CD14 C-159T Research Articles

Association of the CD14 C159T and the Toll-like receptor 4 Asp299Gly polymorphisms with various phenotypes of asthma in adults from Crimea.

Background: This study assessed gene polymorphisms of the CD14 receptor (C-159T) and Toll-like receptor 4 (Asp299Gly) in a patient population in Crimea, Ukraine, stratified by clinical (early versus late onset; frequent versus occasional relapses; fixed versus reversible obstruction) and immunologic (atopic versus nonatopic; eosinophilic; neutrophilic or paucigranulocytic inflammation) subtype. Methods: Two polymorphisms, CD14 C-159T and TLR4 Asp299Gly, were assessed in 331 patients with asthma. The control group included 285 volunteers who were nonatopic. The single nucleotide polymorphisms were studied by using polymerase chain reaction with electrophoretic detection. Results: There were increased odds of asthma development in patients with the Asp299Gly TLR4 mutation compared with the general population underdominant odds ratio (OR) 1.52 [95% confidence interval (CI), 1.00-2.32] and overdominant (OR 1.55 [95% CI, 1.01-2.38]) models after adjustment for gender and age. In addition, mutations in this gene decreased the odds of nonatopic asthma in underdominant (OR 0.26 [95% CI, 0.07-0.93]; p = 0.027), overdominant (OR 0.27 [95% CI, 0.07-0.96]; p = 0.033), and log-additive models (OR 0.26 [95% CI, 0.07-0.93]; p = 0.026) compared with the atopic subgroup after adjustment for gender, age, number of exacerbations, and type of airway inflammation. Allele frequencies for CD14 and TLR4 polymorphisms did not show statistical differences between the patients with asthma and the control subjects. Conclusion: CD14 C-159T polymorphisms were not associated with asthma in the adult population in Crimea. TLR4 Asp299Gly polymorphisms were associated with asthma and with decreased odds of nonatopic asthma compared with atopic asthma in the adult population in Crimea.

The Influence of TLR4, CD14, OPG, and RANKL Polymorphisms in Periodontitis: A Case-Control Study.

The pathogenesis of periodontitis involves a complex interaction between the microbial challenge and the host immune response. The individual immunoinflammatory response has a great contribution in the pathogenesis of the disease and becomes a trigger in the process of bone remodeling which is a characteristic of the disease. Thus, the aim of this study was to evaluate the influence of the TLR4 A896G (rs4986790), TLR4 C1196T (rs4986791), CD14 C-260T (rs2569190), RANKL (TNFSF11, rs2277438), and OPG (TNFSF11B C163T, rs3102735) polymorphisms in periodontitis. A case-control study was conducted on patients with periodontitis (N = 203) and controls (N = 213) over 30 years of age, without diabetes mellitus, acute infections, and osteoarthritis, and patients without aggressive periodontitis, i.e., stage IV and C degree of periodontitis, and any periodontal treatment performed in the last 6 months. Genotypes were determined by the PCR-RFLP and sequencing method. The frequency comparisons between case and controls were performed using the chi-square test and logistic regression (OpenEpi and SNPStats software). The risk (OR) was evaluated for values of P < 0.05. Differences in TLR4, CD14, RANKL, and OPG genotype and allele frequency distributions were not observed between patients and controls. However, some variants were a risk factor for the development of periodontitis when considering gender and smoking habits. The TLR4 896 A/G genotype was a risk factor for periodontitis in males (OR = 2.86), and the TLR4 1196C/C genotype was a risk factor for nonsmoking males (OR = 1.85) when compared to women. The RANKL A/A and the OPG T/C genotype was associated with the risk of the disease in nonsmoking men compared to nonsmoking women with the same genotype (OR = 1.96 and OR = 2.9, respectively). In conclusion, TLR4, CD14, RANKL, and OPG variants were not associated with periodontitis. However, TLR4, RANKL, and OPG polymorphisms could be a risk for periodontitis in males regardless of smoking habits.

CD14 as A Serum Immune Biomarker and Genetic Predisposition Factor for Allergic Rhinitis.

Allergic Rhinitis (AR) is a common inflammatory disease of the nasal mucosa. The CD14 is a receptor for lipopolysaccharide and inhaled endotoxin which can stimulate the production of interleukins by antigen presenting cells. Accordingly, CD14 plays an important role in allergic and atopic diseases, which can be one of the etiological factors for allergic diseases. The present study investigated the association between the CD14 gene polymorphism C-159T and AR and aimed to detect the correlation between serum levels of CD14 and AR. This study was conducted on two groups of participants. The experimental group consisted of 125 patients with AR referring to Ghaem Hospital, Mashhad University of Medical Sciences in Mashhad, Iran, and the control group included 125 healthy subjects from Mashhad National Blood Center, Iran. Serum CD14 levels were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction-restriction fragment length polymorphism was employed to detect C-159T gene polymorphism in the CD14 promoter region. There was a significant association between CD14 C-159T gene polymorphism and AR (P<0.001). The results of the statistical analysis showed that the TT genotype could significantly increase the risk of AR (P<0.001). Additionally, a significant association was observed between C-159T gene polymorphism and the serum level of CD14 (P<0.001). Regardless of the genotypes, the serum CD14 levels were significantly higher in AR patients than in those of the participants in the controls (P=0.007). According to the obtained results of this study, CD14 in serum might be a potential marker for the diagnosis of AR, and in genetic levels it might be a predictive factor for the disease.

Role of TLR4 (C1196T) and CD14 (C-260T) Polymorphisms in Development of Ischemic Stroke, Its Subtypes and Hemorrhagic Stroke.

In the present study, we evaluated the association of TLR4 and CD14 polymorphisms, i.e. C1196T and C-260T, respectively, with ischemic stroke (n=700), its subtypes and hemorrhagic stroke (n=300) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP, and the strength of association between genotypes and stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. The results revealed a lack of association for TLR4 variant with ischemic stroke and hemorrhagic stroke, although a significant association was observed with the subtypes extracranial large artery (p=0.008), other determined aetiology (p=0.03) and undetermined aetiology (p=0.01). Investigations on the variant of CD14 gene revealed negative association among ischemic stroke patients; however, a significant association was observed for hemorrhagic stroke following dominant and recessive genotypic model (p=0.05, p=0.02). Among ischemic stroke subtype, a significant association was observed with intracranial large artery, extracranial large artery, other determined aetiology and undetermined aetiology form of stroke (p<0.01). Further, analysis of the CD14 variant between the two major stroke types revealed a significant difference in genotype distribution following the co-dominant genotypic model (p=0.01).

Investigation of associations of ARMS2, CD14, and TLR4 gene polymorphisms with wet age-related macular degeneration in a Greek population.

BackgroundAge-related macular degeneration (AMD) is a multifactorial degenerative ocular disease that leads to loss of central vision. Functional gene polymorphisms have already been associated with the disease (for example, ARMS2 A69S, rs10490924).AimThe goal of our study was to verify the correlation of the aforementioned ARMS2 variation with the disease, to examine, for the first time, the role of the CD14 C260T variation (rs2569190), and to investigate the association of two TLR4 polymorphisms (Asp299Gly or rs4986790 and Thr399Ile or rs4986791) in a Greek population with the wet form of AMD.Patients and methodsGenomic DNAs were isolated from blood samples of 103 healthy controls and 120 Greek patients with wet AMD who were age- and sex-matched, and all of whom were clinically evaluated. For the genotyping of all selected polymorphisms, polymerase chain reaction–restriction fragment length polymorphism analysis was performed.Results and conclusionsThis study confirmed the association between the ARMS2 variation and AMD, detecting the T risk allele in a significantly higher frequency in the patient group, compared with the control subjects (45% vs 29.13%, P<0.001, odds ratio [OR] 1.99, confidence interval 1.34–2.95). For the CD14 polymorphism, no statistically significant correlation was observed. As for the TLR4 polymorphisms, the percentage of heterozygotes increased from 2.9% to 11.7% in the patient population for Asp299Gly and from 1.9% to 10% for the Thr399Ile polymorphism (ORs 4.40 [P=0.01] and 5.61 [P=0.0088], respectively). Although our ARMS2 and CD14 results provided definite conclusions, the role of innate immunity TLR4 gene awaits further investigation in larger AMD populations with more clinical data collected on past microbial infections.

Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy.

Chronic HIV infection leads to marked depletion of CD4 T cells in the gastrointestinal tract and increased microbial translocation measured by an increase in circulating lipopolysaccharide (LPS) levels. Here, we hypothesized that single-nucleotide polymorphisms (SNPs) in genes encoding the Toll-like receptor 4 (TLR4) and CD14, the principal receptors for LPS, were associated with CD4 T-cell recovery postantiretroviral therapy (ART). Prospective study of predominantly white HIV-infected participants receiving suppressive ART for at least 12 months. We analysed the CD14 SNPs C-260T and the TLR4 SNPs A+896G, C+1196T. We also determined the levels of LPS and soluble CD14 in plasma samples collected pre-ART and post-ART initiation. CD4 T-cell recovery was assessed by linear mixed models. Following ART, individuals with a TT genotype compared with a CT or CC genotype for CD14 C-260T SNP showed higher levels of soluble CD14 (P = 0.008 and 0.003, respectively). The CC genotype for the CD14 C-260T SNP, compared with CT or TT, and the TLR4 SNP (AC/GT), compared with the homozygous genotype (AA/CC), were both independently associated with enhanced long-term CD4 T-cell recovery (>3 months; P < 0.001). Polymorphisms in CD14 and TLR4 are independently associated with long-term CD4 T-cell recovery in HIV-infected individuals post-ART.

The CD14 C-260T single nucleotide polymorphism (SNP) modulates monocyte/macrophage activation in treated HIV-infected individuals.

BackgroundHIV-infected individuals have an increased risk of cardiovascular disease (CVD). T-allele carriers of the CD14 C-260T single-nucleotide polymorphism (SNP) have reported increased expression of the LPS-binding receptor, CD14 and inflammation in the general population. Our aim was to explore the relationship of this SNP with monocyte/macrophage activation and inflammation and its association with sub-clinical atherosclerosis in HIV-infected individuals.MethodsPatients with no pre-existing CVD risk factors on suppressive antiretroviral therapy were recruited from University Malaya Medical Centre, Malaysia (n = 84). The CD14 C-260T and TLR4 SNPs, Asp299Gly and Thr399Ile were genotyped and soluble(s) CD14 and sCD163 and high-sensitivity C-reactive protein, hsCRP were measured in plasma. Subclinical atherosclerosis was assessed by measuring carotid intima media thickness (cIMT). The association between CD14 C-260T SNP carriage and cIMT was assessed in a multivariable quantile regression model where a p-value of <0.05 was considered significant.ResultsWe found the CD14 C-260T T-allele in 56% of the cohort and evidence of subclinical atherosclerosis in 27%. TT genotype was associated with higher sCD163 (p = 0.009) but only marginally higher sCD14 (p = 0.209) and no difference in hsCRP (p = 0.296) compared to CC/CT. In multivariable analysis, only Framingham risk score was independently associated with higher cIMT while lower sCD163 was trending towards significance. No association was found in TT-genotype carriers and cIMT measurements.ConclusionThe CD14 C-260T SNP was associated with increased monocyte activation but not systemic inflammation or cIMT in this HIV-infected cohort with low CVD risk profile.

Genetic features of patients with influenza A / H1N1 / 09 complicated by pneumonia

The aim of this study was to investigate polymorphisms of cytokine genes (TNF G308A, IL 10 C592A, IL 10 C819T, IL 10 G1082A), and molecular regulation of inflammation (CD14 C159T) and vascular tone (еNOS C786T) in patients with A / H1N1 flu complicated by pneumonia. Methods. Patients hospitalized for pneumonia complicating influenza A / H1N1 / 09 were involved in the study: 37 patients with severe pneumonia, 74 patients with non severe pneumonia and 115 healthy subjects as controls. Polymerase chain reaction (PCR) was used for molecular investigations. Results. Patients with influenza A / H1N1 complicated by pneumonia carried the homozygous G allele of TNF gene polymorphism (308 G/A) and the homozygous G allele of IL 10 gene polymorphism (1082 G/A) more often compared with controls. Patients with pneumonia more often carried IL 10 gene 592 C/A allele and largely as homozygous variant. Frequencies of homozygous IL 10 gene polymorphism (819 C/T) T/T and CD14 gene polymorphism (159 C/T) T/T were significantly lower compared with healthy subjects. On contrary, the homozygous T/T polymorphism (786 C/T) of еNOS gene was more common in patients with pneumonia. Prognostic risk factors for occurrence of pneumonia in patients with influenza А / H1N1 were IL 10 gene polymorphisms 592 CC, 819 CC, and 1082 GG. TNF (308 GG); IL 10 (819 CC) and (1082 GG) haplotypes had the highest prognostic value for severe pneumonia in patients with influenza A / H1N1. TNF (308 GG); IL 10 (819 CC); (1082 GG) and TNF (308 GG); IL 10 (819 CC); (1082 GG) and CD14 (159 CC) haplotypes predicted ARDS and death in patients with influenza A / H1N1 / 09, respectively. Conclusion . Identifying genetic status in a patient with influenza A / H1N1 could predict severity and complications of the disease.

Association of CD14 C159T polymorphism with atopic asthma susceptibility in children from Southeastern China: a case-control study

CD14 is involved in primary immune and inflammatory responses. The -159 C/T variation in the CD14 gene plays an important role in regulating CD14 expression and has been associated with the susceptibility to various diseases, including allergies. In this study, we examined the association between the C-159T polymorphism and atopic asthma susceptibility in children from Southeastern China. The study population included 746 unrelated children of Chinese Han nationality (362 patients with atopic asthma and 384 healthy controls). CD14 gene polymorphisms were identified by direct sequencing of polymerase chain reaction products. Total immunoglobulin E (IgE) levels in human serum samples were determined using an enzyme-linked immunosorbent assay. Individuals carrying the TT genotypes for rs2569190 were significantly associated with an increased risk of atopic asthma compared with those carrying the wild-type homozygous CC genotypes [adjusted odds ratio (OR) by gender and age, from 1.075-2.398, P = 0.025]. Total serum IgE levels in TT genotype carriers were significantly higher than those in CC genotype carriers in atopic asthma patients (286.3 ± 161.5 IU/mL vs 248.3 ± 147.8 IU/mL). Our data suggest that the CD14 TT genotype may be a genetic susceptibility marker for atopic asthma in Chinese Han children.

Racial differences in the association of CD14 polymorphisms with serum total IgE levels and allergen skin test reactivity

BackgroundThe CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects.MethodsA total of 291 participants, 18–40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects.ResultsWe found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans.ConclusionThese results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.

Association Between CD14 Gene Polymorphism and Periodontitis: A Meta-Analysis

This meta-analysis aimed to analyze the association between CD14 C-159T and C-260T polymorphisms and periodontitis risks because previous results have been conflicting. We used 12 eligible case-control studies involving 1435 cases and 1446 controls to evaluate this association. Compared with the common CD14 C-159T and C-260T genotypes, there was no significant association of T alleles and the CT/TT genotypes polymorphism with periodontitis risk (odds ratio [OR], 1.03; 95% confidence interval [CI], 0.83-1.27 for C vs. T; OR, 1.07; 95% CI, 0.83-1.38 for CT/TT vs. CC). A similar result was found in a subgroup analysis by ethnicity and periodontitis type. An enhanced risk for periodontitis was demonstrated in the comparison of subjects carrying the CT genotype versus CC homozygotes (overall OR, 1.681; 95% CI, 1.048-2.695; P for heterogeneity=0.367; I2=2.00%) for the C-260T genotype. Our meta-analysis revealed that the 2 common CD14 polymorphisms, C-159T and C-260T, have no association with the likelihood of periodontitis. In subgroup analysis by ethnicity and periodontitis type, the results also did not show any association. The effect of genetic networks and their mutual interactions in the CD14 signaling pathway on susceptibility to periodontitis need to be studied further.

The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis

Monocyte differentiation antigen CD14 is considered an important cell-activating mediator of inflammatory responses that may result in atherosclerosis, coronary heart disease (CHD), thrombus formation, and myocardial infarction (MI). A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with CHD. To investigate this inconsistency, we performed a meta-analysis of 28 studies involving a total of 13,335 CHD cases and 7,979 controls for C-260T of the CD14 gene to evaluate the effect of CD14 on genetic susceptibility for CHD. An overall random effects odds ratio of 1.24 (95 % CI: 1.12-1.36, P < 10(-5)) was found for T allele. Significant results were also observed using dominant (OR = 1.34, 95 % CI: 1.17-1.54, P < 10(-4)) or recessive genetic model (OR = 1.25, 95 % CI: 1.10-1.41, P = 0.0004). There was strong evidence of heterogeneity (P < 10(-5)), which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant results were found in East Asians; whereas no significant associations were found among Caucasians and other ethnic populations in all genetic models. In the stratified analysis according to sample size, CHD endpoints, and HWE status, significantly increased risks for the polymorphism were found in all genetic models. In conclusion, our results indicate that the CD14 C-260T polymorphism is a risk factor of CHD, especially in East Asians. However, additional very large-scale studies are warranted to confirm our results.

CD14 C-159T polymorphism and its association with chronic lung diseases: A pilot study on isocyanate exposed population of Central India.

CONTEXT:CD14 functions as a multifunctional receptor for bacterial cell wall components including endotoxin and lipopolysaccharide and is likely to influence the cytokine profile and subsequent immunoglobulin E production in response to antigen/allergen contact in allergic phenotypes.AIMS:The present study was to investigate genetic polymorphism in CD14 gene - 159C/T, which may be one of the risk factor for increased prevalence of Chronic Lung Diseases in the Central India.SETTINGS AND DESIGN:Survivors of Methyl isocyanates toxicity in Bhopal still suffering from various respiratory ailments were examined.MATERIALS AND METHODS:Polymerase chain reaction-restriction fragment length polymorphism was performed to determine the polymorphism of C-159T.RESULTS:The genotype and allelic frequencies were in Hardy-Weinberg’s equilibrium. Prevalence of CC, CT, and TT were 5.5%, 22.2% and 9.25% respectively in asthmatics; 16.6%, 20.3% and 5.5% respectively in chronic obstructive pulmonary disease (COPD) patients and 5.5%, 14.8% and 1.85 respectively among interstitial lung disorder (ILD) patients; whereas the control cohort with no methyl isocyanate exposure displayed (CC, CT, and TT) cytosine, thymine as 2%, 1.6% and 2% respectively. Increased risk of Asthma among those carrying TT genotype and T allele (odds ratio [OR] =2.61 and 2.02 respectively).CONCLUSION:COPD risk significantly found among those with CC genotype and C allele (OR = 2.81 and 1.50 respectively), whereas ILD risk found significantly among CT genotype and C allele (OR = 1.75 and 1.40 respectively). Therefore, single nucleotide polymorphism (SNP) C-159T polymorphism in CD14 gene might be a risk factor for development of CLD in this population.

CD14 Gene Variants and Their Importance for Childhood Croup, Atopy, and Asthma

Background. The CD14 gene has an important role in the detection of inflammatory provoking pathogens and in the ensuing signaling of the innate immune response. We assessed the role of CD14 C-159T, G-1359T in the expression of asthma, croup, and allergy in Canadian school children of ages 6 to 14 years. Methods. Children attending schools in a rural community participated in a cross-sectional survey of respiratory health. Following consent, we conducted clinical assessments to collect buccal swabs for genotyping and perform skin prick testing (SPT) to determine atopic status. Genotyping and SPT results were available for 533 and 499 children, respectively. Separate multivariable analyses that included both polymorphisms were conducted for each phenotype. Results. The prevalence of asthma, allergy, and croup was 18.6%, 22.4%, and 6.6%, respectively. Children with the T/T variant of CD14 G-1359T were more likely to have physician diagnosed asthma (26.8%). Children with C/C variant of CD14 C-159T had a significantly lower prevalence of croup (2.6%). Haplotype analyses of the two CD14 polymorphisms showed that individuals with the T|T haplotype combination were significantly more likely to have asthma (P = 0.014). Conclusions. In this study, CD14 variants are important for the expression of croup and asthma but not atopy.

Association between the CD14 gene C-159T polymorphism and serum soluble CD14 with pulmonary tuberculosis

Functional C-159T polymorphism in the promoter region of the CD14 lipopolysaccharide receptor has been reported to be associated with the development of tuberculosis (TB). To assess the association of CD14 C-159T polymorphism and serum soluble CD14 (sCD14) levels with pulmonary tuberculosis (TB) in an Iranian population living in a TB-endemic area. A case-control study was performed prospectively on 120 newly diagnosed pulmonary TB patients and 131 healthy subjects. C-159T polymorphism was performed using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Concentrations of sCD14 were measured in serum samples using enzyme-linked immunosorbent assay. The genotype frequencies of C-159T polymorphism differed significantly between TB patients and controls (P = 0.006). The risk of TB was 2.3-fold greater in individuals with the T-allele (CT + TT) in comparison to those without (OR 2.3, 95%CI 1.2-4.3, P = 0.006). Mean total sCD14 was significantly increased in the serum of patients with newly diagnosed pulmonary TB (mean ± SD = 3177 ± 751 ng/ml) compared to healthy controls (mean ± SD = 2955 ± 424 ng/ml, P < 0.004). These data indicate that the C-159T polymorphism of the CD14 gene is associated with TB; serum sCD14 levels were higher in TB patients in a sample of the Iranian population.

Can immune-related genotypes illuminate the immunopathogenesis of cytomegalovirus disease in human immunodeficiency virus–infected patients?

Most human immunodeficiency virus (HIV) patients are seropositive for cytomegalovirus (CMV) but a smaller proportion experience end-organ disease. This observation may reflect variations in genes affecting inflammatory and natural killer cell responses. DNA samples were collected from 240 HIV-infected patients followed at the University Hospitals/Case Medical Center (Cleveland, OH) between 1993 and 2008. Seventy-eight patients (African Americans = 41, Caucasians = 37) experienced CMV disease. Genotypes were determined using allele-specific fluorescent probes or multiplex polymerase chain reaction sequence-specific primers. IL12B3'UTR*(1) and SLC11A1 D543N*(1,2) were associated with CMV disease in African American patients (p = 0.04 and p = 0.02, respectively). IL10-1082*(1,2) and LILRB1 I142T*(1) were associated with CMV disease in Caucasians (p = 0.02 and p = 0.07, respectively). DARC T-46C*(1) and CD14 C-159T*(2) were associated with low nadir CD4(+) T cell counts in African American patients (p = 0.002 and p = 0.01, respectively). Caucasian patients carrying TNFA-308*2, TNFA-1031*(2), IL2-330*(1), CCL2-2518*(2), or LILRB1 I142T*(1) had significantly lower nadir CD4(+) T cells in a bootstrapped multivariable model (p = 0.006-0.02). In general, polymorphisms associated with CMV disease and CD4(+) T cell counts were distinct in Caucasian and African American patients in the United States. The LILRB1 I142T polymorphism was associated with both CMV disease and low nadir CD4(+) T cell counts in Caucasians, but the clearest determinant of low nadir CD4(+) T cell count in African American patients was DARC T-46C.

Gene polymorphisms contributing to hypertension in immunoglobulin A nephropathy

Hypertension, which is affected by genetic and environmental factors, is one of the major risk factors for chronic kidney disease. Identification of the genetic factor contributing to hypertension in patients with chronic kidney disease may potentially refine a therapeutic strategy. In the present multicenter cross-sectional study, 240 patients were eligible (aged 15-50years with urinary protein ≥0.25g/day) out of 429 patients who were diagnosed as having immunoglobulin (Ig) A nephropathy (IgAN) by renal biopsy between 1990 and 2005 and enrolled in our previous study, PREDICT-IgAN. The outcome was hypertension defined as ≥140 and/or ≥90mmHg of systolic and diastolic blood pressure and/or use of antihypertensives at renal biopsy. We assessed associations between hypertension and 28 polymorphisms with the frequency of minor genotype ≥10% among 100 atherosclerosis-related polymorphisms using the Chi-squared test in dominant and recessive models. We identified polymorphisms associated with hypertension in multivariate logistic regression models. Baseline characteristics: hypertension 36.3%. Among 28 polymorphisms, the Chi-squared test revealed that CD14 (-159CC vs CT/TT, P=0.03) and ACE (DD vs DI/II, P=0.03) were significantly associated with hypertension after Bonferroni correction. Multivariate logistic regression models revealed that CD14 -159CC [vs CT/TT, odds ratio (OR) 3.58 (95% confidence interval (CI) 1.66-7.63)] and ACE DD [vs DI/II, OR 4.41 (95% CI 1.80-10.8), P=0.001] were independently associated with hypertension. CD14 C-159T and ACE I/D contributed to hypertension in patients with IgAN.

Genetic polymorphisms of TP53 and FAS promoter modulate the progression of coronary artery disease after coronary artery bypass grafting: a gender-specific view

Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Various data indicate that apoptosis is the main event occurring during development and progression of atherosclerotic plaque. Plaque vascular smooth muscle cells (VSMCs) are more sensitive than regular VSMCs to TP53-mediated apoptosis. We investigated EDTA blood of 192 patients (18% female, age 60.9 ± 7.4 years) who had primary CABG more than 5 years ago. CAD progression was defined as clinical endpoints: re-operation (n = 88; 46%), catheter re-intervention (n = 58; 30%), or angina at follow-up (n = 89; 46%). Apoptotic gene polymorphisms (Toll-like receptor 2 A753G, FAS ligand C-844T, FAS promoter G-670A, TP53 Arg72Pro, and CD14 C-260T) were investigated by PCR-RFLP and compared to healthy controls (n = 200, 24% female, age 63.4 ± 5.4). Gender-specific analysis was carried out. Heterozygous, homozygous and wild-type expression of all five genetic polymorphisms showed almost identical distribution between patients with CAD and healthy controls. Looking at clinical endpoints, with GG expression of Toll-like receptor 2 polymorphism and GG expression of FAS promoter polymorphism, results showed a relative increased risk (p = 0.09) for recurrent symptoms and re-intervention. Patients with FAS promoter polymorphism with AA expression had an increased risk of suffering from recurrent symptoms (n = 28, p = 0.04). We found that patients with homozygous expression of TP53 polymorphisms (n = 3, all male) were prone to needing re-intervention after prior CABG (p = 0.03), but not re-operation. Over a period up to 15 years, the re-intervention rate was significantly different in homozygous genotypes of FAS LG, FAS promoter and TP53. Patients presenting with polymorphisms of FAS LG, FAS promoter and TP53 have an increased risk of CAD progression, as they have a higher rate of re-interventions.

The effect of CD14 C159T polymorphism on in vitro IgE synthesis and cytokine production by PBMC from children with asthma

Even though the genotype at the promoter region of the CD14 molecule is known to affect the atopic phenotypes, the cellular and molecular basis of this association is largely unknown. To investigate the effect of lipopolysaccharide (LPS) on IgE production and cytokine profile by peripheral blood mononuclear cells (PBMC) obtained from asthmatic children with the TT and the CC genotypes at position -159 of the CD14 gene. Peripheral blood mononuclear cells from asthmatic children with alternative genotypes at CD14 C159T locus were stimulated with 2 and 200 ng/ml LPS in vitro. The IgE, IgG and, IgM response was determined by ELISA and Ig έ-germline, IgG, and IgM transcription by real-time PCR. A cluster of cytokines was measured by cytometric bead array. Asthmatic children with the TT genotype but not those with the CC genotype responded with increased IgE synthesis and germline transcription to LPS stimulation. There were no genotype-related differences in IgG and IgM. TT but not the CC genotype was associated with significantly increased interleukin (IL)-4/IL-12 and IL-4/interferon-gamma (IFN-γ) ratios in the culture supernatant. There were no genotype-related differences in IL-1β, IL-7, IL-10, IL-13, IL-17A, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein, and tumor necrosis factor alpha. Peripheral blood mononuclear cells from asthmatic children with the TT genotype at position -159 of the CD14 gene make more IgE than those with the CC genotype following LPS stimulation because of increased germline transcription and have an augmented Th2 cytokine profile.

The importance of environment on respiratory genotype/phenotype relationships in the Inuit

Genetic and environmental influences and their interactions are central to asthma pathogenesis. This study aimed to investigate the effects of different macro-environments on asthma genotype-phenotype associations in two geographically separated populations with common ancestry. To accomplish this, two unselected populations of Inuit were recruited, one living in Greenland (n = 618) and the other in Denmark (n = 739). Subjects were genotyped for CD14 C-159T, SCGB1A1 A38G, ADRB2 Arg16Gly and Gln27Glu. The resulting genetic data were analysed for relationships with asthma-related parameters including lung function, ever asthma, atopy, rhinitis and dermatitis. The results showed contrasting magnitude and direction of genetic associations between the two geographically separate Inuit populations. In Greenland, the ADRB2 16Arg allele was associated with male-specific lower lung function, but in Denmark the same allele was associated with male-specific higher lung function. This allele was also associated with higher incidence of ever asthma in Denmark but not in Greenland. The SCGB1A1 38A allele was associated with lower rhinitis prevalence in Greenland but not in Denmark. These associations suggest that environment interacts with candidate asthma genes to modulate asthma pathogenesis in the Inuit.