 0.58 for the C allele and 0.42 for the T allele. The genotype distribution (TT 0.19, CT 0.47 and CC 0.35) did not differ significantly from a previously reported control group of healthy blood donors. There was no significant difference of the genotype distribution or allele frequency between trauma patients with severe sepsis and patients with an uncomplicated clinical course. This pilot study suggests that the CD14 -260 polymorphism is not associated with an increased risk of severe sepsis in trauma patients.

A recently described polymorphism in the CD28 gene on chromosome 2q33 is not associated with susceptibility to type 1 diabetes.

Type 1 diabetes mellitus is an autoimmune disease with a strong genetic background. The CTLA4 gene region (IDDM12) has been implicated in genetic susceptibility to type 1 diabetes by genome scanning and both family- and population-based analyses. As the genes encoding the costimulatory molecules CTLA4 and CD28, which compete for the receptor B7, reside close together on chromosome 2q33 and have high sequence homology, we investigated a recently described polymorphism in intron 3 of the CD28 gene and the CLTA4 codon 17 polymorphism in 176 patients with type 1 diabetes and 220 healthy controls. Whereas CTLA4 was found to be associated with type 1 diabetes, the frequency of the CD28 polymorphism did not differ between patients and controls, either in the entire sample or after stratification for CTLA4 genotype. Thus, the CD28 intron 3 polymorphism does not appear to be associated with susceptibility to type 1 diabetes.

Lipopolysaccharide receptor CD14 polymorphism and risk of stroke in a South-German population.

The monocyte receptor for bacterial lipopolysaccharide CD14 is an important mediator of the inflammatory response. Recently, a polymorphism in the promotor of the CD14 gene, C (-260) T, was detected as a risk factor for coronary heart disease. We tested the hypotheses that this polymorphism is a risk factor 1. for cerebral ischemia in general and 2. for cerebral ischemia due to large artery atherosclerosis or microangiopathy in particular. We performed a case control study including 151 consecutive patients with acute cerebral ischemia treated at our university hospital and 149 control subjects. All control subjects were randomly selected from the general population of the same region in South-West Germany. Genotype frequencies of the C(-260) T polymorphism in the promotor of the CD14 gene were examined by restriction length analysis. The TT-genotype was not associated with cerebral ischemia in general either in univariate or in multivariate analysis together with classical vascular risk factors (odds ratio in multivariate analysis: 1.11; 95 %CI, 0.63 to 1.95). In 70 patients with cerebral ischemia due to atherosclerosis of large arteries or microangiopathy, there was a significantly higher prevalence of the TT-genotype than into control subjects (38.6 % vs. 23.5 %; odds ratio in multivariate analysis 2.26; 95 %CI, 1.13 to 4.54). We demonstrated that the TT-genotype of the CD14 C(-260) T polymorphism in a South-German population is not associated with an increased risk of cerebral ischemia in general. However, we found that the TT-genotype is associated with a risk of atherosclerotic or microangiopathic stroke. This finding requires confirmation by future studies in larger populations.

The common functional C(−159)T polymorphism of the LPS receptor CD14 does not influence the disease outcome in patients with chronic hepatitis C infection

The common functional C(−159)T polymorphism of the LPS receptor CD14 does not influence the disease outcome in patients with chronic hepatitis C infection

A prospective evaluation of the CD14 and CD18 gene polymorphisms and risk of stroke.

Genetic polymorphisms of the CD14 lipopolysaccharide receptor gene (CD14) and the CD18 leukocyte adhesion molecule gene (CD18) have recently been hypothesized to be risk factors for atherothrombosis. However, no prospective data on subsequent risk of stroke are available. The present investigation was conducted to examine the possible association between the CD14 C(-260)T and CD18 codon 441 gene polymorphisms and the incidence of stroke in a large, prospective, matched case-control sample from the Physicians' Health Study. In the Physicians' Health Study, 14 916 apparently healthy men were followed over a 12-year period for stroke. Using a nested case-control study design, 338 study participants who developed stroke (cases) and 338 age- and smoking-matched study participants who remained free of reported disease during follow-up (controls) were evaluated. Both polymorphisms were determined by polymerase chain reaction with subsequent and respective restriction fragment length polymorphism gel electrophoresis. All observed genotype frequencies were in Hardy-Weinberg equilibrium. The allele and genotype distributions of the polymorphisms tested were similar among cases and controls, such that the relative risk of future stroke was 0.87 for CD14 C(-260)T (95% CI=0.69 to 1.11; P=0.27) and 0.99 for CD18 codon 441 (95% CI=0.77 to 1.28; P=0.96) assuming an additive mode of inheritance. No evidence of association was observed assuming dominant or recessive model, and similar null results were observed in subgroup analysis restricted to thromboembolic events In this large, prospective study, we found little evidence that the two previously described polymorphisms in the CD14 and CD18 genes are associated with risks of future stroke.

Evaluation of CC16 and CD14 polymorphisms in the german MAS cohort

Evaluation of CC16 and CD14 polymorphisms in the german MAS cohort

CD14 and TNFα promoter polymorphisms in patients with acute arthritis

Objective. To examine CD14 and TNF f gene polymorphisms in early arthritis in relation to clinical outcome. Methods. We studied 141 Caucasians who had had early arthritis 10 to 38 years earlier. We analysed CD14 (-159) and TNF f (- 238, - 308, - 376) polymorphisms using a novel cycle minisequencing method. DNA pools from 370 Caucasian blood donors served as controls. Results. CD14 (-159)C M T allele frequencies were comparable among patients and controls (39% vs 40%). Fifty men and 42 women had recovered while 24 men and six women had chronic spondyloarthropathy (SpA). Mutant T allele frequency was higher in the chronic SpA group than in the recovered group in women (75% vs 32%, relative risk 1.3, 95% confidence limit 1.1 to 1.6, P= 0.011), but not in men (38% vs 44%). All female patients with chronic SpA had CD14 (- 159)T allele and none had a possibly protective TNF f (- 308)G M A allele. Conclusion. Possession of CD14 (- 159)T allele does not increase risk of ReA but may increase susceptibility of female patients to development of chronic SpA.

The CD14(−159) polymorphism is not associated with circulating sCD14 nor total serum IgE in an asthmatic population of African descent

The CD14(−159) polymorphism is not associated with circulating sCD14 nor total serum IgE in an asthmatic population of African descent

CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis

Susceptibility to autoimmune hepatitis is associated with particular human leucocyte antigen class II alleles. However, non-HLA genetic factors are likely to be required for development of the disease. Among the candidate genes, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD28 genes, located on chromosome 2q33 in humans, encode a cell surface molecule playing a dominant role in the regulation of T-cell activation. The CTLA-4 and CD28 polymorphisms were investigated in children from 32 families with autoimmune hepatitis (AIH). The transmission/disequilibrium test revealed increased transmission of the (AT)8 (dinucleotide repeat) and A (exon 1) alleles of CTLA-4 gene from heterozygous parents to affected offspring (87.5% and 83.5%) with type 1 AIH, compared with unaffected offspring (50.0% for both, p = 0.009 and 0.02, respectively). In contrast, no deviation in transmission for CTLA-4 polymorphisms was found between type 2 AIH patients and unaffected offspring. No evidence for association was found between CD28 gene polymorphism or D2S72 genetic marker and both types of AIH. This study identified the CTLA-4 gene polymorphism as a non-HLA determinant that predisposes to AIH type 1 in children. The genetic heterogeneity seen in the present study provides a new argument in favor of pathogenic differences between type 1 and type 2 AIH.

A prospective evaluation of the CD14 C(-260) T gene polymorphism and the risk of myocardial infarction

The T allele at position -260 of the CD14 lipopolysaccharide receptor gene (CD14) has recently been hypothesized to be a risk factor for myocardial infarction (MI). However, no prospective data relating this polymorphism to risk of future MI are available. In the physicians’ health study (PHS), 14916 apparently healthy men were followed over a 12-year period for incident MI. Employing a nested case-control study design, the CD14 C(-260) T polymorphism was evaluated among 387 study participants who developed MI (cases) and among an equal number of age- and smoking-matched study participants who remained free of vascular diseases during follow-up (controls). All observed genotype frequencies were in Hardy-Weinberg equilibrium. However, the allele and genotype distributions of the CD14 polymorphism were similar among cases and controls, both in the total cohort and in all subgroups evaluated. Furthermore, no evidence of association was observed assuming additive, dominant, or recessive mode of inheritance. For example, the relative risk of future MI in a comparison of homozygous mutants to homozygous wild types was 1.00 (95% CI=0.7–1.5; P=0.9). In this large prospective study, the CD14 C(-260) T gene polymorphism was not associated with risks of future MI. Thus, in contrast to prior studies, these data indicate that screening for CD14 C(-260) T genotypes is unlikely to be a useful tool for risk assessment.

The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality.

Sepsis is characterised by a systemic inflammatory response to bacterial products during infection, which interestingly both in humans and animal models is gender associated with a higher susceptibility of males than females. The CD14 receptor is involved in activation of cells by lipopolysaccharides released from Gram-negative bacteria and, as recently shown, also by products of Gram-positive bacteria (e.g., peptidoglycans and lipoteichoic acid). The functional relevance of a C(-159)T CD14 polymorphism recently has been shown based on correlation of the T allele to higher plasma levels of soluble CD14, and higher membrane expression on monocytes. We, therefore, now analysed this CD14 polymorphism in 204 patients with severe sepsis and 247 controls. No significant difference of allele frequencies was observed between sepsis patients and controls neither for males nor females. Mortality also was not associated with the polymorphism studied. This may suggest that other mechanisms for lipopolysaccharide recognition, such as the recently described Toll-like receptors are important for inflammatory cell activation in sepsis.

Common polymorphisms in the CTLA-4 and CD28 genes at 2q33 are not associated with asthma or atopy.

Recently, genetic linkage of the chromosomal region 2q33 with asthma has been shown. The genes coding for CD28 and CTLA-4 have been localized to this chromosomal region. CD28 and CTLA-4 have been shown to be involved as an important costimulatory signal in the regulation of allergic inflammation and TH2 cytokine production, and thus both genes are good candidate genes for asthma and atopy. Two common polymorphisms in the CTLA-4 gene and one polymorphism in the CD28 gene found by single-strand conformation polymorphisms (SSCP) analysis and direct genomic sequencing were tested for association with asthma and atopy phenotypes in a population of 260 largely atopic children and young adults. No association was found between any of the three polymorphisms and asthma or atopy phenotypes. The newly described common CD28 polymorphism is situated in the third intron of the gene. We conclude that neither gene is likely to exert a major influence on the development of asthma or atopy in our population. However, it might prove useful to test for association of these polymorphisms with asthma in populations recruited through asthmatic but not necessarily atopic individuals.