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PubMed2005

Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk.

Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with > or = 22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with <22 CAG repeats (covariate-adjusted odds ratios, 1.31; 95% confidence intervals, 1.01-1.69). Five common haplotypes in the AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (> or = 22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (<22 CAG repeats).

Alleles↗

PubMed1999

Major beta-globin gene mutations in eastern India and their associated haplotypes.

324 alleles of the beta-globin gene from unrelated thalassaemia patients native to the eastern region of India (mainly from the state of West Bengal) were analysed for beta-globin gene mutations by the amplification refractory mutation system (ARMS). The major mutations that were detected are IVS-1 pos 5 (G-C), codon 26 (G-A) and codon 30 (G-C) with frequencies of 0.45, 0.33 and 0.05, respectively. Haplotype analysis revealed a very strong linkage disequilibrium of IVS-1 pos 5 (G-C) with one particular haplotype. HbE was found to be associated with two major haplotypes. Codon 30 (G-C) was associated with a haplotype that is the same as that found in the African population. Haplotype associated with codon 8/9 (+G) was the same as that found in northwest India. These findings have implications for the use of molecular diagnosis for genetic counselling and prenatal diagnosis of beta-thalassaemia in this region.

DNA Mutational Analysis↗

PubMedDate not supplied

Haplotyping in pedigrees via a genetic algorithm.

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.

Algorithms↗

PubMed1998

Comparison of the relative quantities of gamma-mRNAs and fetal hemoglobin in SS patients with different haplotypes.

We have studied the relative levels of gamma-mRNA [%gamma/(gamma + beta)], Ggamma- and Agamma-mRNAs [%Ggamma/(Ggamma + Agamma)], hemoglobin (Hb) F, and the Ggamma and Agamma chains in some 50 patients with sickle cell anemia (SS) and with different haplotypes. As expected, the Hb F levels varied greatly and were high in patients with the Saudi Arabian-Indian haplotype. Similarly, the Ggamma values varied greatly (from 19.5 to 76.5%) and depended on the haplotypes. A rare haplotype, named Mor, was found in 3 SS patients, 1 of whom was a homozygote Mor/Mor; this haplotype is associated with the lowest Ggamma value (19.5% in the homozygote) and with a C-->T mutation at position -202 of the Agamma promoter. The levels of gamma-mRNA roughly parallel those of Hb F, but older patients have increased levels of mRNA, which appears not to be efficiently translated into Hb F. Similar observation have been reported for other hemoglobinopathies such as deltabeta-thalassemia heterozygotes and Hb Lepore heterozygotes. The relative quantity of Ggamma-mRNA was closely related to that of the Ggamma chain in the 15 patients who were studied; the Ggamma- to Agamma-mRNA ratio did not change with age.

Adolescent↗

PubMed2002

Entropy as a measure for linkage disequilibrium over multilocus haplotype blocks.

OBJECTIVE: The presence of linkage disequilibrium (LD) forms the basis for a range of uses, including the fine-mapping of diseases and studies on human genealogy. Recent findings indicate that single nucleotide polymorphisms (SNP) can occur in blocks of limited haplotypic diversity with high degrees of LD. Commonly used measures for LD, such as r(2) and D', consider only two loci and might miss information to appropriately describe LD in larger haplotypic structures. METHODS: We introduce the Normalized Entropy Difference, epsilon, as a new multilocus measure for LD. A related quantity, deltaS, provides an approximate chi(2) test for the significance of LD. The ability of the measure to detect haplotype blocks is investigated using simulated data sets as well as a real data set previously analyzed by Daly et al. (2001). RESULTS: epsilon allows for arbitrary numbers of loci, describes LD with regard to the loci sequence, and can be interpreted as a multilocus extension of r(2). The application of epsilon to the data sets demonstrated the measure's ability to appropriately describe simultaneous multilocus LD and to detect haplotype blocks. CONCLUSIONS: epsilon is a reasonable multilocus LD measure and might be of potential use in the construction of the human haplotype map.

Chromosome Mapping↗

PubMed2003

Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study.

We describe an approach for picking haplotype-tagging single nucleotide polymorphisms (htSNPs) that is presently being taken in two large nested case-control studies within a multiethnic cohort (MEC), which are engaged in a search for associations between risk of prostate and breast cancer and common genetic variations in candidate genes. Based on a preliminary sample of 70 control subjects chosen at random from each of the 5 ethnic groups in the MEC we estimate haplotype frequencies using a variant of the Excoffier-Slatkin E-M algorithm after genotyping a high density of SNPs selected every 3-5 kb in and surrounding a candidate gene. In order to evaluate the performance of a candidate set of htSNPS (which will be genotyped in the much larger case-control sample) we treat the haplotype frequencies estimate above as known, and carry out a formal calculation of the uncertainty of the number of copies of common haplotypes carried by an individual, summarizing this calculation as a coefficient of determination, R2h. A candidate set of htSNPS of a given size is chosen so as to maximize the minimum value of R2h over the common haplotypes, h.

Aromatase↗

PubMed2005

Maximum likelihood haplotyping for general pedigrees.

Haplotype data is valuable in mapping disease-susceptibility genes in the study of Mendelian and complex diseases. We present algorithms for inferring a most likely haplotype configuration for general pedigrees, implemented in the newest version of the genetic linkage analysis system SUPERLINK. In SUPERLINK, genetic linkage analysis problems are represented internally using Bayesian networks. The use of Bayesian networks enables efficient maximum likelihood haplotyping for more complex pedigrees than was previously possible. Furthermore, to support efficient haplotyping for larger pedigrees, we have also incorporated a novel algorithm for determining a better elimination order for the variables of the Bayesian network. The presented optimization algorithm also improves likelihood computations. We present experimental results for the new algorithms on a variety of real and semiartificial data sets, and use our software to evaluate MCMC approximations for haplotyping.

Algorithms↗

PubMed2005

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Black or African American↗

PubMedDate not supplied

A bit about haplotypes: using binary digits to code tightly linked loci.

The advent of recombinant DNA techniques has resulted in the detection of a large number of polymorphic marker loci many of which are not useful for linkage studies because of their low degree of polymorphism. However, when no apparent recombination exists between several closely linked markers, the amount of 'information' available can be significantly increased by establishing haplotypes from those loci; that is, haplotyping increases the number of heterozygotes at marker loci. Haplotyping can be problematic when more than one of the loci involved in the haplotyping are heterozygous and the phase of the haplotypes cannot be inferred from the data. We present a method for recoding the phenotypic marker data for pedigree members that will circumvent this difficulty.

Alleles↗

PubMed2003

P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study.

BACKGROUND: We recently described a gain-of-function haplotype, called H2, of the adenosine diphosphate (ADP) receptor P2Y12 gene associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers. Because platelets play a key role in atherosclerosis and arterial thrombosis, we tested the possible link between the H2 haplotype and the risk of peripheral arterial disease (PAD) in a case-control study. METHODS AND RESULTS: We studied 184 consecutive male patients under 70 years of age with PAD and 330 age-matched control subjects free of symptomatic PAD and with no cardiovascular history. Mean age was 57.1+/-7.2 years (cases) and 56.7+/-7.6 years (control subjects). The H2 haplotype was more frequent in patients with PAD than in control subjects (30% and 21%, respectively; OR, 1.6; CI, 1.1 to 2.5; P=0.02 in univariate analysis). This association with PAD remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9; P=0.002) after adjustment for diabetes, smoking, hypertension, hypercholesterolemia, and other selected platelet receptor gene polymorphisms. CONCLUSIONS: These data point to a role of the H2 haplotype in atherosclerosis and raise the possibility of relative thienopyridine resistance in carriers of the P2Y12 H2 haplotype.

Aged↗

PubMed2007

The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells.

A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from -1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, beta-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at -20 and -217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of beta-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the -20 and -217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.

Adipose Tissue↗

PubMed2006

Common sodium channel promoter haplotype in asian subjects underlies variability in cardiac conduction.

BACKGROUND: Reduced cardiac sodium current slows conduction and renders the heart susceptible to ventricular fibrillation. Loss of function mutations in SCN5A, encoding the cardiac sodium channel, are one cause of the Brugada syndrome, associated with slow conduction and a high incidence of ventricular fibrillation, especially in Asians. In this study, we tested the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction. METHODS AND RESULTS: Resequencing 2.8 kb of SCN5A promoter identified a haplotype variant consisting of 6 polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks. Reporter activity of this variant haplotype, designated HapB, in cardiomyocytes was reduced 62% compared with wild-type haplotype (P=0.006). The relationship between SCN5A promoter haplotype and PR and QRS durations, indexes of conduction velocity, was then analyzed in a cohort of 71 Japanese Brugada syndrome subjects without SCN5A mutations and in 102 Japanese control subjects. In both groups, PR and QRS durations were significantly longer in HapB individuals (P< or =0.002) with a gene-dose effect. In addition, up to 28% and 48% of variability in PR and QRS durations, respectively, were attributable to this haplotype. The extent of QRS widening during challenge with sodium channel blockers, known to be arrhythmogenic in Brugada syndrome and other settings, was also genotype dependent (P=0.002). CONCLUSIONS: These data demonstrate that genetically determined variable sodium channel transcription occurs in the human heart and is associated with variable conduction velocity, an important contributor to arrhythmia susceptibility.

Adolescent↗

PubMed2005

Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthma-related phenotypes.

RATIONALE: Tumor necrosis factor is a proinflammatory cytokine found in increased concentrations in asthmatic airways. The TNF-alpha (TNF) and lymphotoxin-alpha (LTA) genes belong to the TNF gene superfamily located within the human major histocompatibility complex on chromosome 6p in a region repeatedly linked to asthma. The TNF position -308 and LTA NcoI polymorphisms are believed to influence TNF transcription and secretion, respectively. OBJECTIVES: This study sought to determine whether polymorphisms in TNF or LTA, or in TNF-LTA haplotypes, are associated with asthma and asthma phenotypes. METHODS: We genotyped the TNF -308 and LTA NcoI polymorphisms, and two other haplotype-tagging polymorphisms in the TNF and LTA genes, in 708 children with mild to moderate asthma enrolled in the Childhood Asthma Management Program and in their parents. Using an extension of the family-based association tests in the PBAT program, each polymorphism was tested for association with asthma, age at onset of asthma, and time series data on baseline FEV(1) % predicted, postbronchodilator FEV(1) % predicted, body mass index, and log of PC(20). MEASUREMENTS AND MAIN RESULTS: Although no associations were found for the individual single-nucleotide polymorphisms, the haplotype analysis found the LTA NcoI_G/LTA 4371T/TNF -308G/TNF 1078G haplotype to be associated with asthma and with all five phenotype groups. CONCLUSIONS: We conclude that it is unlikely that the TNF -308 or LTA NcoI polymorphisms influence asthma susceptibility individually, but that this haplotype of variants may be functional or may be in linkage disequilibrium with other functional single-nucleotide polymorphisms.

Asthma↗

PubMed2007

Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function.

RATIONALE: Previously reported linkage to FEV(1) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. OBJECTIVES: We tested association between SMOC2 polymorphisms and FEV(1) and FVC in unrelated FHS participants. METHODS: Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects. MEASUREMENTS AND MAIN RESULTS: SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever- and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV(1) (p = 0.003) and FVC (p = 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV(1), p = 0.0006; FVC, p = 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV(1) (p = 0.0002) and 157 ml for FVC (p = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV(1), p = 0.03; FVC, p = 0.03). CONCLUSIONS: The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV(1) and FVC.

Calcium-Binding Proteins↗

PubMed1987

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena.

Celiac Disease↗

PubMed2005

Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness. METHOD: In the Irish Study of High-Density Schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness. RESULTS: Subjects in the upper 40th percentile for the negative symptom factor--in both the narrowly (p=0.004) and broadly (p=0.01) defined illness groups--were more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed. CONCLUSIONS: The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the high-risk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.

Carrier Proteins↗

PubMed2003

Interleukin-10 and tumor necrosis factor alpha region haplotypes predict transplant-related mortality after unrelated donor stem cell transplantation.

Certain cytokine gene polymorphisms have been shown to correlate with outcome of human leukocyte antigen (HLA) identical sibling donor stem cell transplantation (SCT), but in unrelated donor SCT such information is scarce. We have studied the association between cytokine gene polymorphism and transplant-related mortality (TRM) in 182 unrelated SCTs performed at a single center. We found association of polymorphism in the tumor necrosis factor alpha (TNF alpha) and interleukin-10 (IL-10) gene and TRM. Both the TNFd4 allele and the TNF alpha -1031C alleles are associated with high risk for TRM. Statistical analysis showed that both polymorphisms were present on a single haplotype. This haplotype was associated with high risk of TRM when present in recipient or donor, 55% (43%-67%) compared with 21% (12%-30%) when absent from both (P <.01). A further allele associated with this haplotype, TNFa5, is also associated with increased risk of TRM. For IL-10, presence of the donor R2-G-C-C haplotype was associated with decreased risk of TRM, 61% (43%-79%) versus 34% (25%-43%), P =.01. In contrast, possession of the R3-G-C-C haplotype by the donor predicted reduced risk of TRM, 30% (19%-41%, 95% CI) versus 53% (40%-66%, 95% CI), P =.01. No independent associations of cytokine polymorphisms with acute graft-versus-host disease were shown.

Adolescent↗

PubMed2003

A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis.

The endothelial cell protein C (PC) receptor (EPCR) facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined 3 haplotypes, 1 of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age- and sex-matched healthy subjects, we found that the A3 haplotype was overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P =.004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.

Adolescent↗