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PubMed2002

Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC. METHODS: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred. RESULTS: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.

Adult↗

PubMed2005

High-resolution association mapping of quantitative trait loci: a population-based approach.

In this article, population-based regression models are proposed for high-resolution linkage disequilibrium mapping of quantitative trait loci (QTL). Two regression models, the "genotype effect model" and the "additive effect model," are proposed to model the association between the markers and the trait locus. The marker can be either diallelic or multiallelic. If only one marker is used, the method is similar to a classical setting by Nielsen and Weir, and the additive effect model is equivalent to the haplotype trend regression (HTR) method by Zaykin et al. If two/multiple marker data with phase ambiguity are used in the analysis, the proposed models can be used to analyze the data directly. By analytical formulas, we show that the genotype effect model can be used to model the additive and dominance effects simultaneously; the additive effect model takes care of the additive effect only. On the basis of the two models, F-test statistics are proposed to test association between the QTL and markers. By a simulation study, we show that the two models have reasonable type I error rates for a data set of moderate sample size. The noncentrality parameter approximations of F-test statistics are derived to make power calculation and comparison. By a simulation study, it is found that the noncentrality parameter approximations of F-test statistics work very well. Using the noncentrality parameter approximations, we compare the power of the two models with that of the HTR. In addition, a simulation study is performed to make a comparison on the basis of the haplotype frequencies of 10 SNPs of angiotensin-1 converting enzyme (ACE) genes.

Alleles↗

PubMed1983

Monoclonal antibodies specific for the b5 allotype of rabbit kappa light chains.

The mouse monoclonal antibodies (mAb), 3B5 and 4B5, which recognize rabbit kappa light chains bearing the b5 allotype, were produced from separate fusions. The specificity of the mAbs was determined by solid-phase inhibition radioimmunoassay. Nonimmune sera of 15 b5b5 rabbits of various heavy chain haplotypes inhibited the binding of both mAbs to b5 IgG, whereas 20 sera from rabbits not expressing the b5 allotype were not inhibitory. In addition, the binding of both mAbs was inhibited by purified b5 light chains, but not by b4 light chains. The b5 epitope recognized by the mAbs was shown by sequential precipitation to be present on all b5-bearing molecules that are defined by an alloantiserum produced in a b4b4 rabbit. Antibody 4B5 forms strong precipitin bands with b5 serum and Ig in gel diffusion assays. An anomalous reaction of nonidentity was observed when mAb was compared to rabbit anti-b5 antiserum and a hypothesis to explain this phenomenon is proposed.

Animals↗

PubMed2005

Targeted, haplotype-resolved resequencing of long segments of the human genome.

Currently, challenges exist to acquire long-range (hundreds of kilobase pairs) phase-discriminated sequence across substantial numbers of individuals. We have developed a straightforward method for isolating and characterizing specific genomic regions in a haplospecific manner. Real-time PCR is carried out to STS content map and genotype pools of fosmid clones arrayed in 384-well microtiter plates. Single-nucleotide polymorphisms, microsatellite markers, and insertion-deletion polymorphisms are used to differentiate the target region into haplotype-specific tiling paths. DNA of clones from these tiling paths is retrieved from the library and either sequenced by standard shotgun methods or amplified in vitro and sequenced by a primer-based, directed method. This approach provides convenient access to complete, haplotype-resolved resequencing data from multiple individuals across tens to hundreds of thousands of basepairs. We illustrate its implementation with a detailed example of more than 400 kbp from the human CFTR region, across 15 individuals, and summarize our experience applying it to many other human loci.

Base Sequence↗

PubMed2005

Inferred HLA haplotype information for donors from hematopoietic stem cells donor registries.

Human leukocyte antigen (HLA) matching remains a key issue in the outcome of transplantation. In hematopoietic stem cell transplantation with unrelated donors, the matching for compatible donors is based on the HLA phenotype information. In familial transplantation, the matching is achieved at the haplotype level because donor and recipient share the block-transmitted major histocompatibility complex region. We present a statistical method based on the HLA haplotype inference to refine the HLA information available in an unrelated situation. We implement a systematic statistical inference of the haplotype combinations at the individual level. It computes the most likely haplotype pair given the phenotype and its probability. The method is validated on 301 phase-known phenotypes from CEPH families (Centre d'Etude du Polymorphisme Humain). The method is further applied to 85,933 HLA-A B DR typed unrelated donors from the French Registry of hematopoietic stem cells donors (France Greffe de Moelle). The average value of prediction probability is 0.761 (SD 0.199) ranging from 0.26 to 1. Correlations between phenotype characteristics and predictions are also given. Homozygosity (OR = 2.08; [2.02-2.14] p <10(-3)) and linkage disequilibrium (p <10(-3)) are the major factors influencing the quality of prediction. Limits and relevance of the method are related to limits of haplotype estimation. Relevance of the method is discussed in the context of HLA matching refinement.

Algorithms↗

PubMed2005

Multiple testing in the context of haplotype analysis revisited: application to case-control data.

We have lately presented a testing procedure for family data which accounts for the multiple testing problem that is induced by the enormous number of different marker combinations that can be analyzed in a set of tightly linked markers. Most methods of haplotype based association analysis already require simulations to obtain an uncorrected P value for a specific marker combination. As shown before, it is nevertheless not necessary to carry out nested simulations to obtain a global P value that properly corrects for the multiple testing of different marker combinations without neglecting the dependency of the tests. We have now implemented this approach for case-control data in our program FAMHAP, as this data structure currently plays a dominant role in the field. We consider different ways to deal with phase ambiguities and two different statistical tests for the underlying single marker combinations to obtain uncorrected P values. One test statistic is chi-square based, the other is a haplotype trend regression. The performance of these different tests in the multiple testing situation is investigated in a large simulation study. We obtain a considerable gain in power with our global P values as opposed to Bonferroni corrected P values for all suggested test statistics. Good power was obtained both with the haplotype trend regression approach as well as with the simpler chi-square based test. Furthermore, we conclude that the better strategy to deal with phase ambiguities is to assign to each individual its list of weighted haplotype explanations, rather than to assign to each individual its most likely haplotype explanation. Finally, we demonstrate the usefulness of our approach by a real data example.

Algorithms↗

PubMed2006

Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia.

Mutations leading to the alteration of cell-cycle checkpoint functions are a common feature of most cancers. Because of the highly regulated nature of the cell cycle, it seems likely that variation in gene dosage of key components due to functional regulatory polymorphisms could play an important role in cancer development. Here we provide evidence of the involvement of promoter single-nucleotide polymorphisms (pSNPs) in the cyclin-dependent-kinase inhibitor genes CDKN2A, CDKN2B, CDKN1A, and CDKN1B in the etiology of childhood pre-B acute lymphoblastic leukemia (ALL). A case-control study, conducted in 240 patients with pre-B ALL and 277 healthy controls, combined with a family-based analysis using 135 parental trios, all of French-Canadian origin, were used to evaluate single-site genotypic as well as multilocus haplotypic associations for a total of 10 pSNPs. Using both study designs, we showed evidence of association between variants CDKN2A -222A, CDKN2B -593A, and CDKN1B -1608A, and an increased risk of ALL. These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis.

Adolescent↗

PubMed1993

Altered CYP21 genes in HLA-haplotypes associated with congenital adrenal hyperplasia (CAH): a family study.

Disorders of the CYP21 gene, which is located within the major histocompatibility complex on the short arm of chromosome 6, are the leading causes of congenital adrenal hyperplasia (CAH). The coding gene and a highly homologous pseudogene are tandemly arranged with the two genes for the fourth component of complement (C4A and C4B). To analyse the prevalence rates of mutations of the CYP21 genes and the segregation of the CYP21 genes with their corresponding human leucocyte antigen (HLA)-haplotypes, 21 families with one or two children with the severe form of 21-hydroxylase deficiency were studied. Mutations of the CYP21 gene on their corresponding HLA-haplotype were detected by hybridisation of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotides and solid phase direct sequencing. Our study has shown the following. (1) A single basepair mutation (A-->G or C-->G) within the second intron is the most frequent mutation leading to impaired 21-hydroxylase activity. This mutation is only detected in HLA-haplotypes associated with the salt-wasting form of CAH. (2) A large deletion of part or all of the CYP21 gene is associated with the HLA-haplotype A3, BW47, C6, DR7, DR53, DQ2 but is also observed in other HLA-haplotypes and can be detected by a simple rapid PCR restriction fragment length polymorphism method. (3) Two alleles of the coding CYP21 gene differing in a leucine codon within the first exon, (formerly described as a mutation associated with 21-hydroxylase deficiency) have been found with an equal distribution in patients with 21-hydroxylase deficiency, non-disease HLA-haplotypes and the local healthy controls.

Adrenal Hyperplasia, Congenital↗

PubMed1995

In vitro impairment of interleukin-5 production in HLA-B8, DR3-positive individuals implications for immunoglobulin A synthesis dysfunction.

Healthy subjects carrying the HLA-B8,DR3 haplotype may show a large number of immune dysfunctions. Concerning T-cell dysfunctions, the most intriguing is a defect of the early phases of T-cell activation, responsible for the impairment of in vitro mitogen-stimulated cytokine production. Regarding B-cell dysfunctions, one the most fascinating topics is the association between this haplotype and IgA deficiency in healthy blood donors. Accordingly, HLA-B8,DR3-positive healthy subjects show significantly lower values of serum IgA than HLA-B8,DR3-negative ones. Because IL-5 is a stimulating factor for the secretion of IgA by committed B cells, we have analyzed the in vitro mitogen-stimulated IL-5 production by MNCs from healthy HLA-B8,DR3-positive individuals to study whether they display an impaired production of IL-5. The results clearly demonstrate that MNCs from HLA-B8,DR3-positive individuals display significant reduction of IL-5 production, suggesting that IgA synthesis dysregulation observed in HLA-B8,DR3-positive subjects could be due to an impairment of IL-5 production.

Adult↗

PubMed2005

Variations of the CFTR gene in the Hanoi-Vietnamese.

In order to investigate polymorphic backgrounds of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in the Vietnamese, we analyzed 495 blood samples of randomly selected healthy individuals in Hanoi for the delta F508 mutation and TG-repeats, poly-T, and M470V polymorphisms. We compared their distributions with those of Caucasians and other Asian populations. No delta F508 mutation was found, being consistent with the extremely low incidence of cystic fibrosis (CF) in Vietnam. Allele frequency of the T5 allele promoting exon 9 skipping was 0.037. Greater number of TG-repeats, which is known to facilitate this aberrant splicing, was a predominant trend in the Vietnamese and other Asians. A "T5-TG12-V470" haplotype was most common (29/37) among T5-bearing haplotypes. Three major haplotypes, T7-TG12-M470, T7-TG11-V470, and T7-TG12-V470, estimated by PHASE program, related to 92% of the population. This is the first study of the CFTR gene among the Vietnamese.

Adolescent↗

PubMed2026

Complex structural variation, phylogeny, and disease associations of the mucin pangenome.

Mucins are large glycoproteins that provide hydration and barrier function to epithelial tissues. Although genetically heterogeneous, all mucins harbor a large exon composed of variable number tandem repeats (VNTRs). Short-read sequencing has limited our understanding of mucin VNTR diversity and makes disease association studies challenging. We leverage 296 long-read phased genome assemblies to characterize 14 mucin family members, achieving ≥97% accuracy across 572 haplotypes. Phylogenetic haplogroup analysis reveals extraordinary structural heterozygosity, with MUC4 harboring the greatest allelic diversity (n=240 distinct lengths) and MUC12 the greatest size range (Δ = 55,233 bp; 23,080 amino acids). Ten mucins show significant population stratification (pFDR < 0.05). At the MUC4/MUC20 locus, we characterize higher-order structural variation, including a recurrent inversion, copy number variation, and interlocus gene conversion. Optimized genotyping achieves ≥95% haplogroup concordance across 10 loci. We apply this to 4,637 deeply phenotyped cystic fibrosis patients and identify a significant association between short MUC1 VNTRs and severe disease (p=0.0056), demonstrating the pangenome's utility for complex locus genotyping and disease discovery.

Journal Article↗

PubMed2005

Regression-based association analysis with clustered haplotypes through use of genotypes.

Haplotype-based association analysis has been recognized as a tool with high resolution and potentially great power for identifying modest etiological effects of genes. However, in practice, its efficacy has not been as successfully reproduced as expected in theory. One primary cause is that such analysis tends to require a large number of parameters to capture the abundant haplotype varieties, and many of those are expended on rare haplotypes for which studies would have insufficient power to detect association even if it existed. To concentrate statistical power on more-relevant inferences, in this study, we developed a regression-based approach using clustered haplotypes to assess haplotype-phenotype association. Specifically, we generalized the probabilistic clustering methods of Tzeng to the generalized linear model (GLM) framework established by Schaid et al. The proposed method uses unphased genotypes and incorporates both phase uncertainty and clustering uncertainty. Its GLM framework allows adjustment of covariates and can model qualitative and quantitative traits. It can also evaluate the overall haplotype association or the individual haplotype effects. We applied the proposed approach to study the association between hypertriglyceridemia and the apolipoprotein A5 gene. Through simulation studies, we assessed the performance of the proposed approach and demonstrate its validity and power in testing for haplotype-trait association.

Apolipoprotein A-V↗

PubMed1986

The use of restriction fragment length polymorphisms in paternity analysis.

This paper examines the utility of restriction fragment length polymorphisms (RFLPs) for paternity analysis. While, on the average, 99% of falsely accused males can be excluded with the standard battery of blood group antigens, red cell enzymes, serum proteins, and HLA antigens, there are still mother-child pairs for whom the exclusion probability is not high. It has been suggested that additional resolution would be available with RFLPs. We have examined the strategic aspects of using RFLPs for paternity analysis, comparing the efficacy and cost of a multimarker haplotypic set with those of a comparable set of unlinked RFLPs, using published frequencies for the beta-globin complex, the serum albumin region, and the growth hormone region. There are four major findings. (1) Greater resolution is obtained with a carefully chosen set of tightly linked RFLPs producing chromosomal haplotypes than with a comparable set (same allele frequencies) of unlinked markers, but only if it is possible to establish linkage phase unambiguously. (2) Assay of linked sets is cheaper than is the assay of unlinked markers, but the cost advantage is optimized with sets of no more than two or three linked markers. (3) Also, with more than two or three tightly linked markers, the haplotypic frequencies are too poorly estimated to provide a reliable measure of the probability of paternity for unexcluded males, given the sample sizes likely to be available in the near future. (4) Optimal resolution, minimal cost, and acceptable accuracy are obtained with several independent sets of no more than two or three tightly linked RFLP markers each. With current technology, RFLP analysis is more expensive for the same level of genetic resolution than is the standard battery, but gradual replacement of the latter can be anticipated as economies of scale reduce the cost of the DNA technology.

Alleles↗

PubMed1988

Carrier detection in 50 haemophilia A kindred by means of three intragenic and two extragenic restriction fragment length polymorphisms.

Carrier detection was attempted in 50 haemophilia A kindred by means of restriction fragment length polymorphism (RFLP) analysis using two linked and three intragenic probes. The sample comprised 330 individuals including 70 haemophiliacs, 45 obligate carriers and 100 possible carriers. Non-related haplotypes contained within the sample group were used to tabulate the intragenic RFLP allele frequencies. The linkage disequilibrium existing between the XbaI and Bc1I RFLP was shown to be less than previously reported, such that 69% of women are informative for at least one of these two polymorphisms. 36 women were subsequently diagnosed as carriers and 37 as being normal: in 52 of these, diagnosis was based either on intragenic RFLPs or linked RFLP plus strong phenotypic data, and was considered to be unequivocal; in the remaining 21, diagnosis was based on linked RFLPs alone and was considered to be probabilistic, with a 5-10% possible error rate. 27 of the possible carriers, either from families with sporadic haemophilia or from families where missing members precluded haplotype analysis, remained unassigned. 72% of the obligate carriers and firmly diagnosed carriers were heterozygous and phase known for at least one intragenic RFLP, whereas 6% were uninformative for the RFLPs for which they were examined. In 54 informative meioses, three recombinations between the factor VIII locus and the DX13 and/or ST14 loci were observed, giving a recombination rate of 5.5%. 15 prenatal diagnoses were carried out. Of the 11 male fetuses, six were shown to be affected and five to be normal. In three of four prenatal diagnoses where only a linked RFLP was informative, the result was confirmed by fetoscopy, fetal blood sampling, and factor VIII assay.

Alleles↗

PubMed2000

Islet cell antibody-positive relatives with human leukocyte antigen DQA10102, DQB10602: identification by the Diabetes Prevention Trial-type 1.

The presence of human leukocyte antigen (HLA) haplotype DQA1*0102, DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type 1 has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African-American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes [insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)] than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Although half of the ICA+ DQB1*0602 relatives had a high risk second haplotype, this was not associated with the additional risk factors for diabetes. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. In conclusion, the presence of ICA in the relatives described here suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, there may be different effects of DQB1*0602 between ethnic groups.

Adult↗

PubMed1998

Influence of the host and parasite strain in a mouse model of visceral Leishmania infantum infection.

We investigated the respective roles of the host and parasite strain in a murine model of visceral leishmaniasis. Balb/c and C57Bl/6 mice were selected for their respective 'non cure' and 'cure' haplotypes vis-a-vis Leishmania major. Mice were infected with 10(7) stationary-phase promastigotes of four strains of Leishmania infantum with different infection profiles in mice: visceralization or regulation, as established by Sulahian et al. (Sulahian et al. (1998) FEMS Immunol. Med. Microbiol. 17, 131-138). The infection was monitored by measuring parasite load in the liver and spleen on days 9, 22, 44 and 87 post-infection, using a sensitive microtitration technique. Similar profiles (visceralizing or regulating) were observed in the two mouse strains, suggesting a predominant role of the Leishmania strain in the visceralization process. The host response was assessed by analyzing the granulomatous response in the liver and by quantifying specific IgG, IgG1 and IgG2a as a marker of the Th1/Th2 immune response. A granulomatous response was observed in both strains of mice but was more pronounced with visceralizing strains of L. infantum and in C57Bl/6 mice compared to Balb/c mice. The kinetics of anti-Leishmania IgG antibody production was similar in all the groups, but the distribution of IgG1 and IgG2a isotypes was different between the two mouse strains: Balb/c mice had a predominantly Th2-like response whereas C57Bl/6 had a mixed Th1/Th2-like response. This study demonstrates the determining role of both the parasite and mouse strain in the outcome of L. infantum infection. The Th1/Th2 concept does not seem to explain susceptibility and resistance to infection in our model of visceral L. infantum infection, contrary to the L. major model.

Animals↗

PubMed2001

Making the animal model for AIDS research more precise: the impact of major histocompatibility complex (MHC) genes on pathogenesis and disease progression in SIV-infected monkeys.

Experimentally infected rhesus monkeys serve as an indispensable animal model to assess the pathogenesis, to validate therapy approaches and to develop vaccination strategies against viral diseases such as AIDS threatening the human population. Upon infection with simian immunodeficiency virus (SIV), a retrovirus closely related to the human immunodeficiency virus (HIV), macaques develop clinical manifestations similar to those of HIV-infected humans. As in humans, the disease course is variable. Polymorphic genes of the major histocompatibility complex (MHC) are required for the initiation and regulation of a specific immune response and represent a major host factor accounting for the differential outcome of infection. During the last few years, our understanding of the structure and function of the rhesus macaque MHC has increased substantially. Functional studies have led to the identification of specific SIV and HIV peptide epitopes presented by rhesus macaque MHC molecules. The subsequent development of MHC class I tetramers has allowed further insight into the cellular immune response following SIV-infection. Detailed studies demonstrated that viral escape mutants are generated during the acute and chronic phase of infection and explain why control of viral replication ultimately fails. Furthermore, particular MHC haplotypes which influence disease progression have been discovered. Thus, MHC-typing can have a prognostic potential. The further elucidation of the rhesus macaque MHC and the search for other relevant genes will remain an important task for future research and will stimulate all immunologically-related investigations in macaques.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the Caerphilly prospective study.

OBJECTIVES: Current evidence demonstrates that both genetic and environmental factors influence blood pressure. The sympathetic nervous system is a key player in blood pressure control and functional genetic variants of the beta-2 adrenergic receptor (B2AR) have been identified and implicated in the pathogenesis of hypertension. The present study aimed to determine the effects of common haplotypes of the B2AR gene upon blood pressure in the Caerphilly Prospective Study. DESIGN: Two thousand five hundred and twelve men (aged 45-59 years) participated in the study. We selected individuals in the upper (n = 347) and lower (n = 279) quintiles of the diastolic blood pressure distribution fixed at two time points [phase 2 (1984-88) or phase 3 (1989-93)] as cases and controls. METHODS: We analysed two functional polymorphisms (Arg16Gly and Gln27Glu) of B2AR and their haplotypes. RESULTS: We found a higher risk of hypertension in individuals homozygous for the Gln27 compared to those individuals homozygous for Glu27 [odds ratio (OR) = 1.94; 95% confidence interval (CI) = 1.34-2.81; P = 0.001]. Three haplotypes (Gly16Gln27, Gly16Glu27 and Arg16Gln27) were present in both quintile groups. Logistic regression analysis showed that haplotypes with a Gln27 allele (Gly16Gln27 and Arg16Gln27) conferred a significantly higher risk for hypertension than the Gly16Glu27 haplotype (OR = 1.55; 95% CI = 1.11-2.17, OR = 1.37; 95% CI = 1.04-1.81; P = 0.009 and P = 0.027, respectively). However, there was no evidence to support a statistically significant difference in odds ratios for the Gly16Gln27 and Arg16Gln27 haplotypes (P = 0.477), suggesting that it is the Gln27 allele alone, rather than any haplotype, which best explains the association. CONCLUSIONS: In a prospectively studied Caucasian male cohort, high diastolic blood pressure was associated with B2AR haplotypes containing the pro-downregulatory Gln27 variant.

Blood Pressure↗