Zilla Y. H. Wong

Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy

Asthma is a manifestation of bronchial hyperreactivity (BHR) and forms part of the spectrum of atopic disease. Some pedigree studies of atopy have suggested linkage with the high-affinity IgE receptor (Fc epsilon RI beta) gene on chromosome 11q13, but others find no linkage. The molecular genetics of asthma and BHR have not been studied in the general population. We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population. We found evidence of significant linkage of a highly polymorphic microsatellite marker in the fifth intron of the Fc epsilon RI beta gene to a diagnosis of asthma (18.0% excess of shared alleles, p = 0.002) and to BHR (21.7% excess of shared alleles, p = 0.001). Significant linkage was also observed in siblings sharing BHR when those with atopy were excluded (32.8% excess of shared alleles, p = 0.004). Atopy in the absence of BHR did not show significant linkage to the Fc epsilon RI beta gene (7.2% excess of shared alleles, p = 0.124). These findings suggest that mutations in the Fc epsilon RI beta gene or a closely linked gene influence the BHR underlying asthma, even in the absence of atopy.

Genome-Wide Linkage Analysis of the Acute Coronary Syndrome Suggests a Locus on Chromosome 2

A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 (P <0.0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 (P <0.005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.

Genetic linkage of β and γ subunits of epithelial sodium channel to systolic blood pressure

Summary Background Mutations in the genes on chromosome 16p12 that encode the β and γ subunits of the epithelial sodium channel ( SCNNIB and SCNNIG , respectively) have been linked with rare sodium-dependent forms of low and high blood pressure. Other DNA variants in or around these genes may contribute to variation in blood pressure and the risk of coronary heart disease and stroke. Methods We studied 286 white families from the general population in Victoria, Australia. Each family comprised both parents and two natural children. All participants were genotyped at chromosome 16p12 by use of four highly polymorphic microsatellite markers. Quantitative phenotype measurements were correlated with genotype in identity-by-descent sibling-pair linkage analyses. Findings We found significant linkage between systolic blood pressure and chromosome 16p12 after parametric analyses (p=0·0003) and non-parametric analyses (p=0·001). The mean difference in systolic blood pressure between siblings identical-by-descent at these loci was half as large (7·1 mm Hg) as the difference between siblings non-identical at these loci (14·0 mm Hg, p=0·001). No linkage between chromosome 16p12 and diastolic blood pressure or body-mass index was observed. Interpretation Chromosome 16p12 and the SCNNIB and SCNNIG genes are implicated in the physiological variation of systolic blood pressure. Our findings are important in explaining individual cardiovascular risk within the general population.

Human α-Adducin Gene, Blood Pressure, and Sodium Metabolism

Abstract —The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human α-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the α-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the α-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Familial and Genomic Analyses of Postural Changes in Systolic and Diastolic Blood Pressure

Abstract—The physiological adaptation to the erect posture involves integrated neural and cardiovascular responses that might be determined by genetic factors. We examined the familial- and individual-specific components of variance for postural changes in systolic and diastolic blood pressure in 767 volunteer nuclear adult families from the Victorian Family Heart Study. In 274 adult sibling pairs, we made a genome-wide scan using 400 markers for quantitative trait loci linked with the postural changes in systolic and diastolic pressures. Overall, systolic pressure did not change on standing, but there was considerable variation in this phenotype (SD=8.1 mm Hg). Familial analyses revealed that 25% of the variance of change in systolic pressure was attributable to genetic factors. In contrast, diastolic pressure increased by 6.3 mm Hg (SD=7.0 mm Hg) on standing and there was no evidence of contributory genetic factors. Multipoint quantitative genome linkage mapping suggested evidence (Z =3.2) of linkage of the postural change in systolic pressure to chromosome 12 but found no genome-wide evidence of linkage for the change in diastolic pressure. These findings suggest that genetic factors determine whether systolic pressure decreases or increases when one stands, possibly as the result of unidentified alleles on chromosome 12. The genetics of postural changes in systolic blood pressure might reflect the general buffering function of the baroreflex; thereby, the predisposition to sudden decreases or increases in systolic pressure might cause postural hypotension or vessel wall disruption, respectively.

Mutational analysis of the high affinity immunoglobulin E receptor beta subunit gene in asthma.

BACKGROUND The gene for the β subunit of the high affinity receptor for immunoglobulin E (FcεRI-β) on chromosome 11q13 is linked with clinical asthma and certain mutations have been identified. A study was undertaken to identify DNA variation in the FcεRI-β gene in a population sample in which linkage between 11q13 and asthma was explained by bronchial hyperreactivity (BHR) but not atopy. METHODS DNA samples from 71 subjects with asthma, atopy, or BHR were analysed. The complete coding region, some of the introns, and some of the 5′ untranscribed region of the FcεRI-β gene were sequenced. RESULTS In the subjects studied there were no deviations from the published sequence in any of the seven coding exons of the FcεRI-β gene. In particular, the three previously reported mutations (Ile181, Leu183, Glu237) were not detected. Two new polymorphisms were discovered, one at position 243 in the 5′ untranscribed region and one at position 4390 in intron III. Neither of these variants showed significant association with asthma, atopy, or BHR. CONCLUSIONS These results suggest that, in the population studied, linkage of asthma and BHR to 11q13 is not explained by mutations in the FcεRI-β gene. Other mutations in the non-coding region of this gene or in adjacent genes must explain the linkage findings in this study.

Linkage analysis of endothelial nitric oxide synthase gene with human blood pressure.

OBJECTIVE Endothelial nitric oxide exerts important effects on the regulation of vascular tone and structure. Variants of the endothelial nitric oxide synthase gene (eNOS) have been associated with hypertension and myocardial infarction, although some reports have shown negative linkage with hypertension. To examine whether the region encoding the eNOS gene is linked with physiological blood pressure variation, we undertook a linkage analysis of this region in the general population. DESIGN In healthy volunteer families, we used two independent quantitative linkage analyses to examine the relationship between genotypes and phenotypes, with both parametric and non-parametric and single-locus and multi-point methods. METHODS We selected 260 families comprising mother and father (aged 40-70 years) and two natural offspring (aged 18-30 years) from the Victorian Family Heart Study. After standardized measurement of clinical data and extraction of DNA, all family members were genotyped at five microsatellite loci including the CA repeat in the eNOS gene by a PCR method. The quantitative linkage analyses were conducted according to two different analysis programs, the Genetic Analysis System (GAS) and the MAPMAKER/SIBS. RESULTS With both linkage analyses, we found no linkage between any of the loci on chromosome 7q35-36 and the phenotypes systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, pulse rate, weight, height and body mass index. CONCLUSION Based on these results, we conclude that in this population the eNOS gene is not linked to the physiological variation of blood pressure and other related phenotypes.

Sex, Genes And Blood Pressure

1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes.

Linkage analysis of glucocorticoid and β2-adrenergic receptor genes with blood pressure and body mass index

Glucocorticoids and catecholamines exert important effects on cardiovascular physiology and metabolism. Variants of the glucocorticoid receptor gene (GRL) and the beta2-adrenergic receptor gene (ADRB2) have been associated with high blood pressure and obesity. These genes are close on human chromosome 5q31-5q32, and we undertook a linkage analysis of this region in 264 families from the general population in relation to systolic and diastolic blood pressure, body mass index, weight, height, and pulse rate. All family members were genotyped at four microsatellite loci (D5S207, D5S210, D5S519, and D5S119) located on chromosome 5q31-5q33.3. Using quantitative identity-by-descent sibling pair linkage analysis, we found that at no loci was genetic similarity associated with phenotypic similarity for systolic and diastolic blood pressure, body mass index, weight, height, or pulse rate. Although it is not possible to exclude the influence of specific combinations of certain GRL and ADRB2 polymorphisms, the absence of significant linkage in our population argues against a role for GRL or ADRB2 in physiological variation of blood pressure and body mass index.