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Gene Variants (gene + variants)

Distribution by Scientific Domains
Medical Sciences71%
Life Sciences26%
Distribution within Medical Sciences
Immunology12%
Psychiatry8%
Dermatology4%
20 Other Subdomains68%

Kinds of Gene Variants

  • common gene variants
    		•

    Selected Abstracts

    HYPERTENSION, OBESITY AND GNB3 GENE VARIANTS

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2006
    María E Danoviz
    SUMMARY 1The polymorphism C825T of the gene encoding the G-protein b3-subunit (GNB3) was found to be associated with an increased prevalence of hypertension in a number of studies. The aim of the present study was to investigate the association between this polymorphism and blood pressure phenotypes in an urban, large and ethnically mixed population of Brazil. 2Individuals (n = 1 568) were randomly selected from the general population of the Vitória City metropolitan area. The GNB3 C825T polymorphism was genotyped in each individual. Baseline cardiovascular risk factors were collected for all participants. Cardiovascular risk variables and genotypes were compared using anova and the Chi-squared test for univariate comparisons and logistic regression for multiple comparisons. 3A statistically significant interaction between the 825T allele and obesity was observed for systolic blood pressure (SBP; P = 0.02). In fact, the C825T genotype was predictive of SBP only in individuals with increased body mass index (P = 0.02). In addition, in a multiple logistic regression model conducted in the obese population and adjusted for age, sex, ethnicity, diabetes, triglycerides and total cholesterol, the presence of the T allele was significantly associated with a 1.5-fold (95% confidence interval 1.04,2.26) increased risk of hypertension. Lack of statistical power does not explain the absence of other positive gene,environment interactions. 4The present results suggest that an important gene ¥ environment interaction may take place between bodyweight regulation and the GNB3 gene. This finding provides further evidence for a role of the 825T allele in hypertension susceptibility and may be used for better disease stratification. [source]

    Association of Common CRP Gene Variants with CRP Levels and Cardiovascular Events

    ANNALS OF HUMAN GENETICS, Issue 6 2005
    D. T. Miller
    Summary C-reactive protein (CRP) is a well-documented marker of atherosclerotic cardiovascular disease risk. We resequenced CRP to identify a comprehensive set of common SNP variants, then studied and replicated their association with baseline CRP level among apparently healthy subjects in the Women's Health Study (WHS; n = 717), Pravastatin Inflammation/CRP Evaluation trial (PRINCE; n = 1,110) and Physicians' Health Study (PHS; n = 509) cohorts. The minor alleles of four SNPs were consistently associated in all three cohorts with higher CRP, while the minor alleles of two SNPs were associated with lower CRP (p < 0.05 for each). Single marker and haplotype analysis in all three cohorts were consistent with functional roles for the 5,-flanking triallelic SNP ,286C>T>A and the 3,-UTR SNP 1846G>A. None of the SNPs associated with higher CRP were associated with risk of incident myocardial infarction (MI) or ischemic stroke in a prospective, nested case-control study design from the PHS cohort (610 case-control pairs). One SNP, ,717A>G, was unrelated to CRP levels but associated with decreased risk of MI (p = 0.001). Taken together, these data imply significant interactions between both genetic and environmental contributions to the increased CRP levels that predict a greater risk of future atherothrombotic events in epidemiological studies. [source]

    G Protein ,3 Subunit Gene Variants and Essential Hypertension in the Northern Chinese Han Population

    ANNALS OF HUMAN GENETICS, Issue 4 2005
    Biao Li
    Summary Recently a novel C825T polymorphism in the G protein ,3 subunit gene was identified that showed an association with hypertension in a German population; the results of studies in other populations have been inconsistent. To examine the contribution of GNB3 polymorphisms to the development of hypertension in the northern Chinese Han population, we conducted a case-control study consisting of 501 hypertensive cases and 503 controls using the G(-350)A, C825T and C1429T polymorphisms. Genotypes of samples were determined by PCR and restriction digestion. Single locus analysis showed a significant association between G(-350)A and hypertension (P = 0.01) but no association for C825T or C1429T. The three polymorphisms were in tight linkage disequilibrium (D,=,1 for G(-350)A-C825T, D,= 0.92 for C825T-C1429T) and a total of 7 haplotypes were observed in the entire population. Haplotype A-C-C was found to be significantly related to hypertension (P = 0.032) and A-C-C carriers had a more than two-fold higher risk of hypertension than non-carriers, after adjustment for BMI and glucose. In conclusion, our study suggests that G(-350)A is a potential functional polymorphism that may be related to hypertension, whereas the C825T and C1429T polymorphisms are not associated with hypertension in the northern Chinese Han population. [source]

    Genetic variation in D7S1875 repeat polymorphism of leptin gene is associated with increased risk for depression: a case-control study from India

    DEPRESSION AND ANXIETY, Issue 9 2009
    Manav Kapoor M.Sc.
    Abstract Background: Epidemiologic data suggest an association between obesity and depression, however findings vary considerably across different studies. Both depression and obesity are disabling disorders associated with loss over appetite control, influenced by genetic and environmental factors and are risk factors for diseases like hypertension, cardiovascular disorders, etc. This study attempts to establish a link between the symptoms of depression, metabolic disorders, and obesity, to unravel the underlying association/s. Methods: This exploratory case,control study comprises 133 clinically diagnosed depressed individuals and 136 age matched controls. DNA from all 269 subjects was genotyped for D7S1875 repeat polymorphism in the promoter region of Leptin (LEP) gene using polymerase chain reaction. Results: Frequency of the shorter allele of D7S1875 (<208,bp) was 0.73 in the depressive group versus 0.67 in the control group (P=.01). Cases homozygous for D7S1875,208,bp alleles had significantly higher value of systolic (130 versus 122; P<.009) and diastolic (85.4 versus 81; P=.01) blood pressure (SBP and DBP) than the individuals homozygous for<208,bp allele. A similar trend was observed for SBP (127.8 versus 123.6; P=.03) among controls homozygous for the longer or the shorter allele. Thus, the LEP gene appears to be an important genetic determinant for susceptibility to depression in the Indian population (OR=1.4913, 95% CI=1.0334,2.1522; P=.04). Conclusions: Our findings suggest that LEP gene variants could be related to depression and associated co-morbidities such as hypertension. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [source]

    Genetics of type 2 diabetes mellitus: status and perspectives

    DIABETES OBESITY & METABOLISM, Issue 2 2005
    Lars Hansen
    Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1,6 according to the mutated genes that by being expressed in the pancreatic ,-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected ,candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-, and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects. [source]

    Effect of RBP4 gene variants on circulating RBP4 concentration and Type 2 diabetes in a Chinese population

    DIABETIC MEDICINE, Issue 1 2008
    C. Hu
    Abstract Aims Retinol binding protein 4 (RBP4) is a newly discovered adipokine, which plays a role in insulin resistance and obesity. The aim of this study was to determine the relationship between genetic variants of the RBP4 gene, circulating RBP4 concentrations and phenotypes related to glucose and lipid metabolism in the Chinese population. Methods We sequenced exons and the putative promoter region to identify single nucleotide polymorphisms (SNPs) in the RBP4 gene in 32 Chinese subjects. Additional SNPs were selected from a public database to increase marker density. Taking account of the pairwise linkage disequilibrium and minor allele frequencies, a subset of SNPs was further genotyped in 255 Type 2 diabetic patients and 372 normal control subjects. Circulating RBP4 concentrations and phenotypes related to glucose and lipid metabolism were measured. Results Ten SNPs were identified and five were further genotyped in the full sample. No individual SNP was significantly associated with Type 2 diabetes, but a rare haplotype CAA formed by +5388 C>T, +8201 T>A and +8204 T>A was more frequent in diabetic patients (P = 0.0343, empirical P = 0.0659 on 10 000 permutations). In both groups, non-coding SNPs were associated with circulating RBP4 concentrations (P < 0.05). In the normal control subjects, the SNP +5388 C>T was associated with serum C-peptide levels both fasting and 2 h after an oral glucose tolerance test (P = 0.0162 and P = 0.0075, respectively). Conclusion Our findings suggest that genetic variants in the RBP4 gene may be associated with circulating RBP4 concentration and phenotypes related to glucose metabolism. [source]

    The genetics of autism

    ACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2001
    M. Lauritsen
    Objective: To review systematically the empirical evidence for the involvement of genetic risk factors in infantile autism. Method: We aimed at including all relevant papers written in English. We conducted a Medline search in September 2000. In addition we searched the reference lists of related papers. Results: A relatively small number of reports including family and twin studies, comorbidity, cytogenetic and molecular genetic studies were reviewed. Conclusion: As well family, twin, cytogenetic and molecular genetic studies supported the importance of genetic risk factors in infantile autism. In most individual cases probably at least a few gene variants simultaneously determine the genetic risk. Presently the most interesting chromosome regions concerning the aetiology of autism are chromosomes 7q31,35, 15q11,13 and 16p13.3 which have been suggested by different lines of genetic research. [source]

    Homologues of nitrite reductases in ammonia-oxidizing archaea: diversity and genomic context

    ENVIRONMENTAL MICROBIOLOGY, Issue 4 2010
    Rita Bartossek
    Summary Ammonia-oxidizing archaea are frequent and ubiquitous inhabitants of terrestrial and marine environments. As they have only recently been detected, most aspects of their metabolism are yet unknown. Here we report on the occurrence of genes encoding potential homologues of copper-dependent nitrite reductases (NirK) in ammonia-oxidizing archaea of soils and other environments using metagenomic approaches and PCR amplification. Two pairs of highly overlapping 40 kb genome fragments, each containing nirK genes of archaea, were isolated from a metagenomic soil library. Between 68% and 85% of the open reading frames on these genome fragments had homologues in the genomes of the marine archaeal ammonia oxidizers Nitrosopumilus maritimus and Cenarchaeum symbiosum. Extensions of NirK homologues with C-terminal fused amicyanin domains were deduced from two of the four fosmids indicating structural variation of these multicopper proteins in archaea. Phylogenetic analyses including all major groups of currently known NirK homologues revealed that the deduced protein sequences of marine and soil archaea were separated into two highly divergent lineages that did not contain bacterial homologues. In contrast, another separated lineage contained potential multicopper oxidases of both domains, archaea and bacteria. More nirK gene variants directly amplified by PCR from several environments indicated further diversity of the gene and a widespread occurrence in archaea. Transcription of the potential archaeal nirK in soil was demonstrated at different water contents, but no significant increase in transcript copy number was observed with increased denitrifying activity. [source]

    Evidence of shared genetic risk factors for migraine and rolandic epilepsy

    EPILEPSIA, Issue 11 2009
    Tara Clarke
    Summary Purpose:, Evidence for a specific association between migraine and rolandic epilepsy (RE) has been conflicting. Children with migraine frequently have electroencephalographic (EEG) abnormalities, including rolandic discharges, and approximately 50% of siblings of patients with RE exhibit rolandic discharges. We assessed migraine risk in RE probands and their siblings. Methods:, We used cohort and reconstructed cohort designs to respectively assess the relative risk of migraine in 72 children with RE and their 88 siblings using International Classification of Headache Disorders (ICHD-2) criteria. Incidences were compared in 150 age and geographically matched nonepilepsy probands and their 188 siblings. We used a Cox proportional hazards model, using age as the time base, adjusting hazard ratios (HRs) for sex in the proband analysis, and for sex and proband migraine status in the sibling analysis. Results:, Prevalence of migraine in RE probands was 15% versus 7% in nonepilepsy probands, and in siblings of RE probands prevalence was 14% versus 4% in nonepilepsy siblings. The sex-adjusted HR of migraine for an RE proband was 2.46 [95% confidence interval (CI) 1.06,5.70]. The adjusted HR of having ,1 sibling with migraine in an RE family was 3.35 (95% CI 1.20,9.33), whereas the HR of any one sibling of a RE proband was 2.86 (95% CI 1.10,7.43). Discussion:, Migraine is strongly comorbid in RE and independently clusters in their siblings. These results suggest shared susceptibility to migraine and RE that is not directly mediated by epileptic seizures. Susceptibility gene variants for RE may be tested as risk factors for migraine. [source]

    Co-inheritance of Hb Hershey [,70(E14) Ala,Gly] and Hb La Pommeraie [,133(H11)Val,Met] in a Sicilian subject

    EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010
    Antonino Giambona
    Abstract Objectives:,This report represents the first observation in Sicily of two rare , -globin gene variants, Hb Hershey [,70(E14) Ala,Gly] and Hb La Pommeraie [,133(H11)Val,Met], found in a 35-year-old male patient from Messina, in the north-east of Sicily during population screening for hemoglobinopathies. Methods: The occurrence of the Hb variants was assessed by cation exchange chromatography while complete blood counts were obtained using automatic cell counters. Red cell lysates were analyzed by electrophoresis at alkaline and acid pH. Stability of hemoglobin was checked by the isopropanol precipitation test and by the heat tests while inclusion bodies and reticulocyte count were determined by incubation of blood samples with brilliant cresyl blue. Molecular analysis was performed by DNA sequencing of ,- and , -globin genes. Results: We observed an abnormally high performance liquid chromatography elution with a slight reduction in mean corpuscular volume and mean corpuscular haemoglobin parameters and mutations at codon 70 GCC,GGC (Hb Hershey) and at codon 133 GTG,ATG (Hb La Pommeraie) in , -globin gene. Conclusion: Family analysis of three generations demonstrated the presence of these two mutations in trans. So it was possible to describe the phenotypes of these variants in a heterozygous state and in double heterozygous state. [source]

    ,-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype

    EXPERIMENTAL PHYSIOLOGY, Issue 7 2010
    John H. Eisenach
    Intermediate physiological phenotype is the genetic and environmental influence on functional physiological characteristics with direct prognostic relevance to distant, more complex phenotypes, such as cardiovascular and metabolic disease. Increasingly available and affordable genotyping techniques have created an explosion of information on candidate gene variation and its relationship to intermediate physiological traits. Variation in ,-adrenoceptor genes is an intense focus of investigation because ,-adrenoceptors are: (1) ubiquitous in organ system distribution; (2) integral to a multitude of physiological processes; (3) well described in cardiovascular and metabolic disease; and (4) major pharmacological treatment targets. Furthermore, knowledge of functional gene variants in these receptors predates the description of the human genome. This review highlights the influence of common gene variation in the three ,-adrenoceptor subtypes on intermediate physiological phenotype predictive of cardiovascular disease and obesity. Although further information is needed to replicate this information across populations, this review condenses and summarizes growing trends in specific pleiotropic effects of ,-adrenoceptor polymorphisms and suggests which variants may be predictive of distant phenotype. [source]

    cagA gene variants in Malaysian Helicobacter pylori strains isolated from patients of different ethnic groups

    FEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2005
    Mohamed Ramelah
    Abstract Helicobacter pylori infection of a distinct subtype of cagA may lead to different pathological manifestation. The aim of this study is to determine the presence of cagA gene and its variants in H. pylori infection among different ethnic groups and its effect on gastroduodenal diseases. Overall detection of cagA among the 205 clinical isolates of H. pylori was 94%. Variations in size of the 3, region of cagA gene were examined among 192 Malaysian H. pylori cagA -positive strains. Results showed that three cagA variants differing in fragment length of PCR products were detected and designated as type A (621,651 bp), type B (732,735 bp) and type C (525 bp). Although there was no association between any of the cagA subtypes with peptic ulcer disease (p > 0.05), an association between cagA subtypes with a specific ethnic group was observed. Specific- cagA subtype A strains were predominantly isolated from Chinese compared to Malays and Indians (p < 0.0005), and cagA subtype B strains were predominantly isolated from Malays and Indians compared to Chinese (p < 0.05). The cagA type A strains of H. pylori is commonly found in the Chinese patients who have a higher risk of peptic ulcer disease, thus indicating that it could be used as an important clinical biomarker for a more severe infection. [source]

    An international multicenter association study of the serotonin transporter gene in persistent ADHD

    GENES, BRAIN AND BEHAVIOR, Issue 5 2010
    E. T. Landaas
    Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5-HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67,1.09; P = 0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00,1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded. [source]

    Glutathione S-transferase P1 and alpha gene variants; role in susceptibility and tumor size development of oral cancer

    HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2010
    Mu-Kuan Chen MD
    Abstract Background. The aim of this study was to estimate the relationship of glutathione S-transferases (GST)P1, GSTA1, GSTM1, and GSTT1 gene polymorphisms to oral cancer risk. Methods. Polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP) was used to measure these 4 gene polymorphisms in 274 controls and 164 oral cancer patients. Results. Individuals with at least 1 varied G allele of GSTP1 had a 1.53-fold risk (95% confidence interval [CI] = 1.01,2.31) of developing oral cancer compared with patients with wild-type A/A homozygotes. Oral cancer patients with at least 1 varied T allele of GSTA1 gene had a 0.42-fold risk (95% CI = 0.18,0.95) of having a tumor size >2 cm compared with patients with C/C homozygotes. Conclusions. The varied G allele of GSTP1 may be considered as a factor contributing to increased susceptibility, whereas the T allele of GSTA1 could be a protective factor for tumor size progression in Taiwanese with oral cancer. © 2009 Wiley Periodicals, Inc. Head Neck, 2010 [source]

    Histopathological features of breast cancer in carriers of ATM gene variants

    HISTOPATHOLOGY, Issue 5 2006
    R L Balleine
    Aims:, Germline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype. Methods:, The histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T,G, 2424V,G or 1420L,F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined. Results:, The histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation. Conclusions:, Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers. [source]

    Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics

    HUMAN MUTATION, Issue 5 2009
    Sven Arnold
    Abstract Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm in vitro, splicing aberrations associated with mismatch repair (MMR) variants identified in familial colon cancer patients. Six programs were used to predict the effect of 13 MLH1 and 6 MSH2 gene variants on pre-mRNA splicing. mRNA from cycloheximide-treated lymphoblastoid cell lines of variant carriers was screened for splicing aberrations. Tumors of variant carriers were tested for microsatellite instability and MMR protein expression. Variant segregation in families was assessed using Bayes factor causality analysis. Amino acid alterations were examined for evolutionary conservation and physicochemical properties. Splicing aberrations were detected for 10 variants, including a frameshift as a minor cDNA product, and altered ratio of known alternate splice products. Loss of splice sites was well predicted by splice-site prediction programs SpliceSiteFinder (90%) and NNSPLICE (90%), but consequence of splice site loss was less accurately predicted. No aberrations correlated with ESE predictions for the nine exonic variants studied. Seven of eight missense variants had normal splicing (88%), but only one was a substitution considered neutral from evolutionary/physicochemical analysis. Combined with information from tumor and segregation analysis, and literature review, 16 of 19 variants were considered clinically relevant. Bioinformatic tools for prediction of splicing aberrations need improvement before use without supporting studies to assess variant pathogenicity. Classification of mismatch repair gene variants is assisted by a comprehensive approach that includes in vitro, tumor pathology, clinical, and evolutionary conservation data. Hum Mutat 0, 1,14, 2009. © 2009 Wiley-Liss, Inc. [source]

    Functional polymorphisms in dopamine and serotonin pathway genes,

    HUMAN MUTATION, Issue 1 2006
    Ursula M. D'Souza
    Abstract There is mounting evidence on the functional significance of single nucleotide and simple repeat sequence polymorphisms in both the coding and regulatory regions of genes in the monoamine neurotransmitter pathways. Many of these gene variants have been associated with human behavioral disorders and traits, and thus have important clinical relevance. This review summarizes the literature on the published functional studies from a molecular, cellular, and neurobiological perspective, and notes their possible behavioral consequences. Functional studies have adopted a variety of strategies. Pharmacological studies have focused on the effects of gene variation at the protein level in terms of binding to ligands or drugs. Other key investigations have determined effects on gene expression at the level of transcription in mammalian cell cultures, lymphoblasts, and/or human postmortem brain tissue. This has enabled the comparison of in vitro and in vivo data, and furthermore provides an improved perceptive of their respective advantages. Additionally, molecular biological approaches have identified transcription factors (DNA-binding proteins) that interact with the motifs within the polymorphisms themselves. Various neuroimaging studies have further determined the relationship of genotype with protein availability in the brain, and thus have contributed to our understanding of the in vivo functional significance of gene variants. Finally, there is growing evidence from both human and animal studies on the interaction of functional polymorphisms with the environment in determining a behavioral outcome. Taken together, these findings have contributed to a greater understanding of the plausible molecular mechanisms that underpin the functional significance of polymorphisms in monoamine neurotransmitter pathway genes, and how they may influence behavioral phenotypes. Hum Mutat 27(1), 1,13, 2006. © 2005 Wiley-Liss, Inc. [source]

    The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: identifying genes that regulate organ-specific and systemic autoimmunity

    IMMUNOLOGICAL REVIEWS, Issue 1 2006
    Gerard F. Hoyne
    Summary:, T-cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self-antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ-specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self-antigens. [source]

    Contribution of IL23R but not ATG16L1 to Crohn's disease susceptibility in Koreans

    INFLAMMATORY BOWEL DISEASES, Issue 9 2009
    Suk-Kyun Yang MD
    Abstract Background: Recent genome-wide association studies in Caucasian populations identified IL23R and ATG16L1 as susceptibility genes to Crohn's disease (CD). We tested 5 IL23R single nucleotide polymorphisms (SNPs) and 12 ATG16L1 SNPs in Korean patients to determine whether these genes are associated with susceptibility to CD in a non-Caucasian population. Methods: We analyzed 5 IL23R SNPs and 12 ATG16L1 SNPs in 380 patients with CD and 380 healthy controls. Results: Two IL23R gene variants, an intronic SNP rs1004819 and intergenic SNP rs1495465, showed significant associations with CD; the adjusted odds ratio (aOR) for rs1004819 was 1.822 (95% confidence interval [CI] = 1.164,2.852, P = 0.009) and aOR for rs1495965 was 1.650 (95% CI = 1.102,2.471, P = 0.015). The genotype,phenotype analysis showed subphenotype specificity to stricturing and penetrating behaviors. On the other hand, none of the 12 ATG16L1 SNPs showed any positive association with CD in Koreans. The contribution of IL23R variants in Korean CD patients overall is low in comparison with studies of Caucasian. Conclusions: Our data in Koreans support the previous Caucasian reports of an association of the IL23R gene with CD. (Inflamm Bowel Dis 2009) [source]

    Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population

    INFLAMMATORY BOWEL DISEASES, Issue 6 2008
    Mark Tremelling MRCP
    Abstract Background: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results:TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01,1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23,1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499,3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies. (Inflamm Bowel Dis 2008) [source]

    Adipokine genes and prostate cancer risk

    INTERNATIONAL JOURNAL OF CANCER, Issue 4 2009
    Steven C. Moore
    Abstract Adiposity and adipocyte-derived cytokines have been implicated in prostate carcinogenesis. However, the relationship of adipokine gene variants with prostate cancer risk has not been thoroughly investigated. We therefore examined common variants of the IL6, LEP, LEPR, TNF and ADIPOQ genes in relation to prostate cancer in a case-control study nested within a large cohort of Finnish men. The study sample consisted of 1,053 cases of prostate cancer, diagnosed over an average 11 years of follow up, and 1,053 controls matched to the cases on age, intervention group and date of baseline blood draw. Logistic regression was used to model the relative odds of prostate cancer. We also examined genotypes in relation to serum insulin, IGF-1 and IGF-1:IGFBP-3 among 196 controls. Variant alleles at three loci (,14858A>G, ,13973A>C, ,13736C>A) in a potential regulatory region of the LEP gene conferred a statistically significant 20% reduced risk of prostate cancer. For example, at the ,14858A>G locus, heterozygotes and homozygotes for the A allele had an odds ratio (OR) of prostate cancer of 0.76 [95% confidence interval (CI) 0.62, 0.93] and 0.79 (95% CI 0.60, 1.04), respectively. At 13288G>A, relative to the GG genotype, the AA genotype was associated with a suggestive increased risk of prostate cancer (OR = 1.29; 95% CI 0.99,1.67; ptrend = 0.05). Polymorphisms in the IL6, LEPR, TNF and ADIPOQ genes were not associated with prostate cancer. Allelic variants in the LEP gene are related to prostate cancer risk, supporting a role for leptin in prostate carcinogenesis. © 2008 Wiley-Liss, Inc. [source]

    Association of longevity with IL-10 ,1082 G/A and TNF-,,308 G/A polymorphisms

    INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2010
    O. F. Khabour
    Summary Cytokines are crucial for the regulation of inflammation development in humans. Many studies have shown that variations in cytokine genes might play a role in determining human longevity. This study examined the changes in the gene pool relevant to the ,308 G/A polymorphism in the promoter region of the proinflammatory cytokine tumour necrosis factor (TNF)-, gene and the ,1082 G/A polymorphism in the promoter region of anti-inflammatory cytokine interleukin (IL)-10 gene with aging and survival selection occurs in the Jordanian population. IL-10 ,1028 G/A and TNF-,,308 G/A were genotyped in 119 randomly selected elderly subjects (41 women and 78 men) with a mean age of 90.2 years and young control subjects of 118 (46 women and 72 men) with a mean age of 31.9 years. No significant differences were found in the genotype and allele frequencies of TNF-, gene variants between the two groups (P > 0.05) while the IL-10 genotype and allele frequencies were significantly associated with longevity in men (P < 0.05) but not in women (P < 0.05). Thus, IL-10 ,1028 G/A polymorphism seems to play a role in the pathway to longevity in Jordanian men. [source]

    Comparison of IL10 and IL2 genotypes of Turkish population with other populations

    INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2009
    A. C. Yaz
    Summary The human genome has been shaped by evolutionary and historical forces. Therefore, genetic polymorphisms are useful tools not only to understand the susceptibility to disease in modern populations, but the history of ancestral populations as well. For this purpose, data on genetic polymorphisms such as human leucocyte antigen, mitochondrial DNA sequence variability and the frequencies of TAP1 and TAP2 gene variants in Turkey have been reported previously. Here we have used interleukin (IL)-10 (,592C/A, ,819T/C, ,1082G/A) and IL-2 (,330T/G) as genetic markers to study the relationship between Turkish population and other populations. [source]

    Iron-overload and genotypic expression of HFE mutations H63D/C282Y and transferrin receptor Hin6I and BanI polymorphism in German patients with hereditary haemochromatosis

    INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2000
    R. Gottschalk
    Gene variations of HFE, a HLA-class I like molecule, are highly associated with hereditary haemochromatosis (HH). Functional as well as molecular studies of the HFE protein have indicated that the molecule is involved in iron metabolism and that the HFE gene variations observed among HH patients affect its interaction with the transferrin receptor (TfR). In the present study, we have therefore analysed the relationship between the HFE gene variants, C282Y and H63D, and body iron status among 85 German HH patients. In addition, two TfR gene polymorphism, TfR-Hin6I and TfR-BanI, were typed that have been reported to define ethnically distinct haplotypes. As controls we used 251/159 healthy German blood donors. Seventy-eight (92%) patients were C292Y homozygous, the H63D mutation was present in five (6%) patients with none of the patients being H63D homozygous. Serum transferrin, transferrin saturation and liver iron content were determined prior to therapeutic intervention. Among C282Y homozygous patients serum ferritin levels (2294 ± 3174 vs. 463 ± 224 µg L,1, P < 0.0001) and transferrin saturation (86 ± 18% vs. 62 ± 25%, P = 0.048) were elevated significantly compared with C282Y and/or H63D heterozygous patients. In addition, the liver iron content (291 ± 165 vs. 138 ± 95 µmol g,1, P = 0.028) and liver iron index (6.4 ± 2.8 vs. 3.2 ± 2.3, P = 0.019) were increased among C282Y homozygotes compared with C282Y heterozygotes. In contrast, no difference was observed between patients and controls regarding the distribution of TfR- Hin6I and TfR- BanI alleles. These data indicate that the iron intake is higher among C282Y homozygous patients compared with C282Y heterozygous or C282Y/H63D compound heterozygous individuals and supports the functional role of the HFE protein in iron metabolism whereas the TfR gene variants seem to have no influence on iron uptake. [source]

    Hip geometry variation is associated with bone mineralization pathway gene variants: The framingham study

    JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010
    Ching-Lung Cheung
    Abstract Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8,×,10,7 being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. © 2010 American Society for Bone and Mineral Research [source]

    PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007
    C. Gragnoli
    Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n,=,237) and controls subjects (n,=,215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case,control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G,>,A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations. J. Cell. Physiol. 212:568,571, 2007. © 2007 Wiley-Liss, Inc. [source]

    TLR4 and IL-18 gene variants in aggressive periodontitis

    JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 12 2008
    Barbara Noack
    Abstract Aim: We aimed to assess the association of different genotypes with increased aggressive periodontitis susceptibility by studying functional relevant variants in the pathogen-recognition receptor Toll-like receptor 4 (TLR4) and variants in the promoter region of the pro-inflammatory cytokine interleukin-18 (IL-18). Material and Methods: One hundred and eleven patients with aggressive periodontitis and 80 periodontally healthy controls were genotyped for four functional variants in the TLR4 gene (c.896A>G and c.1196C>T) and in the IL-18 promoter (c.,368G>C and c.,838C>A). The genotype and allele frequencies, as well as the frequency of combined genotypes were compared between study groups. Results: There were no statistical differences in genotype and allele frequencies within the four variants between the groups. All study subjects were further classified into carriers and non-carriers of at least one variant of both genes. The logistic regression analysis adjusted for gender and smoking showed no association between carrier status of at least one variant of both genes and periodontal status (OR=1.41, 95% CI: 0.43,4.70). Conclusions: Our results reject the hypothesis that functionally relevant IL-18 and TLR4 gene mutations have a major effect on aggressive periodontitis susceptibility alone or in combination. [source]

    HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

    AGING CELL, Issue 5 2010
    S. Michal Jazwinski
    Summary The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity. [source]

    Testing Genetic Susceptibility Loci for Alcoholic Heart Muscle Disease

    ALCOHOLISM, Issue 10 2001
    Olli A. Kajander
    Background: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart. Methods: We studied 700 middle-aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid-phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase ,344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P-450 2E1 Dra I, Pst I, Rsa I, and Msp I. Results: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes. Conclusions: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease. [source]

    A multilocus candidate approach identifies ACE and HIF1A as susceptibility genes for cellulite

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 8 2010
    E Emanuele
    Abstract Background, Cellulite is a common complex cosmetic problem for many post-adolescent women characterised by relief alterations of the skin surface, which give the skin an orange-peel appearance. Although genetic factors have been suggested to play a role in the development of cellulite, the genetic background of this condition remains unclear. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in oestrogen receptors, endothelial function/adipose tissue hypoxia, lipid metabolism, extracellular matrix homeostasis, inflammation and adipose tissue biology, with the risk of cellulite. Methods, Using a case,control study of 200 lean women with cellulite and 200 age- and BMI-matched controls (grade 0 according to Nurnberger,Muller scale), we examined the association of cellulite with 25 polymorphisms in 15 candidate genes. Results, Two of the 25 polymorphisms were significantly associated with cellulite at the P < 0.01 level. After allowance for age, body mass index, the prevalence of contraceptive use and smoking in logistic regression analysis, the multivariable-adjusted odds ratios for cellulite were 1.19 (95% CI: 1.10,1.51; P < 0.01) for ACE rs1799752 and 0.61 (95% CI: 0.45,0.88, P < 0.01) for HIF1A rs11549465. Conclusions, This study, which demonstrates an independent role of ACE and HIF1A in predisposing to cellulite, may provide novel information on the pathophysiology of this common cosmetic problem, and offer a topic for research for novel beautification interventions. [source]