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PubMed2006

Chromosomal damage and polymorphisms of DNA repair genes XRCC1 and XRCC3 in workers exposed to cytostatics.

OBJECTIVES: Medical workers in oncological units have chronically been exposed to low doses of cytostatics (C) with potential consequences on DNA and chromosomal integrity. Our study addresses relationships between chromosomal aberrations (CAs), chromosome (CSA), and chromatid (CTA) types and polymorphisms in DNA repair genes XRCC1 and XRCC3. METHODS: The study was conducted on 72 exposed individuals from hospitals in Martin (HMT; 28 individuals), Ruzomberok (HRK; 31 medical workers) and in Trstená (HTS; 13 individuals), and on 34 unexposed individuals. Conventional cytogenetic analysis was employed for the detection of CAs. XRCC1 and XRCC3 polymorphisms were assayed for by Taqman SNP genotyping assays ("Assay-by-Demand") using Real-Time allelic discrimination on AB 7 500 equipment (all from Applied Biosystems, Foster City, USA). RESULTS: Higher frequencies of CAs were detected in exposed individuals than in controls (1.78% versus 1.32%, respectively). The frequency of aberrant cells (Ab.c.) was highest among workers from HRK (1.97%), followed by those from HMT and HTS (1.54% and 1.85 %, respectively). In the exposed group a moderately higher frequency of CTA (0.93%) in comparison with CSA (0.85%) was detected. Higher CAs were detected in individuals with homozygous variant polymorphism in XRCC1 exon 10 gene than in those with wild-type genotype (1.87% versus 1.60%). Variant T allele in XRCC3 exon 7 was also associated with higher CAs (1.71% and 1.74%) as compared to the wild-type C allele (1.45%). CONCLUSIONS: The detection of individuals with increased susceptibility to genotoxic agents enables to take preventive measures during the working process.

Adult↗

PubMed2005

No evidence of correlation between the single nucleotide polymorphism of DNMT3B promoter and gastric cancer risk in a Japanese population.

DNA methylation is a major epigenetic modification in humans, and aberrant DNA methylation may play an important role in the development of various cancers through the silencing of some tumor suppressor genes. DNMT3B is required for the establishment and maintenance of genomic methylation patterns. The -149 C/T single nucleotide polymorphism (SNP) in the promoter of DNMT3B has been identified. This SNP influences DNMT3B promoter function, with the T allele having greater activity than the C allele, and is associated with an increased risk of lung cancer. The purpose of our study was to investigate the correlation between the DNMT3B promoter polymorphism and the development and progression of gastric cancer. We analyzed the SNP of the DNMT3B promoter in 152 gastric cancer patients and 247 controls from a Japanese population using PCR-RFLP and sequencing analysis, and also studied the association between the genotypes of DNMT3B and clinicopathological parameters among cases. Allelic difference was not found between gastric cancer patients and control subjects at the target site, -149 bp from the transcriptional start site in the DNMT3B gene promoter. Only the T/T genotype was detected in all gastric cancer patients and control subjects. We concluded that there was no association between SNP of the DNMT3B promoter and gastric cancer risk in a Japanese population.

Case-Control Studies↗

PubMed2006

Multiple sclerosis: postlinkage genetics.

Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.

Genetic Linkage↗

PubMed2005

Association testing in a linked region using large pedigrees.

This report describes computer implementation of a scheme for joint linkage and association analysis. The model implemented in the computer package Mendel estimates both recombination and linkage-disequilibrium parameters and conducts likelihood-ratio tests for (1) linkage alone, (2) linkage and association simultaneously, and (3) association in the presence of linkage. Application of the method to data from Finnish pedigrees with familial combined hyperlipidemia illustrates its potential for identification of associated SNP haplotypes in the presence of linkage. For the test results to be valid, good estimates of haplotype frequencies must be used in the analysis.

Female↗

PubMed2005

Inducible nitric oxide synthase (iNOS) expression in monocytes during acute Dengue Fever in patients and during in vitro infection.

UNLABELLED: Mononuclear phagocytes are considered to be main targets for Dengue Virus (DENV) replication. These cells are activated after infection, producing proinflammatory mediators, including tumour-necrosis factor-alpha, which has also been detected in vivo. Nitric oxide (NO), usually produced by activated mononuclear phagocytes, has antimicrobial and antiviral activities. METHODS: The expression of DENV antigens and inducible nitric oxide synthase (iNOS) in human blood isolated monocytes were analysed by flow cytometry using cells either from patients with acute Dengue Fever or after DENV-1 in vitro infection. DENV-1 susceptibility to iNOS inhibition and NO production was investigated using NG-methyl L-Arginine (NGMLA) as an iNOS inhibitor, which was added to DENV-1 infected human monocytes, and sodium nitroprussiate (SNP), a NO donor, added to infected C6/36 mosquito cell clone. Viral antigens after treatments were detected by flow cytometry analysis. RESULTS: INOS expression in activated monocytes was observed in 10 out of 21 patients with Dengue Fever and was absent in cells from ten healthy individuals. DENV antigens detected in 25 out of 35 patients, were observed early during in vitro infection (3 days), significantly diminished with time, indicating that virus replicated, however monocytes controlled the infection. On the other hand, the iNOS expression was detected at increasing frequency in in vitro infected monocytes from three to six days, exhibiting an inverse relationship to DENV antigen expression. We demonstrated that the detection of the DENV-1 antigen was enhanced during monocyte treatment with NGMLA. In the mosquito cell line C6/36, virus detection was significantly reduced in the presence of SNP, when compared to that of untreated cells. CONCLUSION: This study is the first to reveal the activation of DENV infected monocytes based on induction of iNOS both in vivo and in vitro, as well as the susceptibility of DENV-1 to a NO production.

Acute Disease↗

PubMed2005

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22.

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X-chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 post-menopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (P<0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (P=0.018) and genotypes (P=0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (P=0.01) and for haplotypes defined by both SNP (P=0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Absorptiometry, Photon↗

PubMed2005

Identifying genetic variation affecting a complex trait in simulated data: a comparison of meta-analysis with pooled data analysis.

We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.

Computer Simulation↗

PubMed2026

Systematic Approach for Compound Angus Populations Revealing Positional Candidate Genes and Improving Prediction Accuracy in Carcass Traits.

Carcass traits, which reflect growth performance and muscle development, are economically important in beef cattle, yet their genetic determinants remain poorly characterized. Both single-population Genome-wide association studies (GWAS) methods, such as BLINK, and cross-population meta-analysis approaches are widely used to identify genetic variants, yet their comparative performance in genomic prediction for complex traits in structured populations remains underexplored. Few studies have directly compared these methods in genomic prediction. To address this gap, this study aims to (i) identify positional candidate genes associated with carcass traits and (ii) evaluate the context-dependent advantages of Covariate Adjustment (CA) and meta in genomic prediction. In this study, we analyzed carcass weight (CW), live weight (LW), and dressing percentage (DP) in 279 crossbred Angus cattle genotyped with the PHR0105_Bt140K_v1.0 SNP chip. GWAS was performed on the full population using BLINK, and results from three subpopulations were combined via meta-analysis, with significance thresholds for both approaches determined by a shuffle-based method. Candidate genes located within ±10 kb of significant SNPs were associated with different carcass traits, including STRIT1, SEL1L3, NOC4L and ANK1 for DP; SNCA and DNAH5 for CW; and GYPC, GPR158, and GUCY1A1 for LW. Prediction accuracy under MAS and MABLUP showed meta slightly outperformed BLINK in MAS, while BLINK was better with covariate adjustment; after incorporating kinship in MABLUP, meta achieved higher accuracy and population partitioning was negligible. Overall, MABLUP yielded the highest accuracy (0.52-0.79) versus MAS (0.37-0.54) in all traits. These findings provide a methodological basis for selecting appropriate GWAS strategies in structured populations and highlight candidate genes.

GS↗

PubMed2006

Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.

We report the development and validation of experimental methods, study designs, and analysis software for pooling-based genomewide association (GWA) studies that use high-throughput single-nucleotide-polymorphism (SNP) genotyping microarrays. We first describe a theoretical framework for establishing the effectiveness of pooling genomic DNA as a low-cost alternative to individually genotyping thousands of samples on high-density SNP microarrays. Next, we describe software called "GenePool," which directly analyzes SNP microarray probe intensity data and ranks SNPs by increased likelihood of being genetically associated with a trait or disorder. Finally, we apply these methods to experimental case-control data and demonstrate successful identification of published genetic susceptibility loci for a rare monogenic disease (sudden infant death with dysgenesis of the testes syndrome), a rare complex disease (progressive supranuclear palsy), and a common complex disease (Alzheimer disease) across multiple SNP genotyping platforms. On the basis of these theoretical calculations and their experimental validation, our results suggest that pooling-based GWA studies are a logical first step for determining whether major genetic associations exist in diseases with high heritability.

Alzheimer Disease↗

PubMed2005

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study.

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Aged↗

PubMed2005

[Association between single-nucleotide polymorphisms in estrogen receptor beta gene and risk of prostate cancer].

OBJECTIVE: This study was undertaken to investigate the relationship of some single nucleotide polymorphisms (SNPs) of estrogen receptor beta (ERbeta) with the risk of prostate cancer (CaP). METHODS: The allele, genotype distribution in an association study with case-control samples involving 40 CaP cases and 86 unrelated healthy male subjects was analyzed. In these individuals, three upstream regions of the proximal ER promoter SNPs (rs3829768, rs1271572, rs3841304) and exon 7 SNP (rs1256049) were analyzed by directly sequencing amplified PCR products of genomic DNA. RESULTS: Four polymorphisms were identified. The rs3841304 was excluded from further analysis because of significant deviation from the Hardy-Weinberg equilibrium. The genotype and allele frequency of rs3829768 (A/G) and rs1271572 (C/A) in the upstream region of proximal promoter were significantly decreased in the CaP cases versus control (P < 0.01). CONCLUSIONS: Our study suggests that this disease of interest is highly associated with rs3829768 (A/G) and rs1271572 (C/A) in CaP cases. CaP, prostate cancer; ERalpha, estrogen receptor alpha; ERbeta, estrogen receptor beta; SNP, Single nucleotide polymorphisms; betaERKO, ERbeta knockout; PIN, prostatic intraepithelial neoplasia; HWE, Hardy-Weinberg equilibrium; NRE, Negative Regulatory Element.

Aged↗

PubMed2001

The R100Q mutation of the GABA(A) alpha(6) receptor subunit may contribute to voluntary aversion to ethanol in the sNP rat line.

We have investigated the GABA(A) alpha(6) subunit molecular composition in two rat lines selectively bred for high or low ethanol preference and consumption, namely Sardinian alcohol-preferring (sP) and Sardinian non-alcohol-preferring (sNP) rats, which have been bred at the University of Cagliari, Italy, since 1981. A total of 27 sP, 22 sNP and 25 control rats belonging to five other different strains, were studied by direct sequencing and amplification refractory mutation system analysis. Among the sNPs, only one was found to be normal, 11 heterozygotes, and 10 homozygotes for the G-->A substitution in codon 100, the same R100Q point mutation previously described in Alcohol Non Tolerant rats, while no other animal showed any mutated allele. Pharmacological studies have extensively demonstrated that this substitution in the mature peptide changes the benzodiazepine-insensitive receptor to a sensitive one. In order to test the functional significance of this mutation in native cerebellar GABA(A) receptors, selective breeding from Q/R rats was employed to obtain a sufficient number of R/R homozygotes. Xenopus laevis oocytes were then injected with cerebellar synaptosomes extracted from Q/Q, R/Q and R/R sNP rats. Consistently, utilizing the two-electrode voltage-clamp technique, GABA-evoked currents mediated by GABA(A) receptors containing the mutated alpha(6) subunit were potentiated by diazepam with about a two-fold increased potency, as compared to receptors containing the wild-type, benzodiazepine-insensitive alpha(6) subunit. Our data show for the first time that a mutated GABA(A) alpha(6) receptor subunit segregates in a rat line which voluntarily avoids alcohol consumption, and further support a possible involvement of the GABA(A) receptor containing a mutated alpha(6) subunit in the genetic predisposition to alcohol preference.

Alcohol Drinking↗

PubMed2026

Integrated Genome-Wide Association Studies and Selection Signature Analysis Reveal the Genetic Architecture of the Wattle Trait in Goats.

Wattles are finger-like appendages on the ventral neck of goats, serving as a distinctive morphological marker for breed identification that serves potential implications for production performance. However, their genetic basis remains incompletely characterized. Here, we integrated a genome-wide association study (GWAS) and selection signature analysis to identify candidate genes and genomic regions associated with the wattle trait in goats. Using a linear mixed model, GWAS on 463 goats (23 wattled and 440 non-wattled) identified 385 quantitative trait loci (QTLs) at a 5% false discovery rate, yielding 346 candidate genes. The most significant association signal was observed on chromosome 10 (72.61-73.48 Mb), where the lead SNP (rs636481767) is located within a region containing GJD2, GREM1, and FMN1, showing strong linkage disequilibrium (r2 > 0.6) with surrounding loci. Subsequent selection signature analysis (23 wattled and 23 non-wattled) identified 83 genomic regions harboring 119 candidate genes. The strongest signals were detected at MFSD14B on chromosome 8 (FST = 0.154, log2π-ratio = 2.611) and PDLIM7 on chromosome 7 (FST = 0.144, log2π-ratio = 0.806). KEGG pathway enrichment analysis revealed that GWAS-associated genes were involved in glycosylation and immune responses, whereas selection-signature genes were enriched in DNA repair and the Hippo, Notch, and Wnt pathways. Furthermore, cross-species PheWAS revealed that human FMN1 is associated with dermatological, skeletal, and metabolic phenotypes, while porcine FMN1 is associated with backfat thickness and loin muscle depth. Overall, this study provides molecular markers of potential value for goat breeding and pinpoints key candidate genes for future functional validation of wattle development.

Animals↗

PubMed2003

[Polymorphism of interleukin-10 gene promoter and its association with susceptibility to chronic obstructive pulmonary disease in Chinese Han people].

OBJECTIVE: To investigate the polymorphism of interleukin-10 (IL-10) gene promoters in Chinese Han people, and to disclose whether such polymorphism is associated with susceptibility to chronic obstructive pulmonary disease (COPD). METHODS: After the process of extracting genomic DNA from blood of 94 health smokers and 88 COPD smokers by use of phenol-chloroform-isoamyl alcohol, three single nucleotide polymorphism (SNP) sites in IL-10 gene promoter marked as -1082G/A,-819C/T,-592C/A were determined by polymerase chain reaction/restriction fragment length polymorphism analysis. RESULTS: Eleven different promoter genotypes were detected from all of the 182 smokers, and AA*TT*AA, AA*TC*AC, AA*TC*AA genotypes accounted for about 80% of genotypes in the research subjects. Two previously unreported haplotypes of IL-10 gene promoter (ATC and ACA) were found in Chinese Han people by analyzing the promoter genotypes. -1082G/A and -592C/A SNP sites polymorphisms were not associated with susceptibility to COPD, whereas the genotypes of -819C/T SNP site were associated with susceptibility to COPD in Chinese Han people. In respect to the alleles frequencies of the three SNP sites respectively, the Chinese Hans were similar to Japanese, but different from whites. CONCLUSION: Polymorphism of IL-10 -819C/T SNP site is associated with susceptibility to COPD in Chinese Han people; at least five haplotypes of IL-10 gene promoter (ATA, ACC, GCC, ATC and ACA) exist in Chinese Han people.

Aged↗

PubMed2003

Application of haplotype pair analysis for the identification of hemizygous loci.

An expectation maximisation based prediction algorithm was created to identify unusual haplotypes in patient samples that may be caused by small intragenic deletions. In this approach, unphased SNP genotypes are compared to pairs of canonical haplotypes to identify potentially hemizygous regions. This method was successfully applied to identify five deletions in the 3' region of BRCA1.

Algorithms↗

PubMed2007

A new multimarker test for family-based association studies.

We propose a new multimarker test for family-based studies in candidate genes. We use simulations under different genetic models to assess the performance of competing testing strategies, characterized in this study as combinations of the following important factors: genes, statistical tests, tag single nucleotide polymorphisms (SNP) methods, number of tag SNPs and family designs. An ANOVA model is employed to provide descriptive summaries of the effects on power of the above-mentioned factors. We find that tag SNP methods, gene characteristics and family designs have minimal impact on the best testing strategy. The familywise error rate (FWER) controlling multiple comparison procedure and the new multimarker test offer the highest power followed by the asymptotic global haplotype test. Both the FWER and the multimarker test are invariant to family designs and gain power as we increase the number of tag SNPs. However, the performance of the global haplotype test is slightly degraded when analyzing larger numbers of tag SNPs. Within the framework of our study, the best strategy for family-based studies in candidate genes that emerged from our analysis is to use the FWER or the multimarker test and select 6-10 tag SNPs using any of the tag SNP methods considered. We confirm the conclusions of our study with an application to Alzheimer's disease data.

Alzheimer Disease↗

PubMed2002

[Study on single nucleotide polymorphism of TIGR gene in primary open-angle glaucoma patients].

OBJECTIVE: To detect the single nucleotide polymorphism (SNP) of trabecular meshwork-induced glucocorticoid response protein (TIGR) gene and to investigate the association between SNP and primary open-angle glaucoma (POAG) in Chinese Han population. METHODS: High throughput conformation sensitive gel electrophoresis (HTCSGE) and fluorescent labeling automated sequencing method were used to screen and identify the SNPs of TIGR in 82 unrelated patients with POAG. Restriction endonuclease analysis was used to detect the SNPs of TIGR in 150 sex-and age-matched unrelated control subjects without POAG. The frequencies of genotypes and alleles of each SNP between the two groups were compared by chi-square test. RESULTS: A total of six SNPs were identified in TIGR gene with a length of 2172 bp, including all coding regions and part of promoter, introns and 3'UTR region: 1-83(G --> A), G12R, R46X, R76K, IVS2 + 35(A --> G), and T353I. Significant differences were found in frequencies of the genotype TC and the allele T of T353I between POAG patients and control subjects. The frequency of heterozygote TC was 12.20% in POAG patients, significantly higher than that in control subjects (3.33%, kappa(2) = 6.885, P = 0.009, OR = 4.028, OR95% CI = 1.327 approximately 12.223). The frequency of the allele T was 6.10% in POAG patients, significantly higher than that in control subjects (1.67%, kappa(2) = 6.655, P = 0.010). No significant difference was found between the two groups in frequencies of genotypes and alleles of the other SNPs. CONCLUSION: The T353I polymorphism of TIGR gene is associated with POAG in Chinese Han population.

Aged↗

PubMed2005

Standard linkage and association methods identify the mechanism of four susceptibility genes for a simulated complex disease.

The simulated dataset of the Genetic Analysis Workshop 14 provided affection status and the presence or absence of 12 traits. It was determined that all affected individuals must have traits E, F and H (EFH phenotype) and they must also have either trait B (B subtype) or traits C, D, and G (CDG subtype). A genome screen was performed, and linkage peaks were identified on chromosomes 1, 3, 5, and 9 using microsatellite markers. Dense panels of single-nucleotide polymorphism (SNP) markers were ordered for each of the four linkage peaks. In each case, association analyses identified a single SNP that accounted for the linkage evidence. The SNP on chromosome 1 appeared to primarily influence the B subtype, while the SNPs on chromosomes 5 and 9 primarily influenced the CDG subtype. The chromosome 3 SNP had the strongest effect and influenced both subtypes, as well as the requisite EFH phenotype. Recognizing the two subtypes prior to linkage analysis was key to identifying these loci using only a single replicate. This highlights the need in real life situations for careful examination of the phenotypic data prior to genetic analysis.

Chromosome Mapping↗