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Control Association Study (control + association_study)
Selected AbstractsAssociation of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ,pleasurable buzz' during early experimentation with smokingADDICTION, Issue 9 2008Richard Sherva ABSTRACT Aims To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. Design, setting, participants Case,control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). Measurements Cases had smoked , five cigarettes/day for , 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. Findings A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). Conclusions We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence. [source] RhoA, encoding a Rho GTPase, is associated with smoking initiationGENES, BRAIN AND BEHAVIOR, Issue 8 2007X. Chen We used microarray analysis of acute nicotine responses in mouse brain to choose rationale candidates for human association studies on tobacco smoking and nicotine dependence (ND). Microarray studies on the time,course of acute response to nicotine in mouse brain identified 95 genes regulated in ventral tegmental area. Among these, 30 genes were part of a gene network, with functions relevant to neural plasticity. On this basis and their known roles in drug abuse or synaptic plasticity, we chose the genes RhoA and Ywhag as candidates for human association studies. A synteny search identified human orthologs and we investigated their role in tobacco smoking and ND in a human case,control association study. We genotyped five and three single nucleotide polymorphisms from the RhoA and Ywhag genes, respectively. Both single marker and haplotype analyses were negative for the Ywhag gene. For the RhoA gene, rs2878298 showed highly significant genotypic association with both smoking initiation (SI) and ND (P = 0.00005 for SI and P = 0.0007 for ND). In the allelic analyses, rs2878298 was only significant for SI. In the multimarker haplotype analyses, significant association with SI was found for the RhoA gene (empirical global P values ranged from 9 × 10,5 to 10,5). In all multimarker combinations analyzed, with or without inclusion of the single most significant marker rs2878298, identical risk and protective haplotypes were identified. Our results indicated that the RhoA gene is likely involved in initiation of tobacco smoking and ND. Replication and future model system studies will be needed to validate the role of RhoA gene in SI and ND. [source] Case,control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD),HUMAN MUTATION, Issue 4 2007Sheila A. Fisher Abstract This article reports a well-powered age-related macular degeneration (AMD) case,control association study in the HMCN1 gene, showing that common variants do not account for a substantial proportion of AMD cases. Thus, the consistent linkage peak observed by several genome-wide linkage scans within the 1q32 region is unlikely to be attributed to polymorphisms at the HMCN1 locus. In addition, the analysis provides comprehensive data suggesting that low-frequency variants encoding possible functional amino acid polymorphisms in the HMCN1 gene may not contribute substantially to disease, although HMCN1 mutations may still confer disease susceptibility in a small subset of patients. Interestingly, the HMCN1 p.Gln5346Arg mutation, which is thought to be a causal mutation in a large AMD pedigree segregating the disease as a single-gene trait, appears to occur in our control cohort as a low-frequency polymorphism with an allele frequency of approximately 0.0026. Hum Mutat 28(4), 406,413, 2007. © 2007 Wiley-Liss, Inc. [source] Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese populationINTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2007Wataru Obara Aim: Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D3 (1,25(OH)2D3) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)2D3 and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population. Methods: To analyze risk of RCC depending on VDR polymorphism, a case,control association study was performed. The VDR gene polymorphisms at three locations, BsmI, ApaI and TaqI, were genotyped in 135 RCC patients and 150 controls in a Japanese population. Logistic regression models were used to assess the genetic effects on prognosis. Results: Significant differences in the ApaI genotype were observed between RCC patients and controls (,2 = 6.90, P = 0.032). No statistical significant difference was found in the BsmI and TaqI polymorphisms. The frequency of the AA genotype in the ApaI polymorphism was significantly higher in the RCC patients than in the controls (odds ratio, 2.59; 95% confidence intervals, 1.21,5.55; P = 0.012). Multivariate regression analysis showed that the AA genotype was an independent prognostic factor for cause-specific survival (relative risk 3.3; P = 0.038). Conclusion: The AA genotype at the ApaI site of the VDR gene may be a risk of incidence and poor prognosis factor for RCC in the Japanese population. Additional studies with a large sample size and investigation of the functional significance of the ApaI polymorphism in RCC cells are warranted. [source] Association between interleukin-6 promoter haplotypes and aggressive periodontitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 3 2008Luigi Nibali Abstract Background: Interleukin-6 (IL-6) polymorphisms have been shown to affect IL-6 promoter activity. This study investigated the possible role of IL-6 genetic polymorphisms and haplotypes in the predisposition to aggressive periodontitis (AgP). Material and Methods: A case,control association study on 224 AgP patients and 231 healthy controls was performed in order to detect differences in genotype distributions of five single nucleotide polymorphisms (SNPs) located in the promoter region of the IL-6 gene. Results: The IL-6 ,1363 polymorphism was associated with a diagnosis of AgP in subjects of all ethnicities (p=0.006, adjusted logistic regression). The ,1480 SNP was associated with LAgP in subjects of all ethnicities (p=0.003). The ,1480 and ,6106 polymorphisms were associated with Localized AgP in Caucasians (n=24) (p=0.007 and 0.010, respectively). Haplotypes determined by the ,1363 and ,1480 polymorphisms were also associated with LAgP (p=0.001) in Caucasians. Conclusions: This study supports the hypothesis of a link between IL-6 genetic factors and AgP and highlights the importance of two IL-6 polymorphisms (,1363 and ,1480) in modulating disease phenotype and susceptibility. [source] Systematic search for mutations in the human tissue inhibitor of metalloproteinases-3 (TIMP-3) gene on chromosome 22 and association study with schizophreniaAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2001Chao-Chun Hung Abstract Several linkage studies have suggested that chromosome 22q12,q13 is a putative region for schizophrenic genes. In this study, the human tissue inhibitor of metalloproteinase-3 (TIMP-3) gene was investigated as positional candidate gene for schizophrenia because of its regulatory function on extracellular matrix proteins, cell adhesion molecules, and neural cell adhesion molecules in the brain. We systematically searched for the nucleotide variants by sequencing all the exons and their flanking intronic sequences in a sample of Chinese schizophrenic patients from Taiwan. Two silent mutations in the exon 3 were identified: c.249T,C at codon 83 (His) and c.261C,T at codon 87 (Ser). However, no mutations causing amino acid alteration or aberrant splicing of transcripts were observed. Hence, it is unlikely that the TIMP-3 gene itself may play an important role in the genetic susceptibility to schizophrenia. Further case control association study revealed a significant difference of genotype distribution of the c.249T,C between schizophrenic patients and control. This finding supports that 22q12 is a schizophrenia susceptible region, and it is likely that there might be other genetic mutations in the neighborhood of the TIMP-3 gene locus that may contribute to the susceptibility of schizophrenia. © 2001 Wiley-Liss, Inc. [source] Association of the FAM167A,BLK region with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 3 2010Ikue Ito Objective An association of single-nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13),BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A,BLK region is also associated with susceptibility to systemic sclerosis (SSc). Methods Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2-tiered case,control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A,BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113. Results Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17,1.79], P = 6.1 × 10,4). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc. Conclusion Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A,BLK region is a common genetic risk factor for both SLE and SSc. [source] Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese populationARTHRITIS & RHEUMATISM, Issue 6 2009Ikue Ito Objective Interferon regulatory factor 5, an established susceptibility factor for systemic lupus erythematosus (SLE), plays a role in type I interferon and proinflammatory cytokine induction. A recent study showed association of a functional single-nucleotide polymorphism (SNP) in intron 1 of IRF5, rs2004640, with systemic sclerosis (SSc) in a European French population. We undertook the present study to determine whether IRF5 polymorphisms are also associated with a predisposition to SSc in Japanese. Methods A case,control association study was performed for rs2004640 as well as for rs10954213 and rs2280714, all of which were previously reported to be associated with SLE, in 281 SSc patients and 477 healthy controls. Patients with SSc complicated by SLE or Sjögren's syndrome were excluded. Association of the rs2280714 genotype with messenger RNA (mRNA) levels of IRF5 and adjacently located transportin 3 (TNPO3) was examined using the GENEVAR database. Results All 3 SNPs were significantly associated with SSc, with the rs2280714 A allele having the strongest association (allele frequency P = 0.0012, odds ratio 1.42 [95% confidence interval 1.15,1.75]). Association was preferentially observed in subsets of patients with diffuse cutaneous SSc (dcSSc) and anti,topoisomerase I antibody positivity. Conditional analysis revealed that rs2280714 could account for most of the association of these SNPs, while an additional contribution of rs2004640 was also suggested for dcSSc. The genotype of rs2280714 was strongly associated with IRF5 mRNA expression, while only marginal association was detected with TNPO3 mRNA expression. Conclusion Association of IRF5 with SSc was replicated in a Japanese population. Whether the causal SNP is different among populations requires further investigation. [source] Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 3 2009H. M. Albers Objective Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. Methods A case,control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. Results In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55,0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61,1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62,0.93, P = 7.08 × 10,3). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor,negative polyarthritis [P = 0.038]). Conclusion Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA. [source] Replication of the tumor necrosis factor receptor,associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based studyARTHRITIS & RHEUMATISM, Issue 9 2008F. A. S. Kurreeman Objective We recently showed, using a candidate gene approach in a case,control association study, that a 65-kb block encompassing tumor necrosis factor receptor,associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case,control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. Methods A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. Results We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04,1.50). Conclusion Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA. [source] Association of FcGRIIa with Graves' disease: a potential role for dysregulated autoantibody clearance in disease onset/progressionCLINICAL ENDOCRINOLOGY, Issue 1 2010Kadija Yesmin Summary Objective, Although autoantibody production is a key feature of autoimmunity, it is not known whether variation in autoantibody production and clearance pathways is involved in disease susceptibility. The Fc Gamma Receptor IIa (FcGRIIa) molecule is involved in the clearance of autoantibodies and a functional single nucleotide polymorphism (SNP), rs1801274, which has been shown to alter autoantibody clearance, has been associated with a number of autoimmune diseases (AIDs) including systemic lupus erythematosus and type 1 diabetes. This study aimed to determine whether FcGRIIa is associated with Graves' disease (GD) in the UK Caucasian population by Tag SNP screening common polymorphisms within the FcGRIIa region. Design, A case control association study investigating nine Tag SNPs within FcGRIIa, which captured the majority of known common variation within this gene region. Patients, A dataset comprising 2504 UK Caucasian GD patients and 2784 geographically matched controls taken from the 1958 British Birth cohort. Measurements, We used the ,2 -test to investigate association between the Tag SNPs and GD. Results, Association between the rs1801274 (P,= 0·003, OR = 1·12 [95% CI = 1·03,1·22] and rs6427598 (P = 0·012, OR = 0·90 [95% CI = 0·83-0·98]) SNPs and GD was observed. No other SNPs showed association with GD. No associations were seen between any of the SNPs investigated and specific GD clinical phenotypes. Conclusions, This study suggests that variation in FcGRIIa predisposes to GD and further supports the role of FcGRIIa as a susceptibility locus for AIDs in general. [source] | |||||||||||||