与宁夏人群强直性脊柱炎关联的新基因淋巴毒素-α(LTA)的识别

淋巴毒素-α(Lymphotoxin-alpha,LTA)基因与系统性红斑狼疮、银屑病及类风湿性关节炎的遗传性有关,但目前还未有关于LTA基因与强直性脊柱炎(Ankylosing spondylitis,AS)关联的报道。文章采用病例-对照设计,在宁夏人群中对人类白细胞抗原(Human leukocyte antigen,HLA)的Ⅲ类基因约58 kb区域进行了高密度标志的基因组扫描,在33个SNPs及其单倍型中,仅定位于LTA基因中的SNPs组成的TCC单倍型的分布在病例-对照间比较有统计学意义(P=0.0005)。在宁夏群体(病例组:300,对照组:385)中发现,LTA基因中的rs909253 T/C多态性在AS患者中出现的频率显著高于正常对照(28.5%vs 19.7%,P=2×10-6)。结果表明LTA基因变异和AS易感性之间存在相关性,由此识别LTA基因可能与宁夏人群AS关联。     

Interleukin 17A rs3819024 A>G polymorphism is associated with an increased risk of gastric cardia adenocarcinoma in a Chinese population

Abstract

Gastric cardia adenocarcinoma (GCA) is one of the most common malignant tumors. In addition to environmental risk factors, genetic factors might play an important role in GCA carcinogenesis. To evaluate the association between polymorphisms in the interleukin 17A (IL17A) gene on the development of GCA, we conducted a hospital-based case–control study. A total of 243 GCA cases and 476 controls were recruited and their genotypes were determined using a custom-by-design 48-Plex SNPscan? Kit. IL17A rs3819024 A?>?G polymorphism was found to be associated with the increased risk of GCA. When the IL17A rs3819024 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk of GCA (AG versus AA: adjusted OR?=?1.53, 95% CI?=?1.05–2.23, p?=?0.026). However, there was no significant association between five other SNPs and GCA. Stratified analyses indicated that a significantly increased risk of GCA associated with the IL17A rs3819024 A?>?G polymorphism was evident among male patients, patients who drank alcohol or those who never smoked. These findings indicated that functional polymorphism IL17A rs3819024 A?>?G might contribute to GCA susceptibility. Future larger studies with more rigorous study designs are required to confirm the current findings.     

A functional polymorphism in miRNA-196a2 is associated with colorectal cancer risk in a Chinese population

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC.     

The rs9939609 polymorphism in the fat mass and obesity associated (FTO) gene is associated with obesity in Tunisian population

Abstract

Context: Variations in the fat mass and obesity-associated gene (FTO) has been associated with obesity in many populations, but the results are conflicting.

Objective: The aim of this study was to evaluate the effect of the rs9939609 polymorphism in the FTO gene on obesity risk and plasma leptin, adiponectin, insulin and lipid concentrations in Tunisians.

Materials and methods: Four hundred and ninety-four subjects with obesity and 334 non-obese participated in this study. The rs9939609 (T/A) genotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results: Significant differences in genotype frequencies were observed between cases and controls. In the separate analysis by gender, the association between the AA genotype and obesity was statistically significant in women but not in men. After stratification by obesity class this association remains only with obesity class III.

Discussion: Our study is in agreement with studies on Caucasian, Portuguese and Cebu Filipino populations where a gender-specific association was found between rs9939609 polymorphism and obesity. It is also in agreement with studies on Mexican, Spanish and European populations, where an association was found with obesity class III.

Conclusion: The rs9939609 polymorphism of FTO gene is associated with obesity, especially obesity class III in women.     

A LncRNA gene polymorphism (rs1814343) is associated with the risk of coronary artery lesions in southern Chinese Kawasaki disease patients

Background

Kawasaki disease (KD) is a multisystemic angiitis, and its most disastrous complication is coronary artery lesions (CALs). Recently, the role of long non-coding RNAs (lncRNAs) in KD has been reported. rs1814343 is a lncRNA, but the relationship between the lncRNA rs1814343 polymorphism and KD risk remains elusive.

Methods

We enrolled 1625 Kawasaki disease patients (583 patients with CAL and 1042 without CAL) and 1000 healthy controls from a southern Chinese population. We genotyped the rs1814343 C > T polymorphism in KD and control patients using the TaqMan method. The odds ratio (OR) and 95% confidence interval (CI) were used to estimate the strength of the association.

Results

There was no significant association between the lncRNA rs1814343 C > T polymorphism and KD susceptibility. However, we stratified patients in this study by CAL and sex. First, compared with the control groups, we found that the rs1814343 genotype increased risk for KD patients with CAL (TT vs. CC + CT: OR = 1.36, 95% CI = 1.08–1.71, p = 0.009). Moreover, when KD patients were stratified by CAL, the TT genotypes of this lncRNA polymorphism contributed to a relatively higher occurrence of KD with CAL than that was found in the CC/CT genotype patients (TT vs. CC + CT: OR = 1.35, 95% CI = 1.07–1.69, p = 0.011). In addition, our research suggested that the TT variant genotype in the lncRNA rs1814343 had an obvious risk of KD with CAL susceptibility in male children.

Conclusion

The lncRNA rs1814343 C > T polymorphism was related to higher susceptibility of KD with CAL.     

The Per2 polymorphism rs10462023 is associated with the risk of stroke in a Chinese population

The key clock protein Period2 (Per2) has been suggested to play an essential role in regulating endothelial function. It also regulates the expression of plasminogen activator inhibitor-1, but its role in stroke development has not been studied. To explore the possible association between Per2 and ischemic stroke (IS), 479 Chinese IS patients and 306 healthy controls were recruited, and five tag single nucleotide polymorphisms representing the Per2 locus were genotyped using the Sequenom MassARRAY system. A significant difference was observed in the genotypic distribution (p = 0.014) and allele frequency (p = 0.005) of rs10462023, with carriers of the G allele being more prone to developing IS. After adjusting for possible risk factors including smoking, alcohol use, and history of hypertension and diabetes, a significant association was still apparent. Haplotype analysis also supported the association between Per2 and IS. This study suggests that Per2 variations are associated with IS and may represent genetic risk factors for IS in a Chinese population.     

Caspase8 rs1035142 G>T polymorphism was associated with an increased risk of esophageal cancer in a Chinese population

Esophageal cancer is one of the ten most common cancers in the world and has poor prognosis. Apoptosis is considered a fundamental component in cancer pathogenesis. We conducted a hospital-based case–control study to evaluate the genetic effects of 16 apoptosis associated single nucleotide polymorphisms (SNPs) on esophageal cancer development. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. Genotypes were determined using a custom-by-design 48-Plex SNPscan? Kit. The caspase8 (CASP8) rs1035142 G>T polymorphism was associated with increased risk of ESCC by heterozygote comparison, homozygote comparison, a dominant genetic model and a recessive genetic model. However, no significant association was detected between the other 15 SNPs and ESCC risk. Stratified analyses indicated a significantly increased risk of ESCC associated with CASP8 rs1035142 G>T polymorphism was evident among all subgroups. These findings indicated that the functional polymorphism CASP8 rs1035142 G>T might contribute to ESCC susceptibility.     

Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China

Background/aims

The incidence of urolithiasis has considerably increased throughout the world in the last two decades. Clinical researches have showed an association between oxidative stress and stone formation. Emerging evidence indicated a novel function for klotho protein in anti-oxidative stress. In this study, we aimed at investigating a possible relationship between klotho gene polymorphisms and the risk of calcium oxalate urolithiasis in the population of Han nationality in Eastern China.

Methods

Klotho gene polymorphisms rs3752472 in exon3, rs650439 in intron 4 and rs577912 in intron 1 were investigated in 426 patients with calcium oxalate stones compared with 282 age-matched healthy volunteers with no history of stone formation, using TaqMan SNP Genotyping Assays.

Results

Significant differences were found between rs3752472 and the risk of nephrolithiasis as CC genotype of rs3752472 klotho polymorphism had almost 2-fold increased stone risk compared with the heterozygote genotype CT and homozygous genotype TT(95% CI = 1.013–2.255, OR = 1.512,p = 0.043).

Conclusion

Our results showed that the rs3752472 polymorphism of klotho gene is associated with the risk of calcium oxalate urolithiasis and may act as a risk factor during stone formation in our study population.     

A genetic polymorphism (rs17251221) in the calcium-sensing receptor gene (CASR) is associated with stone multiplicity in calcium nephrolithiasis

Calcium nephrolithiasis is one of the most common causes of renal stones. While the prevalence of this disease has increased steadily over the last 3 decades, its pathogenesis is still unclear. Previous studies have indicated that a genetic polymorphism (rs17251221) in the calcium-sensing receptor gene (CASR) is associated with the total serum calcium levels. In this study, we collected DNA samples from 480 Taiwanese subjects (189 calcium nephrolithiasis patients and 291 controls) for genotyping the CASR gene. Our results indicated no significant association between the CASR polymorphism (rs17251221) and the susceptibility of calcium nephrolithiasis. However, we found a significant association between rs17251221 and stone multiplicity. The risk of stone multiplicity was higher in patients with the GG+GA genotype than in those with the AA genotype (chi-square test:P = 0.008;odds ratio  =  4.79;95% confidence interval, 1.44–15.92;Yates'' correction for chi-square test:P = 0.013). In conclusion, our results provide evidence supporting the genetic effects of CASR on the pathogenesis of calcium nephrolithiasis.     

CDH1 -160C>A gene polymorphism is an ethnicity-dependent risk factor for gastric cancer

The associations between E-cadherin (CDH1) gene polymorphisms and gastric cancer (GC) susceptibility are still controversial. Given this uncertainty, we carried out a meta-analysis of published case-control studies to derive more precise estimations of these relationships. Relevant studies were identified from PubMed and EMBASE up to March 2011. Seventeen studies with 3511 GC cases and 4826 controls were selected. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to investigate the strength of the associations. No associations between CDH1 (+54T>C, -160C>A, -347G>GA, -616G>C, -2076C>T and -3159T>C) gene polymorphisms and GC risk for all genetic models were found. As for CDH1 -160C>A polymorphism, subgroup analyses by country, gender, study design, smoking status, Helicobacter pylori infection, and the Lauren classification of GC did not change the results. When stratified by ethnicity, we found the A allele carriers had a significantly increased risk of GC among Caucasians (AA vs. CA+CC: OR=1.50, 95% CI=1.03-2.19, P=0.03), but not among Asians (AA vs. CA+CC: OR=0.87, 95% CI=0.56-1.37, P=0.56). No publication bias was found in the present study. This meta-analysis suggests that CDH1 -160C>A gene polymorphism may contribute to increased risk of GC among Caucasians.     

The HHEX rs1111875A/G gene polymorphism is associated with susceptibility to type 2 diabetes in the iranian population

The illuminating picture of genetic mechanisms underlying the development of type 2 diabetes (T2DM) includes differently accumulated genetic polymorphisms that increase the risk along with environmental factors. A number of single nucleotide polymorphisms (SNPs) are indicated to be linked with T2DM, but also conflicting results have been found. To examine the contribution of these polymorphisms in conferring susceptibility to T2DM, the association of HHEX rs1111875A/G and CDKN2A/B rs10811661C/T common gene polymorphisms with the risk of T2DM in an Iranian population was evaluated. In this study participated 140 patients and 140 controls. Genomic DNA was extracted from samples and genotyping of the polymorphisms was performed by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique. A significant association was found with the G allele (OR = 1.729, CI = 1.184–2.523, P = 0.004) and GG genotype (OR = 2.921, 95% CI = 1.789–4.771, P< 0.001) of the rs1111875A/G SNP for susceptibility to T2DM in the recessive model. Furthermore, compared with the GG genotype, individuals with the GA genotype had a lower risk to develop T2DM (OR = 0.237, 95% CI = 0.137–0.408, P< 0.001) in the additive model. In addition, an association between the polymorphism and BMI in regard to the risk of T2DM was identified. The genotype and allele frequencies of the rs10811661C/T polymorphism did not show a statistically significant association with T2DM in any genetic model. Our results show that the rs1111875A/G polymorphism is an important susceptibility polymorphism for the development of T2DM in the Iranian population. Also, these findings support that this polymorphism is a key genetic risk factor for the development of T2DM in multiple ethnic populations.

     

A genetic variant in 3'-untranslated region of cyclooxygenases-2 gene is associated with risk of gastric cancer in a Chinese population

Cyclooxygenase-2 (COX-2) involves in multiple processes in carcinogenesis, including inflammation, apoptosis inhibition, immune response suppression, tumor cell invasion, and angiogenesis. COX-2 is overexpressed in various cancers, including gastric cancer. COX-2 is encoded by prostaglandin endoperoxide synthase 2 (PTGS2) gene. We hypothesized that potentially functional polymorphisms in PTGS2 may contribute to gastric cancer risk. To assess this hypothesis, we conducted a case-control study with 1681 gastric cancer cases and 1916 control subjects in a Chinese population to evaluate the association between a polymorphism in 3'-untranslated region of PTGS2, rs5275, and the risk of gastric cancer. Logistic regression analysis revealed that variant allele (C) of rs5275 was significantly associated with an increased risk of gastric cancer (per allele odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.01-1.29, p = 0.030). This association was more prominent in females (per allele OR = 1.42, 95% CI = 1.11-1.81, p = 0.005) and nonsmokers (per allele OR = 1.35, 95% CI = 1.14-1.59, p = 0.001). Interestingly, we detected a negative interaction between rs5275 and smoking on the gastric cancer risk (p = 0.007). Our findings indicate that PTGS2 rs5275T/C may be a candidate genetic marker for gastric cancer susceptibility.     

PTPN22 gene functional polymorphism (rs2476601) in older adults with frailty syndrome

The frailty syndrome is a common clinical marker of vulnerability in older adults conducive to an overall decline in inflammatory stress responsiveness; yet little is known about the genetic risk factors for frailty in elderly. Our aim was to investigate the association between the rs2476601 polymorphism in PTPN22 gene and susceptibility to frailty in Mexican older adults. Data included 630 subjects 70 and older from The Coyoacán cohort, classified as frail, pre-frail, and non-frail following Fried’s criteria. Sociodemographic and clinical characteristics were compared between groups at baseline and after a multivariate analysis. The rs2476601 polymorphism was genotyped by TaqMan genotyping assay using real-time PCR and genotype frequencies were determined for each frailty phenotype in all participants and subsets by age range. Genetic association was examined using stratified and interaction analyses adjusting for age, sex and variables selected in the multivariate analysis. Disability for day-life activities, depression and cognitive impairment were associated with the risk of pre-frailty and frailty at baseline and after adjustment. Carrying the T allele increased significantly the risk of frailty in patients 76 and older (OR 5.64, 95% CI 4.112–7.165) and decreased the risk of pre-frailty under no clinical signs of depression (OR 0.53; 95% CI 0.17–1.71). The PTPN22 polymorphism, rs2476601, could be a genetic risk factor for frailty as subject to quality of life. This is the first study analyzing such relationship in Mexican older adults. Confirming these findings requires additional association studies on wider age ranges in populations of older adults with frailty syndrome.

     

G-308A TNF-alpha polymorphism is associated with an increased risk of invasive cervical cancer

Cervical cancer is initiated by high-risk human papillomaviruses (HPV-16 and HPV-18), but an effective immune response may control the progression of this disease. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine, that has been implicated in several cancers. In a case-control study, we evaluated the association between the G-308A TNF-alpha promoter polymorphism and the risk for invasive cervical cancer (ICC). TNF-alpha polymorphism was analyzed by PCR-RFLP and confirmed by sequencing. DNA was obtained from blood samples of 439 individuals, including 195 patients with ICC and 244 normal healthy controls. According to our results, women carrying the A allele present a twofold increased risk of developing ICC (p=0.006; OR=1.88; 95% CI [1.20-2.94]). In conclusion, our study suggests that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of ICC.