SEARCH · PubMed Health

Results for “Haplotypes”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources

PubMed2005

Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.

Single-nucleotide polymorphisms of the beta(2)-adrenergic receptor gene and its 5' promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the beta(2)-adrenergic receptor (position 19 [Cys/Arg] of the 5' leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (-)-isoproterenol-induced cyclic adenosine monophosphate (cAMP) accumulation and beta(2)-adrenergic receptor sequestration and downregulation were measured in relation to beta(2)-adrenergic receptor-mediated inhibition of IFN-gamma and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the beta-agonist-induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of beta-agonist-induced cAMP response was not associated with haplotype-dependent beta(2)-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor-CD3 complex and to costimulatory molecule CD28 (alphaCD3/alphaCD28). This is the first study demonstrating haplotype-related differences in agonist-induced beta(2)-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the beta(2)-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.

Adult↗

PubMed2005

Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma.

RATIONALE: Allergic diseases are influenced by both genes and environment. A 70-kb haplotype block in the G protein-coupled receptor for asthma susceptibility gene (GPR154; alias GPRA) on chromosome 7p was recently identified to influence susceptibility to asthma and elevated total serum IgE levels in adults. OBJECTIVES: To assess the impact of GPR154 on childhood allergic disease, including allergic sensitization, asthma, and rhinoconjunctivitis, in study populations with diverse environmental backgrounds. METHODS: We studied farm children, Steiner school children, and two reference groups from five Western European countries in the cross-sectional PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle) study and a sample of children from the Swedish birth cohort study BAMSE. DNA samples from 3,113 PARSIFAL and 800 BAMSE children were genotyped for 7 GPR154 polymorphisms and haplotypes were inferred. The proportions of alleles and haplotypes (H1-H7) were compared in affected children with their healthy counterparts. RESULTS: Data indicate a global association of the haplotype block to sensitization (allergen-specific serum IgE > or = 0.35 kU/L, p = 0.022), with significant haplotype-specific associations for H1, H5, and H6. Haplotypes H1 and H5 were also significantly associated with childhood allergic asthma (p = 0.045 and p = 0.023, respectively), and H5 to asthma regardless of sensitization. A broader involvement of GPR154 in allergic diseases was further supported in allergic rhinoconjunctivitis (H3: p = 0.046). The associated haplotypes could be allocated into risk (H5/H6) and nonrisk (H1/H3) groups, a pattern supported by allelic association of single nucleotide polymorphisms (SNPs) rs324384 and rs324396. CONCLUSIONS: Our results indicate that polymorphisms and haplotypes in the haplotype block of GPR154 are associated with asthma, rhinoconjunctivitis, and sensitization in European children.

Adolescent↗

PubMed2005

htSNPer1.0: software for haplotype block partition and htSNPs selection.

BACKGROUND: There is recently great interest in haplotype block structure and haplotype tagging SNPs (htSNPs) in the human genome for its implication on htSNPs-based association mapping strategy for complex disease. Different definitions have been used to characterize the haplotype block structure in the human genome, and several different performance criteria and algorithms have been suggested on htSNPs selection. RESULTS: A heuristic algorithm, generalized branch-and-bound algorithm, is applied to the searching of minimal set of haplotype tagging SNPs (htSNPs) according to different htSNPs performance criteria. We develop a software htSNPer1.0 to implement the algorithm, and integrate three htSNPs performance criteria and four haplotype block definitions for haplotype block partitioning. It is a software with powerful Graphical User Interface (GUI), which can be used to characterize the haplotype block structure and select htSNPs in the candidate gene or interested genomic regions. It can find the global optimization with only a fraction of the computing time consumed by exhaustive searching algorithm. CONCLUSION: htSNPer1.0 allows molecular geneticists to perform haplotype block analysis and htSNPs selection using different definitions and performance criteria. The software is a powerful tool for those focusing on association mapping based on strategy of haplotype block and htSNPs.

Algorithms↗

PubMed2005

Inferring haplotypes at the NAT2 locus: the computational approach.

BACKGROUND: Numerous studies have attempted to relate genetic polymorphisms within the N-acetyltransferase 2 gene (NAT2) to interindividual differences in response to drugs or in disease susceptibility. However, genotyping of individuals single-nucleotide polymorphisms (SNPs) alone may not always provide enough information to reach these goals. It is important to link SNPs in terms of haplotypes which carry more information about the genotype-phenotype relationship. Special analytical techniques have been designed to unequivocally determine the allocation of mutations to either DNA strand. However, molecular haplotyping methods are labour-intensive and expensive and do not appear to be good candidates for routine clinical applications. A cheap and relatively straightforward alternative is the use of computational algorithms. The objective of this study was to assess the performance of the computational approach in NAT2 haplotype reconstruction from phase-unknown genotype data, for population samples of various ethnic origin. RESULTS: We empirically evaluated the effectiveness of four haplotyping algorithms in predicting haplotype phases at NAT2, by comparing the results with those directly obtained through molecular haplotyping. All computational methods provided remarkably accurate and reliable estimates for NAT2 haplotype frequencies and individual haplotype phases. The Bayesian algorithm implemented in the PHASE program performed the best. CONCLUSION: This investigation provides a solid basis for the confident and rational use of computational methods which appear to be a good alternative to infer haplotype phases in the particular case of the NAT2 gene, where there is near complete linkage disequilibrium between polymorphic markers.

Algorithms↗

PubMed2006

Multinomial logistic regression approach to haplotype association analysis in population-based case-control studies.

BACKGROUND: The genetic association analysis using haplotypes as basic genetic units is anticipated to be a powerful strategy towards the discovery of genes predisposing human complex diseases. In particular, the increasing availability of high-resolution genetic markers such as the single-nucleotide polymorphisms (SNPs) has made haplotype-based association analysis an attractive alternative to single marker analysis. RESULTS: We consider haplotype association analysis under the population-based case-control study design. A multinomial logistic model is proposed for haplotype analysis with unphased genotype data, which can be decomposed into a prospective logistic model for disease risk as well as a model for the haplotype-pair distribution in the control population. Environmental factors can be readily incorporated and hence the haplotype-environment interaction can be assessed in the proposed model. The maximum likelihood estimation with unphased genotype data can be conveniently implemented in the proposed model by applying the EM algorithm to a prospective multinomial logistic regression model and ignoring the case-control design. We apply the proposed method to the hypertriglyceridemia study and identifies 3 haplotypes in the apolipoprotein A5 gene that are associated with increased risk for hypertriglyceridemia. A haplotype-age interaction effect is also identified. Simulation studies show that the proposed estimator has satisfactory finite-sample performances. CONCLUSION: Our results suggest that the proposed method can serve as a useful alternative to existing methods and a reliable tool for the case-control haplotype-based association analysis.

Algorithms↗

PubMed2003

HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama.

BACKGROUND: We wanted to quantify HLA-A and -B phenotype and haplotype frequencies in Alabama index patients with common variable immunodeficiency (CVID) and selective IgG subclass deficiency (IgGSD), and in control subjects. METHODS: Phenotypes were detected using DNA-based typing (index cases) and microlymphocytotoxicity typing (controls). RESULTS: A and B phenotypes were determined in 240 index cases (114 CVID, 126 IgGSD) and 1,321 controls and haplotypes in 195 index cases and 751 controls. Phenotyping revealed that the "uncorrected" frequencies of A*24, B*14, B*15, B*35, B*40, B*49, and B*50 were significantly greater in index cases, and frequencies of B*35, B*58, B*62 were significantly lower in index cases. After Bonferroni corrections, the frequencies of phenotypes A*24, B*14, and B*40 were significantly greater in index cases, and the frequency of B*62 was significantly lower in index cases. The most common haplotypes in index cases were A*02-B*44 (frequency 0.1385), A*01-B*08 (frequency 0.1308), and A*03-B*07 (frequency 0.1000), and the frequency of each was significantly greater in index cases than in control subjects ("uncorrected" values of p < 0.0001, 0.0252, and 0.0011, respectively). After performing Bonferroni corrections, however, the frequency of A*02-B*44 alone was significantly increased in probands (p < 0.0085). Three other haplotypes were also significantly more frequent in index cases (A*03-B*14, A*31-B*40, and A*32-B*14). The combined frequencies of three latter haplotypes in index patients and control subjects were 0.0411 and 0.0126, respectively ("uncorrected" value of p < 0.0002; "corrected" value of p = 0.0166). Most phenotype and haplotype frequencies in CVID and IgGSD were similar. 26.7% of index patients were HLA-haploidentical with one or more other index patients. We diagnosed CVID or IgGSD in first-degree or other relatives of 26 of 195 index patients for whom HLA-A and -B haplotypes had been ascertained; A*01-B*08, A*02-B*44, and A*29-B*44 were most frequently associated with CVID or IgGSD in these families. We conservatively estimated the combined population frequency of CVID and IgGSD to be 0.0092 in adults, based on the occurrence of CVID and IgGSD in spouses of the index cases. CONCLUSIONS: CVID and IgGSD in adults are significantly associated with several HLA haplotypes, many of which are also common in the Alabama Caucasian population. Immunoglobulin phenotype variability demonstrated in index cases and family studies herein suggests that there are multiple gene(s) on Ch6p or other chromosomes that modify immunoglobulin phenotypes of CVID and IgGSD. The estimated prevalence of CVID and IgGSD in central Alabama could be reasonably attributed to the fact that many HLA haplotypes significantly associated with these disorders are also common in the general population.

Adult↗

PubMed2005

A comprehensive literature review of haplotyping software and methods for use with unrelated individuals.

Interest in the assignment and frequency analysis of haplotypes in samples of unrelated individuals has increased immeasurably as a result of the emphasis placed on haplotype analyses by, for example, the International HapMap Project and related initiatives. Although there are many available computer programs for haplotype analysis applicable to samples of unrelated individuals, many of these programs have limitations and/or very specific uses. In this paper, the key features of available haplotype analysis software for use with unrelated individuals, as well as pooled DNA samples from unrelated individuals, are summarised. Programs for haplotype analysis were identified through keyword searches on PUBMED and various internet search engines, a review of citations from retrieved papers and personal communications, up to June 2004. Priority was given to functioning computer programs, rather than theoretical models and methods. The available software was considered in light of a number of factors: the algorithm(s) used, algorithm accuracy, assumptions, the accommodation of genotyping error, implementation of hypothesis testing, handling of missing data, software characteristics and web-based implementations. Review papers comparing specific methods and programs are also summarised. Forty-six haplotyping programs were identified and reviewed. The programs were divided into two groups: those designed for individual genotype data (a total of 43 programs) and those designed for use with pooled DNA samples (a total of three programs). The accuracy of programs using various criteria are assessed and the programs are categorised and discussed in light of: algorithm and method, accuracy, assumptions, genotyping error, hypothesis testing, missing data, software characteristics and web implementation. Many available programs have limitations (eg some cannot accommodate missing data) and/or are designed with specific tasks in mind (eg estimating haplotype frequencies rather than assigning most likely haplotypes to individuals). It is concluded that the selection of an appropriate haplotyping program for analysis purposes should be guided by what is known about the accuracy of estimation, as well as by the limitations and assumptions built into a program.

Algorithms↗

PubMed2004

Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study.

INTRODUCTION: The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. METHODS: We conducted a nested case-control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. RESULTS: Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (chi2 = 3.43, five degrees of freedom, P = 0.63). CONCLUSION: There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.

Adult↗

PubMed1991

Association between haplotypes and specific mutations in Swiss cystic fibrosis families.

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in Caucasian populations, with an incidence of about 1 in 2000 live births, implying a carrier frequency of about 1 in 22. In 1989, the CF gene was isolated and characterized and the major mutation (delta F508), a 3-bp deletion that results in the loss of a phenylalanine residue at position 508, was detected. To determine the frequency of the delta F508 mutation and the predicted number of additional mutations in our population, we have undertaken a collaborative study of 215 CF patients and 175 CF parents in Switzerland. The delta F508 mutation in exon 10 has been found in 70% of the CF chromosomes, and the exon-11 mutation R553X seems to be the second most common CF mutation in our population, with a frequency of 5.3%, whereas the G551D mutation (also in exon 11) has not been detected at all. Haplotype determination of 430 CF and 175 normal chromosomes using XV-2c, KM19, MP6d-9, and J3.11 has been proven to be very helpful in providing additional carrier risk calculations: Haplotypes 1 (1221), 2 (1222), 6 (2111), and 7 (2221) increase the risk of being a carrier from 1 in 55 (haplotype 6) to 1 in 17 (haplotype 1), whereas haplotypes 3 (1122), 4 (1112), 8 (2222) and 10 (1111) lower the risk from 1 in 144 (haplotype 3) to 1 in 1678 (haplotype 10). Moreover, the mutation R553X shows strong correlation with haplotype 3, leading to the suggestion that haplotypes 1, 2, 5, and 6 may account for four additional mutations in Switzerland.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Aberrations↗

PubMed2006

Associations of body size at birth with late-life cortisol concentrations and glucose tolerance are modified by haplotypes of the glucocorticoid receptor gene.

CONTEXT: Small body size at birth is associated with cardiovascular disease and type 2 diabetes in adult life. This link may be in part mediated by early-life programming of the hypothalamic-pituitary-adrenal axis (HPAA) function. OBJECTIVE: Our objective was to assess whether haplotypes of the glucocorticoid receptor (GR) gene modify this link. DESIGN AND PARTICIPANTS: We conducted a birth cohort study that included 437 men and women born in Helsinki, Finland, during 1924-1933, whose birth measurements were recorded. MAIN OUTCOME MEASURES: We studied how the oral glucose tolerance test and fasting plasma total and free cortisol concentrations and, in a subset of 162 women, a more detailed HPAA evaluation, are predicted by body size at birth and haplotypes of the GR locus. We also measured the haplotype-specific relative mRNA expression level for the haplotype of interest. RESULTS: One of the haplotypes was associated with lower birth weight and length and higher fasting plasma and mean 24-h salivary cortisol. Moreover, this haplotype modified the association of length at birth with adult phenotypes; in carriers, short length at birth was associated with increased fasting plasma cortisol, cortisol/corticosteroid-binding globulin ratio, impaired glucose tolerance or diabetes [1 cm decrease corresponded to 1.36-fold odds ratio; 95% confidence interval (CI), 1.09-1.70; P = 0.007], and higher 120-min glucose (5.8%; 95% CI, 2.5-9.1%; P = 0.0007), but no association was seen in noncarriers (P for interaction was 0.06, 0.01, 0.02, and 0.01, respectively). The mRNA expression level of this haplotype was 93.7% (95% CI, 90.5-96.8%; P = 2.2 x 10(-4)) of the expression level of the other haplotypes. CONCLUSIONS: A common GR haplotype may contribute to and modify the association of short length at birth with adult glucose tolerance and HPAA function by a mechanism that affects regulation of GR expression.

Aged↗

PubMed2002

Lineage classification of canine inheritable disorders using mitochondrial DNA haplotypes.

To estimate the maternal effects of dog breeds using mitochondrial DNA(mtDNA) haplotypes in the dogs with several clinical disorders, 600 base pairs of mtDNA D-loop region were amplified from 365 dogs and were determined for mtDNA sequences. The diversity of the 600-bp sequences was classified into 64 haplotypes, including 46 newly discovered haplotypes, and the haplotypes were grouped into four clusters I to IV. Lineage analysis using the mtDNA haplotype indicated that each dog breed genetically comprises one or a few mtDNA haplotypes. When the relationship between genetic background and occurrences of clinical diseases was estimated, canine lineage analysis using mtDNA haplotype revealed that the disorders distributed in the dominant mtDNA haplotypes of each dog breed, but no disorder closely associated with mtDNA haplotypes was detected.

Animals↗

PubMed2004

Rapid, long-range molecular haplotyping of thiopurine S-methyltransferase (TPMT) 3A, 3B, and *3C.

BACKGROUND: Haplotyping is an important technique in molecular diagnostics because haplotypes are often more predictive for individual phenotypes than are the underlying single-nucleotide polymorphisms (SNPs). Until recently, methods for haplotyping SNPs separated by kilobase distances were laborious and not applicable to high-throughput screening. In the case of thiopurine S-methyltransferase (TPMT*), differentiating among TPMT*3A, *3B, and *3C alleles is sometimes necessary for predictive genotyping. METHODS: The genomic region including the two SNPs that define TPMT*3A, *3B, and *3C alleles was amplified by long-range PCR. The resulting PCR product was circularized by ligation and haplotyped by allele-specific amplification PCR followed by product identification with hybridization probes. RESULTS: Critical points were the long-range PCR conditions, including choice of buffer and primers, optimization of the ligation reaction, and selection of primers that allowed for strict allele-specific amplification in the second-round PCR. Different underlying TPMT haplotypes could then be differentiated. Results from the haplotyping method were in full agreement with those from our standard real-time PCR method: TPMT*1/*3A (n = 20); TPMT*1/*3C (n = 4); TPMT*1/*1 (n = 6); and TPMT*3A/*3A (n = 6). One TPMT*1/*3A sample failed to amplify, and no whole blood was available for repeat DNA isolation. CONCLUSIONS: This method for rapid-cycle real-time, allele-specific amplification PCR-assisted long-range haplotyping has general application for the haplotyping of distant SNPs. The procedure is simpler and more rapid than previous methods. With respect to TPMT, haplotyping has the potential to discriminate the genotypes TPMT*1/*3A (intermediate metabolizer) and TPMT*3B/*3C (poor metabolizer).

DNA↗

PubMed2002

Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population.

OBJECTIVE: The polymorphisms of two genes have recently been associated with complex forms of type 2 diabetes mellitus (T2DM): calpain 10 and peroxisome proliferator-activated receptor-gamma (PPARgamma). Calpain 10 is a member of a large family of intracellular proteases. It was shown in Mexican-Americans and other populations that variants of three single nucleotide polymorphisms (SNPs), -43, -19, and -63, of this ubiquitously expressed protein influence susceptibility to T2DM. However, substantial differences were shown between ethnic groups in at risk alleles and haplotypes as well as in their attributable risk. Thus, it is important to determine the role of calpain 10 in various populations. AIM: To examine the role of calpain 10 SNPs -43, -19, and -63 in genetic susceptibility to T2DM in a Polish population. METHODS: Overall, 377 individuals were examined: 229 T2DM patients and 148 control individuals. The groups were genotyped for calpain 10 SNP-43, SNP-19, and SNP-63. SNP-19 was examined by electrophoresis of the PCR product on agarose gel by size, while the restriction fragment length polymorphism (RFLP) method was used for the two other markers. Differences in allele, genotype, haplotype, and haplotype combination distribution between the groups were examined by chi(2) test. RESULTS: Distributions of alleles, genotypes, and haplotypes at three loci defined by examined SNPs were not significantly different between the groups. However, the homozygote combination of 121 haplotype was more prevalent in the T2DM group than in the controls (17.9% vs 10.1%, P=0.039). No difference was observed in the 112/121 haplotype distribution. This heterozygous haplotype combination was associated with increased risk of T2DM in several populations. CONCLUSION: The results of our study suggest the association of calpain 10 121/121 haplotype combination created by SNPs -43, -19, and -63 with T2DM in a Polish population. However, we were not able to confirm the previously described role of the heterozygous 112/121 haplotype combination in susceptibility to T2DM.

Adult↗

PubMed2006

Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients.

Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P < 0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95% confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95% CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14% lower (geometric mean ratio 0.86; 95% CI 0.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels.

Aged↗

PubMed2004

Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes.

Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator implicated in transcriptional programs of hepatic gluconeogenesis, oxidative phosphorylation, and insulin release by beta-cells. To study associations of the PGC-1alpha gene locus with carbohydrate metabolism and type 2 diabetes in humans, we identified several polymorphisms in the promoter region that were located in a haplotype block distinct from a second haplotype block containing part of intron 2 and extending beyond exon 13. Each block contained five common haplotypes. Oral glucose tolerance testing revealed associations of promoter haplotype combinations with 30- and 60-min postload plasma glucose levels, whereas haplotypes in both blocks were associated with indexes of beta-cell function. The associations of promoter haplotypes are supported by functional studies showing that some polymorphisms are located in transcription factor binding sites and affect transactivation in an allele-specific manner. By comparing patients with type 2 diabetes and control subjects, we observed borderline significant differences of four-loci haplotype distributions in the downstream haplotype block. Moreover, the haplotype that was associated with the strongest insulin response to glucose conferred the lowest risk of type 2 diabetes (P < 0.01). Thus, the PGC-1alpha gene locus influences carbohydrate metabolism and contributes to type 2 diabetes in the population studied.

Aged↗

PubMed2005

Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women.

We assessed the association of four polymorphisms (promoter P3 -681C>G, P2 -689C>T, Pro12Ala, and 1431C>T) in peroxisome proliferator-activated receptor gamma (PPARgamma) with the metabolic syndrome risk in a large, French population study (n = 1,155). In this sample, 279 men and women presented with metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. When taken individually, none of the polymorphisms was significantly associated with the metabolic syndrome. Haplotype analyses, in contrast, revealed a significant enrichment of the GTGC haplotype frequency (corresponding to the P3 -681C>G, P2 -689C>T, Pro12Ala (C/G), and 1431C>T polymorphisms in this order) among those with metabolic syndrome compared with control subjects. Compared with the most common CCCC haplotype, the adjusted odds ratio (OR) (95% CI) of the metabolic syndrome for bearers of the GTGC haplotype was 2.37 (1.42-3.95; P = 0.002), 1.92 (1.00-3.72; P = 0.05), and 2.47 (1.09-5.62; P = 0.045) in the whole sample of men and women, respectively. Similar results were obtained when using another haplotype (GCCC, GTGT, CCCT, or GCCT) as a reference. Furthermore, when the GTGC haplotype frequency was tested alone (i.e., versus the frequency of the five other haplotypes together), the OR (95% CI) of the metabolic syndrome was 2.30 (1.05-5.00; P = 0.022). These data show that only the frequency of the GTGC haplotype was different between subjects with and without metabolic syndrome. Further analyses stratified on the 1431C>T single nucleotide polymorphism (SNP) indicated that the rare alleles of the P2 -689C>T and Pro12Ala SNPs were associated with an increased risk of the metabolic syndrome when combined to the 1431CC genotype. In conclusion, a specific haplotype of PPARgamma polymorphisms is associated with an increased risk of the metabolic syndrome in a French general population.

Adult↗

PubMed2002

The identification of common haplotypes on bovine chromosome 5 within commercial lines of Bos taurus and their associations with growth traits.

The cosegregation between a genetic marker and the QTL in a well-designed mapping population is the basis for successful QTL mapping. Linkage disequilibria are, however, also expected among individuals that descended from the same breeding line, and some common haplotypes should carry on and segregate among individuals of the line. These identical by descent haplotypes make it possible to identify and locate the QTL segregating in the line. We report the identification of common haplotypes within commercial lines of Bos taurus and their associations with growth traits. One hundred and seventy six male calves and their 12 sires (9 to 30 male calves of each sire) of the Beefbooster, Inc., M1 line selected for maternal traits over 30 yr were genotyped using 16 microsatellite markers chosen from bovine chromosome 5 for the initial haplotype and growth association analysis. In order to verify the results from the M1 line, another 170 male calves and their 14 sires from the Beefbooster M3 line were genotyped using nine microsatellite markers chosen from bovine chromosome 5. The alleles of each male calf contributed by the sire and by the dam were identified, and haplotypes in the M1 line were established along 93% of bovine chromosome 5. The haplotypes in the M3 line were established along the chosen regions of bovine chromosome 5. Regression analysis detected 10 haplotypes in three chromosomal regions (0 to 30 cM, 55 to 70 cM, and 70 to 80 cM) that showed significant associations with birth weight, preweaning average daily gain, and average daily gain on feed in M1 line and 9 haplotypes associated with the growth traits in the same chromosomal regions in the M3 line at the comparisonwise threshold level. On average, the 19 haplotypes have an effect of 0.68 SD on the growth traits, ranging from 0.41 SD to 1.02 SD The results provide a useful reference for further positional candidate gene research and marker-assisted selection.

Alleles↗

PubMed2001

Associations between casein haplotypes and first lactation milk production traits in Finnish Ayrshire cows.

The objective of this study was to estimate the effects of beta-kappa-casein (CN) haplotypes on first-lactation milk production traits. The beta-kappa-CN haplotypes were deduced using information on beta- and kappa-CN genotypes of cows and their sires for 16,973 Finnish Ayrshire cows that had at least nine paternal half sibs. Effects of CN haplotypes on milk production traits were estimated for one haplotype at a time using an animal model, which included the fixed effects for calving year and month, age at calving, days open, beta-lactoglobulin, and a beta-kappa-CN haplotype. Differences in milk production traits were also estimated between haplotype combinations A1A+A2B and A1B+A2A within beta-kappa-CN genotype A1A2AB and between combinations A1E+A2A and A1A+A2E within genotype A1A2AE. The beta-kappa-CN haplotypes A2A and A2B were associated with high milk and protein yields and low fat content, and those that included the beta-CN A1 allele were associated with low yields and high fat content. Protein content was affected by the kappa-CN locus; haplotype A1B was associated with high protein content and A1E was with low protein content. The haplotype combination A1A+A2B was associated with 140 kg more milk yield (P = 0.045) and 0.03 percentage units less protein content (P = 0.055) than combination A1B+A2A, and combination A1A+A2E showed 0.02 percentage units greater protein content (P = 0.098) than A1E+A2A. These results indicate that genes linked to the CN loci contribute to the variation in milk yield and protein content.

Alleles↗