Published online before print October 4, 2004, doi: 10.1161/01.HYP.0000145474.23750.2b
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(Hypertension. 2004;44:668.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Gender-Specific Influence of NO Synthase Gene on Blood Pressure Since Childhood
The Bogalusa Heart Study
From the Tulane Center for Cardiovascular Health and Department of Epidemiology (W.C., S.R.S., S.L., G.S.B.), Tulane University Health Sciences Center, New Orleans, La; and Human Genetics Center and Institute of Molecular Medicine (E.B.), University of Texas-Houston Health Science Center.
Reprint requests to Gerald S. Berenson, MD, Tulane Center for Cardiovascular Health, 1440 Canal St, Suite 1829, New Orleans, LA 70112. E-mail berenson{at}tulane.edu
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Abstract |
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Impaired endothelial function caused by decreased NO production plays a pathophysiologic role in essential hypertension. Although cross-sectional data are available on the association between endothelial NO synthase gene polymorphisms and hypertension, whether the gene variants and their haplotypes affect the long-term cumulative burden and trend of blood pressure since childhood is not known. This aspect was examined using 4 polymorphisms and a community-based longitudinal cohort of 347 blacks and 801 whites aged 18 to 45 years who have been examined serially 4 to 13 times (7705 observations) over an on average of 23.4 years. The area under the curve calculated using a growth curve of serial measurements of mean arterial pressure was used as a long-term cumulative burden. Blacks compared with whites displayed significantly lower frequencies of the rare alleles for G894T (0.112 versus 0.325), G10T (0.209 versus 0.323), T-786C (0.147 versus 0.372), and A-922G (0.131 versus 0.355). In addition, T-786C and A-922G polymorphisms were in complete linkage disequilibrium in both races. After adjusting for age and body mass index, the 894T and 10T alleles were significantly associated with lower long-term burden of blood pressure since childhood in black females and white females, respectively. With respect to haplotypes, the G894-10T carriers compared with (G894-G10)/(G894-G10) showed significantly lower long-term burden and trend of blood pressure in white females. In conclusion, the endothelial NO synthase gene influences the long-term burden and trend of blood pressure since childhood in females and may contribute to their predisposition to hypertension.
Key Words: nitric oxide synthase • haplotypes • blood pressure
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Introduction |
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Nitric oxide, which is synthesized from L-arginine in vascular endothelial cells by NO synthase, plays a key role in the regulation of vascular tone, blood flow, and blood pressure.1–4 The gene encoding endothelial NO synthase (eNOS), which has 26 exons and spans
22 kb of the genome, maps to chromosome 7q35-7q36.5 In humans, several sequence variants in the promoter region, exons and introns, have been identified.5,6 Of these variants, A-922G and T-786C are located in the promoter region: G894T in exon 7, and G10T in intron 23. Although the relationship between endothelial NO production and blood pressure has been studied extensively, information on the association of the eNOS gene variants and their haplotypes with blood pressure is limited and conflicting.7–13 Moreover, association studies on the eNOS gene and blood pressure have been so far cross-sectional in nature. Blood pressure increases with age at different rates14,15 and has a large variability over time, including inherent physiological fluctuations and measurement errors.16 In addition to the levels at a specific time point, genes may affect the longitudinal trends of blood pressure determined by within-person variability. A substantial genetic contribution to changes in blood pressure over time has been demonstrated in longitudinal twin and family studies.17,18 Further, using serial measurements of a trait at multiple time points dilutes the measurement errors and minimizes the short-term fluctuations.19,20 This notion is supported by earlier findings from studies on the epidemiology and genetics of blood pressure.21–23 Therefore, measures of long-term burden and trend of blood pressure from childhood to adulthood may provide better insight into the influence of functional genes on blood pressure over time.
As part of the Bogalusa Heart Study, a biracial (65% white, 35% black) community-based epidemiologic study of cardiovascular disease risk factors beginning in childhood, the present study examines (1) the black–white difference in linkage disequilibrium (LD) patterns of the 4 eNOS gene polymorphisms (A-922G, T-786C, G894T, and G10T), and (2) effects of these polymorphisms, individually and as haplotypes, on the long-term burden and trends of blood pressure since childhood in blacks and whites.
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Materials and Methods |
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Study Population
In the community of Bogalusa, La, 15 cross-sectional surveys of children aged 4 to 17 and adults aged 18 to 45 years were conducted between 1973 and 2003. This panel design of repeated cross-sectional examinations resulted in serial observations on the study cohort. Subjects eligible for this longitudinal analysis include 801 white and 347 black adults who have been typed for the eNOS gene polymorphisms and screened 4 to 13 times, at least 2 times in childhood and at least 2 times in adulthood, with 7705 observations. The follow-up period ranged from 10.7 to 29.5 years (average 23.4 years).
This study was approved by the institutional review board of the Tulane University Health Sciences Center. All adult subjects gave informed consent at each examination. For subjects <18 years of age, parental consent was obtained.
Examinations
All examinations followed the same basic protocols described previously.24 Indirect blood pressures were recorded in a relaxed atmosphere with Hg sphygmomanometers. Subjects were randomly assigned to 2 different stations. Well-trained observers recorded first, fourth, and fifth Korotkoff phases for systolic and diastolic blood pressures, respectively. Each observer recorded 3 measurements, resulting in a total of 6 readings, and the average was used as a blood pressure value at a single time point. For longitudinal analysis of diastolic blood pressure since childhood, the fourth phase was used. Mean arterial pressure (MAP) was calculated as diastolic blood pressure+pulse pressure/3. Subjects taking antihypertensive medications (n=38) at any examination have been excluded.
Genotyping for eNOS Gene Polymorphisms
Genotyping procedures of the eNOS polymorphisms have been described previously for G894T,25 G10T,11 T-786C,26 and A-922G.26 Based on the analysis of 67 pairs of blind duplicates, there was 100% concordance in genotyping for all 4 polymorphisms.
Statistical Methods
Pairwise LD of the 4 eNOS polymorphisms was examined using the classical LD coefficient D, which measures deviation from random association between alleles at different loci.27 The D value was standardized by the maximum value it can take given the allele frequencies and denoted by D'. The absolute value of D' of 1 indicates complete LD, and 0, no LD. D' values, allele frequencies, and Hardy–Weinberg equilibrium statistics were estimated by use of the program ARLEQUIN 2.0.28 For the estimation of D', double heterozygotes (4.4% to 26.6% of the sample) were excluded because of unknown gametic phase. The program PHASE29 was used in defining haplotypes of multiple polymorphisms on each individual.
A growth curve of MAP versus age was determined for each subject in a random-effects model using Statistical Analytical Software proc MIXED.30 A cubic curve was fit for MAP in the 4 race–gender groups. The area under the curve (AUC) of MAP was calculated as the integral of the growth curve during the follow-up period for each individual.21 Total AUC is a measure of long-term burden. Incremental AUC (total AUC–baseline AUC) measures combined linear and nonlinear long-term trends. Because individuals had different follow-up periods, AUC values were divided by the number of follow-up years. Analysis of covariance was performed separately in race–gender groups using generalized linear models to examine the effects of the polymorphisms, haplotypes, and their interaction with age on the long-term burden and trend of blood pressure. Because of the small number of the rare homogyzotes and a smaller number of blacks in this sample, the homozygous and heterozygous genotypes of the rare alleles were combined to increase the statistical power.
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Results |
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Frequencies of the rare alleles (894T, 10T, -786C, and -922G) were 0.325, 0.323, 0.372, and 0.355 in whites, respectively, and 0.112, 0.209, 0.147, and 0.131 in blacks, respectively. The frequencies of the 4 polymorphisms differed significantly between blacks and whites in each case (P<0.001). All the genotype distributions were in accordance with Hardy–Weinberg equilibrium expectations in blacks and whites (P=0.23 to 0.91). The haplotype pair GGTA/GGTA was the most common in whites (0.145) and blacks (0.401). The haplotype pairs with a frequency >0.05 were GGTA/GTTA (0.100), GGTA/TGCG (0.136), GGTA/TGTA (0.072), GGTA/GTCG (0.089), and GTTA/TGCG (0.115) in whites, and GGTA/GTTA (0.199), GGTA/TGTA (0.104), and GGTA/GTCG (0.081) in blacks. As shown in Table 1, T-786C and A-922G polymorphisms were in complete LD in blacks and whites. The -786C allele occurred in almost all subjects carrying -922G. The G894 and 894T alleles were strongly associated with 10T and G10 alleles, respectively, in both races. The 894T and 10T alleles were significantly associated with -786C and -922G alleles in whites, whereas the association of 894T with -786C and -922G was not significant in blacks.
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As shown in Table 2, the average age did not differ between males and females, whereas whites were older than blacks. Blacks and males had significantly higher total and incremental AUC values of systolic and diastolic blood pressure and MAP than whites and females, respectively.
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In Table 3, average age and body mass index AUC were similar between genotype groups in the 4 race–gender groups (data not shown). Carriers of 894T showed significantly lower total AUC of MAP than noncarriers in black females. Incremental AUC of MAP in black females showed a similar trend, but the difference between carriers and noncarriers of 894T was marginal (P=0.081). Carriers of 10T had a significantly lower value of total AUC of MAP than noncarriers in white females, but incremental AUC of MAP was similar in noncarriers versus carriers of 10T. Total AUC and incremental AUC of MAP did not show any difference between T-786C and A-922G genotype groups (data not shown).
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To increase the number of subjects for haplotype analyses in Table 4, we focused on the haplotypes of G894T and G10T because T-786C and A-922G were not associated with MAP. Using (G894-G10)/(G894-G10) as a reference, white female carriers of G894-10T showed significantly lower total AUC and incremental AUC of MAP. Carriers of 894T-G10 showed lower total AUC and incremental AUC values than (G894-G10)/(G894-G10) carriers in black and white females, but the difference was not significant. The number of 894T-10T carriers was smaller because of the significant LD of G894-10T and 894T-G10. The difference in total AUC between 894T-10T carriers and (G894-G10)/(G894-G10) pairs was even greater in white females (P=0.111) and black females (P=0.088). For incremental AUC, the difference was marginally significant and opposite in white males (894T-10T carriers greater than (G894-G10)/(G894-G10); P=0.093) and white females (894T-10T carriers less than (G894-G10)/(G894-G10); P=0.051). In addition, the haplotype analyses of all 4 polymorphisms gave very similar results to the G894T-G10T haplotypes in spite of a smaller number of subjects (data not shown).
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The Figure illustrates the haplotype-specific growth curves of MAP with age by race and gender, plotted using the original values of serial measurements, which are supposed to be generally consistent with the incremental AUC analysis. The age trajectories of MAP were nonlinear in blacks and whites. The age–haplotype interactions in white females were significant for cubic age (P=0.018), indicating that the acceleration of the rate of change in MAP was different between G894-10T and (G894-G10)/(G894-G10) groups.
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Discussion |
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The allele frequencies of the 4 polymorphisms among whites in this study were similar to those found in other white populations,10,11,31–34 except for slightly lower frequencies of the -786C and -922G alleles in this study than in others.33,34 In the current study, blacks compared with whites showed significantly lower rare allele frequencies of the 4 polymorphisms. However, there have been so far no corresponding black–white data available from other studies for comparison in this regard.
Because loci located more distantly from one another undergo recombination more frequently, they are expected to exhibit less LD than more closely linked loci. An inverse relationship between LD and physical distance between loci has long been recognized theoretically.35 In this study, the T-786C and A-922G polymorphisms located in the promoter region were in complete LD in both blacks and whites. A complete LD between T-786C and A-922G was also observed in France, Northern Ireland, and Japanese populations.34,36 G894T and G10T variants, which are located 13 kb apart, were significantly associated with each other in blacks and whites in our study population. The association of G894T and G10T each with (T-786C)-(A-922G) haplotypes was moderate in whites, which is consistent with other studies.34 The association between G894T and T-786C (or A-922G) was not significant in blacks in this study. A lack of LD between G894T and T-786C (or A-922G) was also observed in Japanese populations.36 It should be noted that frequencies of the 4 rare alleles were lower in black and Japanese populations7–9,36 than in whites.10,11,31–34
Although the relationship between endothelial NO production and blood pressure has been well established,1–4 published findings on the effect of eNOS gene variations on blood pressure are not consistent.7–13 With respect to the G894T polymorphism, the current findings are in agreement with an earlier study conducted in a French–Caucasian population in which subjects with hypertension showed a significantly higher frequency of the G894 allele than normotensives.10 In contrast, a significantly higher frequency of the 894T allele has been found to be associated with hypertension7 and higher blood pressure levels in Japanese.8 On the other hand, no association of the G894T polymorphism has been found with either hypertension status or blood pressure levels in another larger study in Japanese population.9 The discrepancies in the eNOS gene effect on blood pressure are possibly attributable to confounding factors such as race, gender, age, and obesity. We also found previously that insulin resistance status modified the association between the eNOS gene and blood pressure levels in adults.25 Further, the gender-specific genotype effect of the eNOS gene found in this study may also partly explain the discrepancies in studies that consisted of different proportions of males and females.
Apart from other confounding factors, the short-term fluctuations and measurement errors of blood pressure levels may substantially influence estimates of the gene effect. All the studies focusing on the eNOS gene and blood pressure have been so far cross-sectional in nature.7–13 The total AUC calculated based on multiple measurements in this study minimized the short-term influences and represented a more reliable measure of overall long-term levels. This notion is supported by findings from other studies using average value of multiple measurements.21–23 However, the average value does not reflect longitudinal trends. The AUC measures used in the present study provide a better insight into the genetic influence not only on long-term burden but also on long-term trends of blood pressure from childhood to adulthood.
In addition to blood pressure levels at a specific time point, there may also be genetic effects on the longitudinal trends determined by the within-person variations over time. In the previous longitudinal studies, significant genetic heritabilities17 and a recessive major-gene effect18 have been demonstrated for the changes in blood pressure over time. Further, the eNOS gene G894T polymorphism was found to influence the blood pressure response to exercise.31 The findings from the present and previous studies provide supporting evidence for the concept of "variability genes," which may influence within-person variability in phenotypes over time through the gene–environment interactions.37
It is well known that males generally have higher blood pressure levels and prevalence of hypertension than females.15,38 A gender difference in genetic influence on blood pressure was found among male and female twins.39 Further, in a large-scale genetic association study in US white coronary heart disease patients,40 among 110 candidate genes related to cardiovascular risk factors, including hypertension-related genes, evidence of gender–gene interactions was found in a number of genes and revealed that the effects of genes were stronger among women. In the present study, the G894T and G10T polymorphisms and their haplotypes showed a stronger effect on longitudinal profiles of blood pressure in females than in males. The biological basis of gender–gene interactions in the etiology of hypertension remains to be elucidated.
In the present study, the 894T and 10T alleles were individually associated with lower blood pressure levels from childhood to adulthood in females. However, individual analyses on G894T and G10T did not separate the effect of 894T-10T haplotype on MAP. In the haplotype analysis using (G894-G10)/(G894-G10) as a reference, the influence of G894-10T haplotype on MAP with 894T effect removed was stronger than that of 894T-G10 haplotype with 10T effect removed among females. Further, the haplotype analyses of all 4 polymorphisms gave very similar results to the G894T-G10T haplotypes. Although the G894T variant located in exon 7 results in a replacement of Glu by Asp at amino acid residue 298, information is limited on the influence of G894T genotype on the eNOS activity. To our knowledge, only 1 study reported that the G894T genotype has no appreciable effect on enzyme activity of the eNOS.41 Together, the stronger effect of the 10T allele, which is located in intron 23, found in our study suggests that the haplotype might be in LD with a yet unknown eNOS gene variant(s) or some other causal loci influencing the blood pressure regulation and the predisposition to hypertension.
In conclusion, blacks compared with whites had lower rare allele frequencies of G894T, G10T, T-786C, and A-922G polymorphisms of the eNOS gene. T-786C and A-922G polymorphisms were in complete LD in blacks and whites. The eNOS gene G894T and G10T polymorphisms, individually and as haplotypes, were associated with the long-term burden and trend of blood pressure since childhood, especially in females. These results suggest that the eNOS gene locus (or other closely linked causal loci) may be one of the genes contributing to the predisposition to hypertension.
Perspectives
It is well established that impaired endothelial function resulting from decreased NO production plays a pathophysiologic role in essential hypertension. However, the association between eNOS gene polymorphisms and blood pressure is not consistent in cross-sectional studies. The present study demonstrated that blacks compared with whites had lower rare allele frequencies of G894T, G10T, T-786C, and A-922G polymorphisms of the eNOS gene, T-786C and A-922G polymorphisms were in complete LD in blacks and whites, and the G894 and 894T alleles were strongly associated with 10T and G10 alleles, respectively, in both races. Further, the eNOS gene G894T and G10T polymorphisms, individually and as haplotypes, were associated with the long-term burden and trend of blood pressure from childhood to adulthood, especially in females. These results suggest that the eNOS gene locus (or other closely linked causal loci) may be one of the genes contributing to the predisposition to hypertension. In view of these results, future research should focus on the eNOS genotype effect on blood pressure in race–sex subgroups and in haplotypes in a larger sample. The gender-specific influence of the eNOS gene on blood pressure needs to be further elucidated to explain the discrepancies found in different studies.
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Acknowledgments |
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This study was supported by grants 0160261B from the American Heart Association, HL-38844 from the National Heart, Lung, and Blood Institute, and AG16592 from the National Institute on Aging of the US Public Health Service.
Received July 2, 2004; first decision July 30, 2004; accepted September 9, 2004.
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