中国汉族人群中RELN基因rs7341475位点与精神分裂症的相关性分析

精神分裂症是一种常见的复杂精神疾病.大量的实验证据表明,遗传因素在精神分裂症的发生中起到了重要的作用.截至目前,有报道称至少100个基因与精神分裂症相关,但它们在不同人群中的重复性不好.在这些基因中,RELN在多个人群中都被证实与精神分裂症相关,表明它可能是一个真实的易感基因.目前,在RELN基因上有很多个单核苷酸多态性位点被证实与精神分裂症相关,其中研究最多的是通过全基因组关联分析发现的在RELN基因第四个内含子中的单核苷酸多态性位点rs7341475,它被证明与精神分裂症的发生相关.为了验证该位点在中国人群中是否与精神分裂症相关,作者对来自中国玉溪的病例——对照样本(400位患者和400位正常人)进行了遗传分析.结果显示,在该样本中rs7341475与精神分裂症不相关,这表明rs7341475在中国人群中可能不是致病多态性位点.     

Genetic variants in the RELN gene are associated with otosclerosis in multiple European populations

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian–Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.     

The common SNP (rs9939609) in the FTO gene modifies the association between obesity and high blood pressure in Chinese children

Previous studies have suggested that common variants in fat mass- and obesity-associated (FTO) gene are associated with body mass index (BMI) and the risk of obesity. Since obesity plays an important role in the etiology of high blood pressure (HBP), we aim to investigate the association between obesity and HBP in a population with different variants of the FTO gene. A total of 3,494 children (1,775 boys, 50.8 %) aged 6–18 years were recruited for measuring pubertal status, BMI and systolic and diastolic blood pressure. The single nucleotide polymorphism rs9939609 of the FTO gene was genotyped. The blood pressure levels increased by 1.4, 1.5 and 1.8 mmHg for systolic blood pressure and 0.8, 0.9 and 1.2 mmHg for diastolic blood pressure per 1-unit BMI increase in subjects carrying TT, TA and AA genotypes, respectively. After stratifying for FTO rs9939609 genotypes (TT, TA and AA), the odds ratios (95 % confidence intervals) of HBP in obese versus non-obese children were 4.26 (3.18–5.71), 5.13 (2.96–8.90) and 10.37 (1.59–67.43), respectively, with adjustment for age, gender and pubertal status. The FTO rs9939609 SNP modifies the effect of obesity on HBP in Chinese children, with obese ones carrying the AA homozygous genotype of the FTO rs9939609 having the highest risk of developing HBP.     

Lack of association between the rs2294008 polymorphism in the prostate stem cell antigen gene and colorectal neoplasia: a case-control and immunohistochemical study

ABSTRACT: BACKGROUND: Prostate stem cell antigen (PSCA) has been implicated in the pathogenesis of several solid tumours, either due to changes in protein expression, or through association with the rs2294008 polymorphism in the PSCA gene. To our knowledge, the role of PSCA in the development of colorectal neoplasia has not been explored. We performed a genotyping study to assess for associations between the rs2294008 polymorphism and risk of adenomatous polyps and colorectal cancer. DNA samples were available from 388 individuals with colorectal neoplasia and 496 controls, all of whom had undergone screening colonoscopy. In addition, we performed immunohistochemical staining for PSCA in colonic tissue representing all stages of the adenoma-carcinoma sequence. RESULTS: No genotypic associations were found between the rs2294008 polymorphism and the risk of colorectal adenomata or cancer. Immunohistochemical staining did not reveal any alteration in PSCA expression accompanying the adenoma-carcinoma sequence. CONCLUSION: From these data it seems unlikely that PSCA has a role in the initiation or progression of colorectal neoplasia.     

Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population

Atrial fibrillation (AF) is the most common cardiac rhythm disorder at the clinical setting and accounts for up to 15% of all strokes. Recent genome-wide association studies (GWAS) identified two single nucleotide polymorphisms (SNPs), rs2106261 and rs7193343 in ZFHX3 (zinc finger homeobox 3 gene) and rs13376333 in KCNN3 (encoding a potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3) that showed significant association with AF in multiple populations of European ancestry. Here, we studied a Chinese Han, GeneID cohort consisting of 650 AF patients and 1,447 non-AF controls to test whether the GWAS findings on ZFHX3/KCNN3 and AF can be expanded to a different ethnic population. No significant association was detected for rs7193343 in ZFHX3 and rs13376333 in KCNN3. However, significant association was identified between rs2106261 in ZFHX3 and AF in the GeneID population for both allelic frequencies (P=0.001 after adjusting for covariates of age, gender, hypertension, coronary artery disease, and diabetes mellitus; OR=1.32), and genotypic frequencies assuming either an additive or recessive model (OR=1.29, P=0.001 and OR=1.77, P =0.00018, respectively). When only lone AF cases were analyzed, the association remained significant (OR=1.50, P=0.001 for allelic association; OR=1.45, P=0.001 for an additive model; OR=2.24, P=0.000043 for a recessive model). Our results indicate that rs2106261 in ZFHX3 confers a significant risk of AF in a Chinese Han population. The study expands the association between ZFHX3 and AF to a non-European ancestry population and provides the first evidence of a cross-race susceptibility of the 16q22 AF locus.     

Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case–control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel–Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR = 1.212 for T allele, 95% CI = 1.097–1.340, p-value = 0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR = 1.187 for T allele, 95% CI = 1.058–1.332, p-value = 0.004) and Asian samples (allelic model, pooled OR = 1.293 for T allele, 95% CI = 1.058–1.580, p-value = 0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value = 0.0149) and CHB (Chinese, p-value = 0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD.     

Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance

Glucocorticoid resistance due to mutations in the gene for the glucocorticoid receptor has been suggested to be more common than is thought at present, owing to the relative mildness of its symptoms and the difficulty of its diagnosis. To investigate the prevalence of mutations in the glucocorticoid receptor gene responsible for relative insensitivity to glucocorticoids, we carried out polymerase chain reaction/single-strand conformation analysis of the glucocorticoid receptor gene in a group of 20, otherwise healthy, persons with a reduced response in a dexamethasone suppression test and in 20 controls. We did not find mutations or polymorphisms associated with a reduced sensitivity to glucocorticoids. However, we identified five novel polymorphisms in the gene for the human glucocorticoid receptor, which may be useful in analyzing whether loss of (part of) the glucocorticoid receptor gene plays a role in glucocorticoid-resistant malignancies. Although relative resistance to glucocorticoids seems to be rather frequent in otherwise healthy persons, it is not usually associated with mutations or polymorphisms in the glucocorticoid receptor gene. Received: 17 July 1996 / Revised: 26 November 1996     

Lack of association between TLR4 rs4986790 polymorphism and risk of cardiovascular disease in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Toll-like receptor-4 (TLR4) activates the innate immune response via NF-kB pathway and mitogen-activated protein kinase signaling, leading to expression of proinflammatory cytokines and chemokines. The G allele of TLR4 rs4986790 (+896A>G, Asp299Gly) gene polymorphism has been implicated in reduction of risk of atherosclerosis. In this study, 1481 RA patients fulfilling the 1987 American College of Rheumatology (ACR) criteria were genotyped for the rs4986790 TLR4 variant to determine the influence of this variant in the risk of CV events in these patients. Also, HLA-DRB1 status was determined using molecular based methods. Moreover, potential influence of rs4986790 variant in the development of subclinical atherosclerosis was assessed in a subgroup of RA patients with no history of CV events by the measurement of surrogate markers of subclinical atherosclerosis. No statistically significant differences in allele or genotype frequencies for the rs4986790 variant between RA patients who experienced CV events or not were found. Likewise, no significant association between this gene variant and any of the surrogate markers of subclinical atherosclerosis was found. In summary, results in our study do not support the hypothesis that the rs4986790 (+896A>G, Asp299Gly) TLR4 variant may influence predisposition for subclinical atherosclerosis and clinically evident CV disease in RA patients.     

Lack of association between the Val158Met catechol-O-methyltransferase gene polymorphism and methamphetamine dependence

OBJECTIVES: About 25,000 serious methamphetamine abusers live in the Czech Republic among the total population of 10 million. Dependence on methamphetamine is markedly related to the brain neurotransmitter dopamine, metabolised by catechol-O-methyltransferase enzyme. The main aim of the study was to ascertain whether the Val158Met catechol-O-methyltransferase gene polymorphism is associated with methamphetamine dependence in this Central European country. Methods: One hundred and twenty-three subjects dependent on methamphetamine (women N=44), parents of sixty-seven dependent individuals, and four hundred healthy controls (women N=250) were involved into the study. We performed a population-based as well as family-based genetic association studies. Results: We did not find any significant association between the Val158Met catechol-O-methyltransferase gene polymorphism and methamphetamine dependence using the population-based or family-based design (p=0.41-0.66; Chi-Square Test or UNPHASED program, Version 3.1.4, respectively). We found a trend toward a statistically significant difference between the Val allele carriers and Met/Met homozygotes in the frequence of psychotic symptoms induced by methamphetamine (more frequent in Val carriers; p=0.062; Chi-Square Test). Conclusion: Further research involving haplotype analysis and other dopamine-related genetic polymorphisms in large populations is needed. More attention should also be paid to possible role of the Val158Met catechol-O-methyl-transferase gene polymorphism in individual clinical subtypes of dependence on methamphetamine involving e.g. psychotic features or violence.     

Lack of association between orexin receptor gene polymorphisms and obstructive sleep apnea syndrome in Japanese

Sleep and Biological Rhythms - The pathogenesis of obstructive sleep apnea (OSA) is not fully understood, particularly at the genetic level. The orexins have pleiotropic effects on several aspects...     

The effects of FTO gene rs9939609 polymorphism on the association between breast cancer and dietary intake

Breast cancer (BC) is the leading cause of cancer‐related deaths in females worldwide and is related to genetic and environmental factors. Dietary components may strongly influence the risk of BC. A possible association was also reported between the fat mass and obesity‐associated (FTO) single‐nucleotide polymorphisms (SNPs) and BC. This study aimed to investigate the impact of FTO rs9939609 polymorphism on the association between BC and dietary intake. This study was conducted on 180 women with BC as the case group and 360 healthy women as the control group. The dietary intakes were assessed by a valid 168‐item food frequency questionnaire (FFQ). The FTO gene was genotyped for rs9939609 polymorphism. After adjusting the confounding variables, there was no significant association between dietary intake and BC in individuals without risk allele. A positive association between dietary intake of omega‐6 fatty acids and BC was found only in individuals with risk allele of FTO gene (OR: 1.31, 95% CI: 1.08–1.60, p: 0.006). FTO gene risk allele may influence the effect of diet on breast cancer risk. Further studies are needed to assess the possible effects of the FTO genotype on the association between BC risk and dietary components.     

Molecular cloning and SNP association analysis of chicken PMCH gene

The pre-melanin-concentrating hormone (PMCH) gene is an important gene functionally concerning the regulations of body fat content, feeding behavior and energy balance. In this study, the full-length cDNA of chicken PMCH gene was amplified by SMART RACE method. The single nucleotide polymorphisms (SNPs) in the PMCH gene were screened by comparative sequence analysis. The obtained non-synonymous coding SNPs (ncSNPs) were designed for genotyping firstly. Its effects on growth, carcass characteristics and meat quality traits were investigated employing the F₂ resource population of Gushi chicken crossed with Anak broiler by AluI CRS-PCR–RFLP. Our results indicated that the cDNA of chicken PMCH shared 67.25 and 66.47 % homology with that of human and bovine PMCH, respectively. The deduced amino acid sequence of chicken PMCH (163 amino acids) were 52.07 and 50.89 % identical to those of human and bovine PMCH, respectively. The PMCH protein sequence is predicted to have several functional domains, including pro-MCH, CSP, IL7, XPGI and some low complexity sequence. It has 8 phosphorylation sites and no signal peptide sequence. gga-miR-18a, gga-miR-18b, gga-miR-499 microRNA targeting site was predicted in the 3′ untranslated region of chicken PMCH mRNA. In addition, a total of seven SNPs including an ncSNP and a synonymous coding SNP, were identified in the PMCH gene. The ncSNP c.81 A > T was found to be in moderate polymorphic state (polymorphic index = 0.365), and the frequencies for genotype AA, AB and BB were 0.3648, 0.4682 and 0.1670, respectively. Significant associations between the locus and shear force of breast and leg were observed. This polymorphic site may serve as a useful target for the marker assisted selection of the growth and meat quality traits in chicken.     

A new single-nucleotide mutation (rs362719) of the reelin (RELN) gene associated with schizophrenia in female Chinese Han

Reelin is an extracellular signaling protein that plays an important role in the development of the central nervous system. Post-mortem studies have shown lower reelin protein levels in the brains of patients with schizophrenia and bipolar disorder compared with controls. Genetic studies have also shown that mutations in the reelin gene (RELN) increase the risk for schizophrenia and bipolar disorder. We evaluated whether an RELN gene variant, rs362719, which has been associated with increased susceptibility to bipolar disorder, is also associated with susceptibility to schizophrenia. We included 405 Chinese Han schizophrenia patients and 390 controls in our study. The polymorphism was genotyped by PCR and RFLP methods. We found a significant difference in allele frequency distribution (P< 0.05) between schizophrenia patients and controls. The frequency of the A allele was significantly higher in schizophrenia patients than in healthy controls. The effect of SNP rs362719 on allele distribution was significant in female (P < 0.05) but not in male participants (P = 0.473). Besides the gender factor, demographic and clinical characteristics of the rs362719 genotype groups were also analyzed using the chi-square test, but no significant differences were found. We conclude that rs362719 of the RELN gene is associated with susceptibility to schizophrenia in Chinese Han, possibly through a gender-specific mechanism. Further studies will be needed to confirm this genetic risk factor for schizophrenia.