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Haplotype Analysis (haplotype + analysis)
Selected AbstractsHaplotype Analysis Confirms the Association Between the HCRTR2 Gene and Cluster HeadacheHEADACHE, Issue 7 2008Innocenzo Rainero MD Background., Several studies suggested that genetic factors play a role in cluster headache (CH) susceptibility. We found a significant association between the 1246 G>A polymorphism of the hypocretin receptor-2 (HCRTR2) gene and the disease. This association was confirmed in a large study from Germany but was not replicated in a dataset of CH patients from Northern Europe. Objective., The purpose of this study was to further evaluate the association between CH and the HCRTR2 gene using new polymorphisms, estimating the frequency of different gene haplotypes, searching for gene mutations, and evaluating the effects of the examined polymorphisms on hypocretin binding sites. Methods., We genotyped 109 CH patients and 211 healthy controls for 5 new polymorphisms of the HCRTR2 gene and we inferred different gene haplotypes. Complete HCRTR2 sequencing was undertaken for 11 independent CH patients, 5 of whom had a positive family history. The effects of the 1246 G>A polymorphism on the hypocretin binding sites were evaluated using different computer-assisted analyses. Results., Three new polymorphisms of the HCRTR2 gene resulted significantly associated with CH. The GTAAGG haplotype resulted more frequent in cases than in controls (OR: 3.68; 95% CI: 1.85-7.67). No point mutation of the HCRTR2 gene was found. Binding analyses showed that the 1246 G>A polymorphism (substitution of valine at position 308 by isoleucine) has no effect on the hypocretin binding sites but could influence the dimerization process of the receptor. Conclusion., Our data confirm previous studies suggesting that the HCRTR2 gene or a linked locus significantly modulates the risk for CH. In addition, we suggest that the V308I substitution of the HCRTR2 may interfere with the dimerization process of the receptor, thereby influencing its functional activity. [source] Haplotype Analysis of the Stromelysin-1 (MMP3) and Gelatinase B (MMP9) Genes in Relation to Coronary Heart DiseaseANNALS OF HUMAN GENETICS, Issue 4 2009Naqiong Wu Summary The functional genetic polymorphisms present in the promoters of stromelysin-1 (MMP3) and gelatinase B (MMP9) have been shown to be associated with angiographically measured atherosclerosis; however, haplotype analysis of the genetic polymorphisms occurring in the promoters and coding regions of MMP3 and MMP9 has been infrequently performed in the past. The aim of this study was to analyze the occurrence of the -1612 5A/6A, -376C/G, and Glu45Lys polymorphisms of MMP3 and the -1562C/T and R279Q polymorphisms of MMP9 and their relation to the risk of coronary heart disease (CHD; stenosis ,50% of the diameter in at least one major coronary artery) in a Chinese Han population. The present study involved 1373 patients with CHD and 695 healthy controls. The Glu45Lys polymorphism of MMP3 was significantly associated with an increased risk of CHD. Compared with the 45Glu homozygotes, 45Lys allele carriers had a significantly elevated risk of CHD (adjusted OR = 1.50; 95%CI 1.11,2.03; p= 0.008). Moreover, haplotype analysis identified both the 6A-C-Lys (-1612 6A, -376C, 45Lys) haplotype and the 6A-G-Lys (-1612 6A,-376G, 45Lys) haplotype of MMP3 as associated with an increased risk of CHD. Our study suggests that common genetic variations in the MMP3 gene may affect the risk of CHD in the Chinese population. [source] SNP Discovery and Haplotype Analysis in the Segmentally Duplicated DRD5 Coding RegionANNALS OF HUMAN GENETICS, Issue 3 2009Donna J. E. Housley Summary The dopamine receptor 5 gene (DRD5) holds much promise as a candidate locus for contributing to neuropsychiatric disorders and other diseases influenced by the dopaminergic system, as well as having potential to affect normal behavioral variation. However, detailed analyses of this gene have been complicated by its location within a segmentally duplicated chromosomal region. Microsatellites and SNPs upstream from the coding region have been used for association studies, but we find, using bioinformatics resources, that these markers all lie within a previously unrecognized second segmental duplication (SD). In order to accurately analyze the DRD5 locus for polymorphisms in the absence of contaminating pseudogene sequences, we developed a fast and reliable method for sequence analysis and genotyping within the DRD5 coding region. We employed restriction enzyme digestion of genomic DNA to eliminate the pseudogenes prior to PCR amplification of the functional gene. This approach allowed us to determine the DRD5 haplotype structure using 31 trios and to reveal additional rare variants in 171 unrelated individuals. We clarify the inconsistencies and errors of the recorded SNPs in dbSNP and HapMap and illustrate the importance of using caution when choosing SNPs in regions of suspected duplications. The simple and relatively inexpensive method presented herein allows for convenient analysis of sequence variation in DRD5 and can be easily adapted to other duplicated genomic regions in order to obtain good quality sequence data. [source] An Exact Test for the Association Between the Disease and Alleles at Highly Polymorphic Loci with Particular Interest in the Haplotype AnalysisBIOMETRICS, Issue 3 2001Chihiro Hirotsu Summary. The association analysis between the disease and genetic alleles is one of the simple methods for localizing the susceptibility locus in the genes. For revealing the association, several statistical tests have been proposed without discussing explicitly the alternative hypotheses. We therefore specify two types of alternative hypotheses (i.e., there is only one susceptibility allele in the locus, and there is an extension or shortening of alleles associated with the disease) and derive exact tests for the respective hypotheses. We also propose to combine these two tests when the prior knowledge is not sufficient enough to specify one of these two hypotheses. In particular, these ideas are extended to the haplotype analysis of three-way association between the disease and bivariate allele frequencies at two closely linked loci. As a by-product, a factorization of the probability distribution of the three-way cell frequencies under the null hypothesis of no three-way interaction is obtained. [source] Association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set shifting in healthy individualsGENES, BRAIN AND BEHAVIOR, Issue 5 2010B. T. Baune Set-shifting and maintenance are complex cognitive processes, which are often impaired in schizophrenia. The genetic basis of these processes is poorly understood. We aimed to investigate the association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set-shifting in healthy individuals. The relationship between 14 selected single nucleotide polymorphisms (SNPs) of the GRM3 gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 ± 0.19). Results show that SNP rs17676277 is related to the performance on the MCST. Subjects with the TT genotype showed significantly less perseverative errors as compared with the AA (P = 0.025) and AT (P = 0.0005) and combined AA/AT genotypes (P = 0.0005). Haplotype analyses suggest the involvement of various SNPs of the GRM3 gene in perseverative error processing in a dominant model of inheritance. The findings strongly suggest that the genetic variation (rs17676277 and three haplotypes) in the metabotropic GRM3 is related to cognitive set-shifting in healthy individuals independent of working memory. However, because of a relatively small sample size for a genetic association study, the present results are tentative and require replication. [source] Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patientsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Muhammad U. Rashid Abstract Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (,30 years) and was 9.0% for single cases of early-onset ovarian cancer (,45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan. © 2006 Wiley-Liss, Inc. [source] A Haplotype-Based Analysis of the LRP5 Gene in Relation to Osteoporosis Phenotypes in Spanish Postmenopausal Women,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2008Lídia Agueda Abstract LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5,-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype "GC" of the block located at the 3,end of the gene. This haplotype spans intron 22 and the 3, untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site. [source] Brief communication: Patterns of linkage disequilibrium and haplotype diversity at Xq13 in six Native American populationsAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 3 2010Sijia Wang Abstract Comparative studies of linkage disequilibrium (LD) can provide insights into human demographic history. Here, we characterize LD in six Native American populations using seven microsatellite markers in Xq13, a region of the genome extensively studied in populations around the world. Native Americans show relatively low diversity and high LD, in agreement with recent genome-wide survey and a scenario of sequential founder effects accompanying human population dispersal around the globe. LD in Native Americans is similar to that observed in some recently described small population isolates and higher than in large European isolates (e.g., Finns), which have been extensively analyzed in medical genetics studies. Haplotype analyses are consistent with a colonization of the New World by a differentiated East Asian population, followed by extensive genetic drift in the Americas. Am J Phys Anthropol, 2010. © 2009 Wiley-Liss, Inc. [source] Novel haplotypes in 17q21 are associated with progressive supranuclear palsyANNALS OF NEUROLOGY, Issue 2 2004Pau Pastor MD Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau-positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case,control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E,), which extends 1.04Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E,A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E,A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients. Ann Neurol 2004;56:249,258 [source] Refinement of 2q and 7p loci in a large multiplex NTD family,BIRTH DEFECTS RESEARCH, Issue 6 2008Demetra S. Stamm Abstract BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of ,3.0 mapping to 2q33.1,q35 and 7p21.1,pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of ,3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1,q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1,21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc. [source] A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutationGENES, CHROMOSOMES AND CANCER, Issue 1 2005Anders Molven Mutations in two loci encoding cell-cycle-regulatory proteins have been shown to cause familial malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus, which encodes two unrelated proteins, p16INK4A and p14ARF. Mutations in the other locus, CDK4, are much rarer and have been linked to the disease in only three families worldwide. In the 1960s, a large Norwegian pedigree with multiple atypical nevi and malignant melanomas was identified. Subsequently, six generations and more than 100 family members were traced and 20 cases of melanoma verified. In this article, we report that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. Intriguingly, one of the family members had ocular melanoma, but the CDK4 mutation could not be detected in archival tissue samples from this subject. Thus, the case of ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. The CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England. Haplotype analysis using microsatellite markers flanking the CDK4 gene and single-nucleotide polymorphisms within the gene did not support the possibility that there was a common founder, but rather indicated at least two independent mutational events. All CDK4 melanoma families known to date have a substitution of amino acid 24. In addition to resulting from selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hot spot in the CDK4 gene. © 2005 Wiley-Liss, Inc. [source] Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma familiesGENES, CHROMOSOMES AND CANCER, Issue 2 2001Jamileh Hashemi Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52,167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow ,1-cM region on 9p21. © 2001 Wiley-Liss, Inc. [source] Haplotype analysis in the presence of informatively missing genotype dataGENETIC EPIDEMIOLOGY, Issue 4 2006Nianjun Liu Abstract It is common to have missing genotypes in practical genetic studies, but the exact underlying missing data mechanism is generally unknown to the investigators. Although some statistical methods can handle missing data, they usually assume that genotypes are missing at random, that is, at a given marker, different genotypes and different alleles are missing with the same probability. These include those methods on haplotype frequency estimation and haplotype association analysis. However, it is likely that this simple assumption does not hold in practice, yet few studies to date have examined the magnitude of the effects when this simplifying assumption is violated. In this study, we demonstrate that the violation of this assumption may lead to serious bias in haplotype frequency estimates, and haplotype association analysis based on this assumption can induce both false-positive and false-negative evidence of association. To address this limitation in the current methods, we propose a general missing data model to characterize missing data patterns across a set of two or more markers simultaneously. We prove that haplotype frequencies and missing data probabilities are identifiable if and only if there is linkage disequilibrium between these markers under our general missing data model. Simulation studies on the analysis of haplotypes consisting of two single nucleotide polymorphisms illustrate that our proposed model can reduce the bias both for haplotype frequency estimates and association analysis due to incorrect assumption on the missing data mechanism. Finally, we illustrate the utilities of our method through its application to a real data set. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Common CX3CR1 Alleles Are Associated With a Reduced Risk of HeadachesHEADACHE, Issue 7 2008Christophe Combadière PhD Objectives., The aim of this study was to investigate the role of the chemokine receptor CX3CR1 in headaches and migraine. Methods., Distribution of 2 polymorphisms of the chemokine receptor CX3CR1 (V249I and T280M) was determined in a population-based sample of 1179 elderly individuals. Results., Heterozygotes for both CX3CR1 polymorphisms had a reduced risk of recurrent headaches, with an odds ratio (OR) of 0.64 (95% confidence interval [CI] = 0.46-0.90) for the I249 allele and 0.55 (95% CI = 0.38-0.81) for the M280 allele. Haplotype analysis showed that carriers of the rarer CX3CR1 I249-M280 haplotype had a reduced risk of recurrent headaches, with an OR of 0.57 (95% CI = 0.41-0.80, P = .001). This association was seen for both nonmigraine headaches (OR = 0.47, 95% CI = 0.28-0.79, P = .004) and migraine (OR = 0.65, 95% CI = 0.43-0.98, P = .041). Conclusions., These results need to be replicated but suggest that the chemokine receptor CX3CR1 may play a role in recurrent headaches. [source] A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy,HUMAN MUTATION, Issue 6 2008Montserrat Rodríguez-Ballesteros Abstract Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy. Hum Mutat 29(6), 823,831, 2008. © 2008 Wiley-Liss, Inc. [source] Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis,,HUMAN MUTATION, Issue 1 2005Stefan J. White Abstract We have designed Multiplex Amplifiable Probe Hybridization (MAPH) probes for 28 exons of the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD. The set was used to screen DNA from limb-girdle muscular dystrophy (LGMD) patients for the presence of pathogenic deletion or duplication mutations. An unexpected heterozygous deletion of SGCG exon 7 was detected in a patient from a consanguineous family in which a known c.525delT mutation segregates. The exon 7 deletion was inherited from the father, who was part of the consanguineous c.525delT branch of the family but who did not carry the c.525delT mutation. A similar, homozygous deletion had been identified in two unrelated LGMD patients from southern Italy. The deletion breakpoints were mapped, isolated, and sequenced, and were identical in all cases. Haplotype analysis showed the same alleles segregating with the mutation in all three patients, suggesting a common ancestor. Exonic deletions in sarcoglycanopathies appear to be rare events. However, we recommend screening for exonic deletions/duplications in patients where a mutation has not been identified in both alleles, as well as in seemingly homozygous cases where segregation of the mutations can not be confirmed in the parents. © 2005 Wiley-Liss, Inc. [source] Molecular basis of phenylketonuria in CubaHUMAN MUTATION, Issue 3 2001L.R. Desviat Abstract In this study we report the mutation analysis performed in Cuban PKU patients using DGGE and direct sequencing. Sixteen different mutations have been detected, which account for 91% of the total mutant alleles. Haplotype analysis and genealogical data support the European (mainly Spanish) origin of the mutations. Two mutations were found at unexpectedly high frequencies, E280K and R261Q, possibly due to consanguinity and genetic drift, among other factors. Hum Mutat 18:252, 2001. © 2001 Wiley-Liss, Inc. [source] Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer riskINTERNATIONAL JOURNAL OF CANCER, Issue 11 2008Victoria L. Stevens Abstract Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29,38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations. © 2008 Wiley-Liss, Inc. [source] HRAS1 and LASS1 with APOE are associated with human longevity and healthy agingAGING CELL, Issue 5 2010S. 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] Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strainsAGING CELL, Issue 5 2010Magalie S. Leduc Summary The IGF-1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF-1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF-1 levels. Quantitative trait loci (QTL) analysis of IGF-1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF-1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co-localized with IGF-1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF-1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL. [source] CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancersJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2007Abolghasem Hadinia Abstract Background and Aim:, Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. Effects of several polymorphisms in CTLA-4 on CTLA-4 expression and function have been previously documented. The aim of this study was to investigate the putative effect of CTLA-4 polymorphisms on susceptibility to gastric and colorectal cancers in an Iranian population. Methods:, A total of 155 patients (109 with colorectal cancer and 46 with gastric cancer) and 190 age- and sex-matched healthy controls were evaluated. Genotyping of ,1722T/C, ,1661A/G, and +49A/G were performed by PCR restriction fragment length polymorphism methods and of ,318C/T by a PCR amplification refractory mutation system technique. Results:, No statistically significant differences were found in the genotype distribution and allele frequencies among patients and controls. Haplotype analysis demonstrated that the TACG haplotype (,1722T, ,1661A, ,318C, +49G) frequency was significant increased in patients with colorectal cancer (P = 0.009) and gastric cancer (P = 0.006) in comparison to the control group. In contrast, the TACA haplotype frequency was significantly decreased in patients with colorectal cancer (P = 0.02) and not significantly decreased in patients with gastric cancer (P = 0.13) compared to the control group. Conclusion:, A positive association between CTLA-4 TACG haplotype and gastric and colorectal cancers was found in an Iranian population. A protective role for TACA haplotype is postulated. [source] Polymorphisms of the IL-1 Gene Complex Are Associated With Alcohol Dependence in Spanish Caucasians: Data From an Association StudyALCOHOLISM, Issue 12 2009Pilar A. Saiz Background:, There is growing evidence for involvement of pro-inflammatory cytokines in alcohol dependence. The aim of this study was to investigate whether 4 functionally relevant polymorphisms of the interleukin-1 (IL-1) and tumor necrosis factor-alpha genes were associated with alcohol dependence and with measures of clinical severity and treatment outcome. Methods:, Two hundred alcohol-dependent (AD) patients and 420 healthy controls from the same Spanish Caucasian population were genotyped using standard methods. Baseline and 6-month assessments included alcohol intake, addiction severity, and biomarkers of alcohol intake. Results:, Alcohol-dependent patients showed an excess of IL-1,,889 C/T [50.8% vs. 39.3%, ,2 (df) = 7.30 (2), uncorrected p = 0.026, corrected p = 0.104] and IL-1RA (86 bp)n A1/A1 genotypes [64.8% vs. 50.8%, ,2 (df) = 12.65 (3), corrected p = 0.020]. The A1/A1 excess was associated with alcohol dependence only in men [69.9% vs. 49.5%, ,2 (df) = 15.72 (2), corrected p < 0.001]. Six-month clinical and hematological outcome measures did not vary by genotype of the 4 polymorphisms. Haplotype analysis revealed an excess of the IL-1,,889 C/IL-1, +3953 C/IL-1RA A2 haplotype in the control group compared with AD patients [20.0% vs. 14.1%, ,2 (df) = 7.25 (1), p = 0.007; odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.46,0.89] and in the abstainers after 6 months of treatment compared with nonabstinent patients [14.7% vs. 6.2%, ,2 (df) = 5.65 (1), p = 0.017; OR = 2.56, 95% CI = 1.15,5.62]. Conclusions:, Our findings provide further tentative evidence of the role of IL-1 in alcohol dependence as well as evidence that the nature of the associations may be direct, gender-specific, or involve haplotype effects. However, findings from single association studies constitute tentative knowledge and must be interpreted carefully and precise replication is required. [source] A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiencyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004P. H. B. Bolton-Maggs Summary., Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect. [source] A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitisALLERGY, Issue 9 2009M. Benson Background:, Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. Objective:, To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. Methods:, CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. Results:, Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. Conclusion:, Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR. [source] Haplotype analysis of the PARK 11 gene, GIGYF2, in sporadic Parkinson's disease,MOVEMENT DISORDERS, Issue 3 2009Greg T. Sutherland PhD Abstract Familial Parkinsonism (PARK) genes are strong candidates for conferring susceptibility to common forms of PD. However, most studies to date have provided little evidence that their common variants substantially influence disease risk. Recently, mutations were described in the gene, GIGYF2 (TNRC15), located at the PARK11 locus (2q37.1). Here, we use a haplotype tagging approach to examine common variation in the GIGYF2 gene and PD risk. PD cases (n = 568) and age and gender-matched control subjects (n = 568) were recruited from three specialist movement disorder clinics in Brisbane (Australia) and the Australian electoral roll. Twelve tagging SNPs were assessed in all subjects and haplotype and genotype associations were explored. Overall our findings suggest that common genetic variants of GIGYF2 do not significantly affect sporadic PD risk in Australian Caucasians. © 2008 Movement Disorder Society [source] XPC genetic polymorphisms correlate with the response to imatinib treatment in patients with chronic phase chronic myeloid leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2010Vicent M. Guillem Chronic myeloid leukemia (CML) is driven by the BCR-ABL protein, which promotes the proliferation and viability of the leukemic cells. Moreover, BCR-ABL induces genomic instability that can contribute to the emergence of resistant clones to the ABL kinase inhibitors. It is currently unknown whether the inherited individual capability to repair DNA damage could affect the treatment results. To address this, a comprehensive analysis of single nucleotide polimorfisms (SNPs) on the nucleotide excision repair (NER) genes (ERCC2-ERCC8, RPA1-RPA3, LIG1, RAD23B, XPA, XPC) was performed in 92 chronic phase CML patients treated with imatinib upfront. ERCC5 and XPC SNPs correlated with the response to imatinib. Haplotype analysis of XPC showed that the wild-type haplotype (499C-939A) was associated with a better response to imatinib. Moreover, the 5-year failure free survival for CA carriers was significantly better than that of the non-CA carriers (98% vs. 73%; P = 0.02). In the multivariate logistic model with genetic data and clinical covariates, the hemoglobin (Hb) level and the XPC haplotype were independently associated with the treatment response, with patients having a Hb ,11 g/dl (Odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.5,16.1) or a non-CA XPC haplotype (OR = 4.1, 95% CI = 1.6,10.6) being at higher risk of suboptimal response/treatment failure. Our findings suggest that genetic polymorphisms in the NER pathway may influence the results to imatinib treatment in CML. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Bovine umbilical hernia maps to the centromeric end of Bos taurus autosome 8ANIMAL GENETICS, Issue 6 2004M. Ron Summary Twelve bull calves were produced by mating elite Israeli cows to ,Glenhapton Enhancer', a Canadian Holstein bull. The frequency of umbilical hernia (UH) in the progeny of the sons ranged from 1 to 21%, consistent with the hypothesis that Enhancer is the carrier of major dominant or codominant gene with partial penetrance for UH. Five sons of Enhancer produced progeny with >10% frequency of UH including sire 3259, whereas progeny of three sons had <3% UH. A total of 116 grand-progeny of Enhancer, all progeny of 3259, were genotyped for 59 microsatellites spanning the 29 bovine autosomes. Of these offspring, 41 were affected. Significant differences in paternal allele frequencies between the affected and unaffected progeny groups were found for marker BMS1591 on bovine chromosome 8 (BTA8). The UH-associated paternal allele originated from Enhancer. The chromosomal segment associated with UH was more precisely mapped between UWCA47, on the centromeric end of BTA8 and RM321, 12 cM from the centromere. A maximum LOD score of 3.84 was obtained 2.5 cM from the centromere with a support interval of 8 cM. Haplotype analysis of eight sons of Enhancer suggested that the UH gene is located in the centromeric end of BTA8 beyond ARO71/ARO72. Thus, by integrating the results from progeny of sire 3259 and sons of Enhancer the location of the UH gene was further refined to the BTA8 segment between ARO71/ARO72 and UWCA47. [source] Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia FamiliesANNALS OF HUMAN GENETICS, Issue 5 2009Luciana Chessa Summary We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of ,mild' hot spots of mutation located along the sequence of the ATM gene. [source] Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non-Fatal Myocardial InfarctionANNALS OF HUMAN GENETICS, Issue 6 2008V. Meiner Summary Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP ,2708 G/A, ,971 A/G, ,629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (,2708 G, ,971 G, ,629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (,2708 G, ,971 A, ,629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4,14.8] and haplotype B (,2708 G, ,971 G, ,629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 , 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations. [source] SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery DiseaseANNALS OF HUMAN GENETICS, Issue 6 2003D. A. Tregouet Summary P-selectin and P-selectin glycoprotein ligand (SELPLG, selectin P ligand) constitute a receptor/ligand complex that is likely to be involved in the development of atherosclerosis and its complications. While the genetic variability of P-selectin has already been investigated in depth, that of the SELPLG gene has not yet been extensively explored. The coding and regulatory sequences of the SELPLG were screened and nine polymorphisms were identified. The identified polymorphisms were genotyped in the AtheroGene study, a case-control study of coronary artery disease (CAD). Haplotype analysis revealed that two polymorphisms of SELPLG, the M62I and the VNTR, independently influenced plasma SELPLG levels. Conversely, haplotypes of SELPLG were not associated with CAD risk. [source] | ||||||||||||||||||||||||||||