A polymorphism in the CD14 gene is associated with Crohn disease

BACKGROUND: Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Although genetic factors play an important role in the pathogenesis, little is known about the genes accountable. Immune response to intestinal bacteria seems to be crucial in the pathogenesis of IBD. METHODS: To evaluate the role of the CD14 gene in IBD, a functionally relevant polymorphism in the promoter region (T/C at position -159) has been genotyped in 219 patients with Crohn disease (CD), 142 patients with ulcerative colitis (UC) and 410 healthy controls by RFLP analysis. RESULTS: T allele and TT genotype frequencies were found increased in CD patients compared to controls (Pc=0.044 and 0.005, respectively). CONCLUSION: An altered immune response to LPS seems to play a role in the genetic predisposition to CD but not to UC.     

CD14的基因型及血清水平与急性心肌梗死的关系

目的 研究CD14基因启动子-159C/T、-260C/T多态性各等位基因及基因型在急性心肌梗死(AMI)患者中的分布频率,初步分析其基因型及血清水平与AMI的相关性.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,检测120例AMI患者及130例正常对照组CD14的基因多态性,同时采用酶联免疫吸附试验(ELISA)检测血清CD14水平.结果 AMI组血清CD14水平显著高于对照组(P<0.01),CD14基因-159C/T多态性在AMI组和正常人群中的分布差异无显著性(P>0.05),而CD14基因-260C/T多态性在两组人群中的分布差异存在显著性(P<0.05),等位基因频率的相对风险分析发现,T等位基因携带者患AMI的风险是C等位基因的1.654倍(OR=1.654,95%CI:1.161～2.356),携带T等位基因的AMI患者血清CD14水平显著高于不携带者(P<0.05).结论 CD14基因启动子-260C/T多态性与AMI的发病具有相关性,其中T等位基因可能是AMI发病的遗传易感基因;携带T等位基因的个体可能通过促进CD14的高度表达进而增加了AMI的发病风险.     

Interaction of Polymorphisms in the CARD15 and CD14 Genes in Patients with Crohn Disease

Background: Associations of variations in the CARD15 gene (Arg702Trp, Gly908Arg and Leu1007fsinsC) and Crohn disease (CD) have been shown recently. These variations are neither necessary nor sufficient for the genetic predisposition of CD. Further genetic and environmental factors play a crucial role in the pathogenesis of CD. Methods: To evaluate putative interactions between the CARD15 and CD14 genes in CD, a functionally relevant polymorphism in the promoter region (T/C at position &#109 159) has been genotyped for 650 healthy controls and 253 patients with CD by RFLP analyses. CD patients were genotyped for the variations of the CARD15 gene. Results: T allele and TT genotype frequencies of the CD14 promoter were significantly increased only in CD patients with at least one variation in the CARD15 gene compared to controls ( P &#114 = &#114 0.02 and 0.0002, respectively). No significant association was found in CD patients without any of the variations. Conclusion: Interactions of the CARD15 and CD14 genes, both of which are involved in the recognition of lipopolysaccharides, increase the risk for developing CD.     

Polymorphism of CD14 gene but not the mutation of TLR4 gene is associated with colorectal cancer in Chinese patients

Objectives: Toll‐like receptor 4 and CD14 are components of the lipopolysaccharide receptor complex. Our study aimed to investigate an association between TLR4 Asp299Gly and CD14‐260 polymorphisms in Chinese patients with colorectal cancer. Method: By a method of polymerase chain reaction–based restriction fragment length polymorphism (PCR‐RFLP), we genotyped TLR4 Asp299Gly and CD14‐260 polymorphisms in 110 unrelated patients with colorectal cancer and 160 healthy controls from the Chinese Han population. Results: We found significant differences in CD14 genotypes between healthy controls and patients with colorectal cancer. The frequency of the C/C genotype in healthy controls (15.6%) was significantly lower than in the group of colorectal cancer patients (32%). The frequency of the C/T genotype in healthy controls (48.1%) was significantly higher than that in the group of colorectal cancer patients (31%). No TLR4 Asp299Gly mutation was detected in any patients or healthy controls in the Chinese Han population. Conclusions: These findings indicated that the polymorphism of CD14 but not TLR4 Asp299Gly mutation was associated with Chinese patients with colorectal cancer, and the CD14 gene may contribute to the predisposition to colorectal cancer. Screening for the CD14 C‐260T genotype is likely to be a useful tool for risk assessment or prognostication for colorectal cancer in the Chinese Han population.     

CD14 gene -260 C/T polymorphism is associated with chronic heart failure

BACKGROUND: Patients with chronic heart failure (CHF) show inflammatory changes and elevated plasma levels of TNFalpha and endotoxins. However, the role of the CD14 C(-260)T polymorphism in patients with CHF is unclear. Therefore, we sought to determine whether the C=>T promoter polymorphism (position -260) of the CD 14 gene is associated with a higher risk for the development of CHF. METHODS: We studied 100 patients with CHF (mean age 62+/-3 years, LVEF 28+/-8%) and 100 healthy controls (59+/-10 years, p=NS; LVEF 60+/-4%, p<0.05). CD14 genotyping was performed using a PCR-RFLP technique. RESULTS: Among CHF patients, the frequency of the T allele was lower (38% vs. 48%, p<0.05) and the frequency of the C allele higher (62 % vs. 52 %, p<0.05) than among controls. The distribution of CD14 genotypes in healthy controls was as follows: CC 32%, CT 40%, and TT 28%. Among CHF patients, the TT genotype was significantly underrepresented compared to controls: CC 38%, CT 48%, and TT 14% (p<0.05). CONCLUSIONS: The C -260T polymorphism of CD14 seems to influence the susceptibility for the development of CHF. The T allele is less frequent among CHF patients than among controls. The TT genotype could be a new genetic protective factor against the development of CHF.     

Ulcerative colitis is associated with a promoter polymorphism of lipopolysaccharide receptor gene,CD14

BACKGROUND: Inflammatory bowel disease (IBD) is a multifactorial disease with a significant genetic background. Evidence is accumulating that molecules such as CD14, which interact with luminal bacterial constituents, are involved in the pathogenesis. It has recently been shown that the T allele of the 5'-flanking region of the CD14 gene at position -159 is related to high expression of CD14. In further exploring the genetic background of IBD, we investigated this novel polymorphism of CD14 gene in patients with ulcerative colitis or Crohn disease. METHODS: DNA was obtained from 101 patients with ulcerative colitis, 82 with Crohn disease and 123 healthy controls. All were typed for the promoter polymorphism of the CD14 gene at position -159 by restriction fragment length polymorphism analysis. Serum samples were obtained from 105 healthy controls and serum sCD14 levels were measured. RESULTS: T allele frequencies were 57.4%, 48.2% and 44.7% in ulcerative colitis, Crohn disease and healthy controls, respectively. The T allele and T/T genotype frequencies were significantly higher in ulcerative colitis patients than in healthy controls (P = 0.0074, OR = 1.67, 95% CI = 1.15-2.42, P = 0.022, OR= 1.96 95% CI: 1.10-3.48, respectively). The sCD14 level was significantly higher in TT genotype populations than CC (P = 0.0205). CONCLUSIONS: The promoter polymorphism of the CD14 gene at -159T plays a significant role in regulating the CD14 expression and is positively associated with ulcerative colitis, and this polymorphism may confer a genetic predisposition to ulcerative colitis. The results also support the concept that bacterial constituents may be involved in the pathogenesis of ulcerative colitis.     

Polymorphisms in COL15 gene are not associated with systemic sclerosis

OBJECTIVE: Systemic sclerosis (SSc) is marked by microvascular abnormalities leading to ischemic features such as Raynaud's phenomenon and fingertip ulcers. Digital ischemia in turn results in hypoxia, which is expected to drive compensatory angiogenesis; however, this phenomenon is deregulated in SSc. Vascular basement membrane (VBM) that consists of type IV, XV, and XVIII collagens supports the growth and survival of vascular endothelial cells and plays a key role in regulating angiogenesis. Recent gene expression analyses of skin tissue and dermal fibroblasts from patients with SSc revealed COL15 to be one of the significantly differentially regulated genes. We undertook an association study to explore the role of COL15 single-nucleotide polymorphisms (SNP) in SSc disease development. METHODS: Eleven SNP across COL15 were genotyped in a cohort of 175 UK Caucasian patients with SSc and 190 population-matched unrelated healthy subjects using 2 methods: TaqMan and SNaPshot. Statistical analysis was performed by Pearson's chi-square test and HelixTree software was utilized for haplotype analysis. RESULTS: No difference in genotype or allele frequencies were detected between patients with SSc and controls. None of the haplotype frequencies were found to differ between patients and controls. CONCLUSION: Failure to detect an association may reflect a true lack of association or could be a false-negative result arising as a result of low power of the study. Our study had sufficient power to detect an effect size of 2.1 (p = 0.05); however, larger patient cohorts may be needed for exclusion of COL15 from a possible candidacy in SSc.     

CD14及Toll样受体4基因多态性与大肠癌的相关性研究

目的探讨我国湖北汉族人Toll样受体（TLR）4基因Asp299Gly和CD14 C-260T基因多态性分布与大肠癌的相关性。方法采用聚合酶链反应限制性片段长度多态性（PCR—RFLP）方法，检测110例大肠癌患者及160例正常对照者TLR4基因Asp299Gly及CD14 C-260T基因型及等位基因频率的分布。结果大肠癌组CD14 C-260T基因型与正常对照组比较，差异有统计学意义（P〈0．05）。正常对照组CC基因型的频率为15．6%，明显低于大肠癌组的31．8％（P=0．0027，OR=0．3968，95％CI=0．2209～0．7129）；正常对照组中CT基因型的频率为48．1％，明显高于大肠癌组的30．9％（P=0．0056，OR=2．074，95%CI=1．246～3．452）。所有样本中均未发现TLR4基因Asp299Gly的突变型。结论CD14 C-260T基因多态性与中国湖北汉族大肠癌显著相关，而TLR4基因Asp299Gly多态性与大肠癌无关。     

Waist circumference associated with pulmonary function in children

In adults abdominal obesity is related to lung dysfunction and waist circumference (WC) predicts pulmonary function. It is not known how WC affects pulmonary function in children. A cross‐sectional study of 718 children 6–17 years of age was conducted in a rural community to determine the predictability of WC for pulmonary function in children. Height, weight, WC, and pulmonary function were measured. Multivariate analysis was conducted. WC was positively associated with FVC and FEV₁ and was more strongly associated with FVC than with FEV₁. Increase in WC significantly predicted a reduction in FEV₁/FVC. After adjustment for sex, age, and height, an increase of 1 cm for WC was associated with an increase of 7 ml of FVC and 4 ml of FEV₁, and with an increase of 4 ml of FVC and 2 ml of FEV₁ with an additional adjustment for weight. Height and weight were not significantly associated with FEV₁/FVC. WC but not body mass index predicted a decline of FEV₁/FVC. WC had a larger impact on FVC than FEV₁. WC, but not BMI, was negatively associated with FEV₁/FVC in children. Pediatr Pulmonol. 2009; 44:216–221. © 2009 Wiley‐Liss, Inc.     

Polymorphisms of estrogen receptor beta gene are associated with hypospadias

INTRODUCTION: Hypospadias is a common male congenital urethral malformation, defined as the displacement of the urethral meatus ventrally from the tip of the glans penis. The importance of androgen receptor in male external genitalia development has been well recognized. Recently, the presence of active estrogen receptors (ER) in the developing male external genitalia has also been demonstrated. There are two isoforms of the human estrogen receptor, ESR1 and ESR2, which occur, with distinct tissue and cell patterns of expression. We hypothesized that modifications in these nuclear receptors' genes could lead to hypospadias. MATERIALS AND METHODS: We screened 60 boys with hypospadias for mutations in the coding regions of ESR1 and ESR2 genes, by denaturing high-performance liquid chromatography and automated sequence analysis. We also genotyped the CA repeat polymorphism in ESR2 and the TA repeat polymorphism in ESR1. RESULTS: The CA repeat polymorphism in ESR2 is prolonged in hypospadias patients compared to controls (p < 0.05). Prolongation of this CA repeat polymorphism has previously been associated with lower levels of testosterone. Six patients presented the genetic variant 2681-4A > G (rs944050) in the heterozygous form in ESR2, which was a significantly higher frequency than in the control population (p < 0.05). One of these patients also presented a 266_267insC in exon 1 of ESR2, which is also a known single nucleotide polymorphism (SNP; rs3832949). In ESR1, no significant gene alteration was found to be associated with hypospadias. CONCLUSIONS: Our results suggest that variations in the ESR2 might influence susceptibility to hypospadias.     

CD14 expression on monocytes and soluble CD14 plasma levels in correlation to the promotor polymorphism of the endotoxin receptor CD14 gene in patients with inactive Crohn's disease

BACKGROUND/AIMS: The association of the single nucleotide polymorphism in the promotor of the lipopolysaccharide receptor CD14 gene (T/C at position -159) with Crohn's disease has recently been demonstrated. This CD14 polymorphism is a potential predisposition factor responsible for inter-individual differing inflammatory reactions involving the CD14 receptor. We studied the correlation between the CD14 genotype (CC, CT, TT) and the membrane-bound CD14 monocyte expression and soluble CD14 in patients with inactive Crohn's disease. METHODOLOGY: In 23 patients and 29 healthy volunteers the membrane-bound CD14 density on unstimulated monocytes and soluble CD14 plasma levels were examined using quantitative flow cytometry and enzyme-linked immunosorbent assay. RESULTS: In normal controls membrane-bound CD14 monocyte density did not differ significantly between the genotypes CC, CT, or TT. In contrast, patients with inactive Crohn's disease and genotype TT showed a significantly lower membrane-bound CD14 density on monocytes compared to patients with genotype CC. Soluble CD14 plasma levels were significantly higher in patients with inactive Crohn's disease compared to the same genotype of healthy controls, but there was no significant difference between the genotypes CC, CT, and TT. CONCLUSIONS: Our data show that the membrane-bound CD14 monocyte expression and the soluble CD14 plasma levels in patients with inactive Crohn's disease completely differ from that in healthy individuals. In order to develop individualized therapy strategies further studies should be carried out to evaluate whether the TT genotype is associated with differences in the clinical course of Crohn's disease and in the response to antibacterial treatment.     

Common polymorphism in the promoter of the CD14 monocyte receptor gene is associated with acute myocardial infarction in Japanese men

We investigated whether C(-260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene predisposed to coronary atherosclerosis and acute myocardial infarction (AMI) in Japanese men. The frequencies of T allele and T/T homozygotes in patients with AMI were significantly higher than in controls and in patients with angina without prior AMI, suggesting that the CD14 promoter polymorphism is associated with AMI rather than with coronary atherosclerosis, and this polymorphism may be one of the genetic risk factors for AMI in Japanese men.     

Genetic polymorphism in CD14 gene,a co-receptor of TLR4 associated with non-alcoholic fatty liver disease

AIM To evaluate the pathogenic role of toll-like receptor(TLR) gene polymorphisms in patients with nonalcoholic fatty liver disease(NAFLD).METHODS Two hundred and fifty subjects(NAFLD = 200, healthy volunteers = 50) underwent polymerase chain reaction and restriction fragment length polymorphism to assess one polymorphism in the toll-like receptor 2(TLR2) gene(A753G), two polymorphisms in the TLR4 gene(TLR4 Asp299 Gly and Thr399 Ile allele), and two polymorphisms in the cluster of differentiation 14(CD14)(C-159 T and C-550T) gene, a co-receptor of TLR4. Association of TLR gene polymorphisms with NAFLD and its severity was evaluated by genetic models of association.RESULTS On both multiplicative and recessive models of gene polymorphism association, there was significant association of CD14 C(-159) T polymorphism with NAFLD; patients with TT genotype had a 2.6 fold increased risk of developing NAFLD in comparison to CC genotype. There was no association of TLR2 Arg753 Gln, TLR4 Asp299 Gly, Thr399 Ile, and CD14 C(-550) T polymorphisms with NAFLD. None of the TLR gene polymorphisms had an association with histological severity of NAFLD.CONCLUSION Patients with CD14 C(-159) T gene polymorphism, a co-receptor of TLR4, have an increased risk of NAFLD development.