We suggest that these quantitative trait loci may represent the presence of variations in LQT genes that could be important to the risk for rhythm disturbances in the general population.
Abstract-Blood pressure and heart rate are strongly influenced by genetic factors; however, despite the pivotal role of genetics in short-term cardiovascular regulation, little is known about the genetic contribution to baroreflex function. We assessed genetic influence on baroreflex sensitivity (BRS) in 149 twin pairs (88 monozygotic of age 33Ϯ13 years and BMI 23Ϯ4 kg/m 2 and 61 dizygotic of age 33Ϯ11 years and BMI 24Ϯ4 kg/m 2 ). ECG and finger arterial blood pressures were measured continuously under resting conditions. BRS values were calculated by use of cross-spectral analysis (baroreflex slope calculated as mean value of transfer function between systolic blood pressure and the R-R interval in the low-frequency band [BRSLF] and baroreflex slope calculated as the mean value of transfer function between systolic blood pressure and R-R interval in the respiratory frequency band [BRSHF]) and the sequence technique (BRSϩ, BRS-). Heritability (h 2 ) was estimated with a path-modeling approach. BRS values did not differ significantly between groups (monozygotic, BRSLF, 17Ϯ13; BRSHF, 21Ϯ18; BRSϩ, 19Ϯ16; and BRS-, 21Ϯ15, and dizygotic, BRSLF, 16Ϯ9; BRSHF, 20Ϯ14; BRSϩ, 18Ϯ10; and BRS-, 20Ϯ11 ms/mm Hg), and were significantly correlated (PϽ0.001). When variances and covariances for monozygotic and dizygotic twins were compared, significant correlations were found for BRS in monozygotic (range, rϭ0.38 to 0.48) but not in dizygotic twin pairs (rϭ-0.03 to 0.09). Thus, BRS is heritable; the variability can be explained by genetic influences (PϽ0.01; h 2 range, 0.36 to 0.44). The genetic influence on BRS remained strong after correction for BMI and blood pressure. Therefore, BRS is strongly genetically determined, probably by different genes than are resting blood pressure and BMI. Key Words: blood pressure Ⅲ function, autonomic Ⅲ analysis, spectral Ⅲ baroreflex Ⅲ twins Ⅲ genetics T he baroreflexes play a pivotal role in short-term blood pressure (BP) and heart rate regulation. 1 Carotid and aortic baroreceptors sense changes in stretch that result from BP alterations. 2,3 The signal generated in these receptors travels to cardiovascular control centers in the brain stem. This afferent input results in counterregulatory adjustments of sympathetic and parasympathetic tone and prevents excessive fluctuations in BP. Interruption of the afferent arc (baroreflex failure) or the efferent arc (autonomic failure) is associated with extremely labile BP and heart rate. 4,5 Considering the profound effect of complete baroreflex dysfunction on BP and heart rate, even mild abnormalities in baroreflex function could result in substantial changes in cardiovascular regulation. Several studies suggested that baroreflex abnormalities are an important contributing factor to the pathogenesis of arterial hypertension. 1,6 -10 Baroreflex disturbances are associated with increased cardiovascular morbidity and mortality. 11 Thus, defining the mechanisms that affect baroreflex function could have an important effect on our understanding of cardi...
Abstract-Genetic variability, which influences cardiovascular phenotypes in normal persons, is likely to be relevant to cardiovascular disease. We studied normal monozygotic and dizygotic twins and found strong genetic influences on blood pressure and heart size. We then relied on the dizygotic twins and their parents to apply molecular genetic techniques. We performed a linkage analysis with markers close to the -2 adrenergic receptor (AR) gene locus in the dizygotic twins and their parents and found strong evidence for linkage to the quantitative traits of blood pressure and heart size. We then used allele-specific polymerase chain reaction to genotype the subjects further. We performed an association analysis and found that 4 functionally relevant polymorphisms in the -2 AR gene, namely Arg16/Gly, Gln27/Glu, Thr164/Ile, and a variant in the promoter region (Ϫ47C/T), were variably associated with blood pressure and heart size differences but were in linkage dysequilibrium with each other. A subsequent conditional analysis suggested that the Arg16/Gly polymorphism exerted the predominant effect. These findings underscore the importance of the -2 AR gene to blood pressure regulation, heart size, and probably to the development of hypertension. We suggest that a combined linkage and association approach will elucidate the genetic variability influencing blood pressure and other cardiovascular phenotypes. (Hypertension. 2000;35:555-560.)Key Words: receptors, adrenergic, beta Ⅲ genetics Ⅲ hypertension, genetic Ⅲ twins Ⅲ blood pressure T he -2 adrenergic receptor (-2 AR) has been implicated in the pathogenesis of hypertension, both on the basis of studies suggesting altered -2-mediated vasodilation 1 and on the basis of molecular genetic association studies. 2,3 Recently, Kotanko et al 4 found an association between the Arg16/Gly polymorphism in the -2 AR gene and hypertension in an African Caribbean population. They showed that the Gly16 allele was more common in hypertensive subjects than in normotensive African Caribbean control subjects. Since the Gly16 allele indicates an increased propensity for downregulation of the receptor, 5 the authors raised the possibility that an impaired vasodilation in peripheral arteries in response to -2 AR agonists may play a role in the hypertension of individuals carrying the Gly16 allele. We subsequently examined the firstborn normotensive adult children of couples documented to be normotensive or hypertensive in the Bergen Blood Pressure Study. 6 Offspring of 2 hypertensive parents had higher blood pressures and a preponderance of the Arg16 allele compared with offspring of 2 normotensive parents. To further examine the genetic variability at the -2 AR locus and its relevance for the cardiovascular system in northern Europeans, we performed a combined linkage and association study in normotensive twin subjects. We used allele-specific polymerase chain reaction (PCR), which allowed us to examine other polymorphisms in the -2 AR gene. MethodsWe recruited 166 pairs of t...
We studied 100 healthy monozygotic and 72 dizygotic twin pairs (mean age, 34 +/- 14 years) to test for genetic influences on blood lipids and to examine relevant gene loci. Total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were determined after a 12-hour fast. Zygosity was determined with the use of microsatellite markers. Heritability estimates were conducted by using the lisrel 8 program; a sib-pair analysis was conducted by using the sibpal program. Linear regression analyses were carried out between identical-by-descent status and squared within-pair differences of TC, LDL-C, HDL-C, and TG values. Heritability estimates of the lipid serum concentrations ranged from .58 to .66. A significant linkage relationship was found for HDL-C (P = .008) and TGs (P = .05) with D8S261 on chromosome 8p. However, no linkage was found between any of the lipid variables and the lipoprotein lipase gene locus (LPL GZ14/15 and D8S282). Because D8S261 is located approximately halfway between the LPL and macrophage scavenger receptor genes, we examined the nearby markers D8S549 and D8S1731. Linkage was found for HDL-C and D8S549 (P = .001) and for HDL-C and D8S1731 (P = .04). On the other hand, we found no linkage between the LDL receptor gene locus and LDL-C serum concentrations nor between the LPL gene locus and the various other lipid fractions. Our data suggest a significant influence of the macrophage scavenger receptor gene locus on HDL-C and weak influence on TG levels. We suggest that inherited variability in the macrophage scavenger receptor gene has an influence on serum lipid concentrations.
We suggest that hereditary effects on certain coping style preferences cannot be explained solely by genetic influences on major personality traits and temperament. An analysis of the relationships between coping and personality in twin subjects may elucidate the distinction between genetic and environmental effects.
Abstract-The peroxisome proliferator-activated receptor ␥ (PPAR␥) gene has been implicated in morbid obesity and is important to lipid and carbohydrate metabolism. However, the relevance of gene variations in healthy nonobese subjects has not been defined. We recruited monozygotic and dizygotic healthy nonobese twin subjects to test the hypothesis that the PPAR␥ gene is important to body mass index and lipid concentrations in healthy nonobese subjects. Both linkage and association strategies were used in the same dizygotic twins. The PPAR␥ gene locus was linked (PϽ0.01) to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and body mass index as quantitative traits. A biallelic variant in the PPAR␥ gene was associated with high-density lipoprotein cholesterol and body mass index (PϽ0.05). We also looked for linkage between the same variables and the retinoic X receptor gene locus. This locus was linked to total and low-density lipoprotein cholesterol as well as triglycerides. We conclude that the PPAR␥ gene is highly relevant to lipid metabolism and body mass index, not only in the morbidly obese but also in healthy nonobese subjects. The same appears to be true for its binding partner. Sequencing these genes in twins would serve to identify gene variations contributing to body mass index and lipid concentrations in healthy nonobese subjects. Key Words: genetics Ⅲ PPAR␥ Ⅲ quantitative trait loci Ⅲ body mass index Ⅲ cholesterol, HDL Ⅲ cholesterol, LDL Ⅲ twins P eroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear hormone receptor superfamily that heterodimerizes with the retinoid X receptor and functions as a transcriptional regulator of genes linked to lipid metabolism and energy balance. The thiazolidine class of antidiabetic drugs and 15-deoxy-⌬12,14-prostaglandin J2 are ligands for this receptor. 1-3 PPAR␥ expression is highest in adipose tissue but is detectable at lower levels in other tissues (eg, kidney and liver). 4,5 Tontonoz et al 6 recently reported that PPAR␥ promotes monocyte/macrophage differentiation and uptake of oxidized LDL cholesterol. Ristow et al 7 recently reported a PPAR␥ mutation in 4 patients with massive obesity. When expressed in fibroblasts, the mutated gene accelerated lipid uptake of the cells and caused them to differentiate into adipocytes. These observations prompted us to test the hypothesis that the PPAR␥ locus is linked to lipid values and body mass index (BMI) in healthy nonobese dizygotic (DZ) twin subjects in terms of a quantitative trait locus (QTL). We then took advantage of a biallelic marker in the PPAR␥ gene and were able to associate the genotypes with BMI and HDL cholesterol. We also searched for linkage between the retinoic X receptor gene locus and the same phenotypes and showed that this locus is a QTL for total and LDL cholesterol. Our data support the notion that PPAR␥ and its binding partner are relevant to BMI and lipid levels in healthy nonobese persons. Methods Study PopulationWe recruited 222 pairs of monozy...
We tested the hypotheses that anglotensm-convertmg enzyme msertlon/deletlon (I/D) and anglotensmogen 235 methlomne/threomne (M/T) substitution gene polymorphisms mfluence anglotensm-converting enzyme and anglotensmogen serum concentrations and cardiac dimensions m 91 monozygotlc and 4 1 dlzygotlc twm pairs Cardiac dlmenslons were determined echocardlographlcally Anglotensm-converting enzyme levels were 242 11,43f. 18, and 58+-24 U/L for the II, ID, and DD genotypes, respectively (P<.Ol)Posterior wall thickness was 8 121 3, 8.62 1 7, and 8 9+ 1.9 mm for these genotypes (P< 05) Anglotensm-converting enzyme levels were correlated with posterior wall thickness (r= 15, P< 05) The mtrapalr differences in anglotensm converting enzyme levels for monozygotlc, concordant dlzygotlc, and discordant dlzygotlc twins were 1 361-l 6, 1 8651 6, and 17 2524 3 U/L, respectively The anglotensmogen M/T genotypes exerted no influence on cardiac dimensions or on anglotensmogen concentrations The additive genetic effect on anglotensm-convertmg enzyme levels (0 49), on posterior wall thickness (0 26), and on septum thickness (0.37) was significant (P<.Ol), although shared and nonshared envlronmental effects were also identified Our data confirm the impressive effect that the anglotensm-converting enzyme D allele exerts on anglotensm-converting enzyme plasma levels Furthermore, our data also suggest that the anglotensm-converting enzyme gene locus IS pnmanly responsible for anglotensm-converting enzyme plasma levels. Our twm study also indicates that the anglotensm-convertmg enzyme gene locus IS genetlcally linked to posterior wall thickness. The correlation between anglotensm-converting enzyme levels and posterior wall thickness suggests that this effect 1s exerted by anglotensm-converting enzyme We were unable to demonstrate genetic linkage between the anglotensmogen gene locus and cardiac dimensions m this study (Hypertension. 1997;29[part 2]:165-170.) Key Words l genetics l twins l ACE polymorphisms l anglotensmogen polymorphisms l cardiac hypertrophy A diallehc polymorphtsm m the ACE gene, characterized by a D or I allele m the 16th mtron of the ACE gene, has been associated with differences m plasma ACE levels, as well as risk for myocardial mfarctlon and cardiac hypertrophy 1 Tlret et al* used evidence from combined segregation and linkage analysis and showed that the I allele was characterized by lower ACE levels. A stmilar associatton between the I and D alleles and ACE m monocytes has also been tdenttfied 3 Cambten et a14 relied on an assoctation study, m which the DD genotype was associated with myocardial infarction m men with low risk They found that m that group, ACE levels did not decrease with age and were higher m patients with the DD and ID genotypes than m control SubJects Schunkert et a15 reported an excess homozygostty for the D allele among SubJects with cardiac hypertrophy as assessed by electrocardtographtc crttena. The D allele has also been associated with the severtty of cardiac hypertrophy m patie...
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