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Hypertension. 2008;51:1156-1162
Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.105247
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(Hypertension. 2008;51:1156.)
© 2008 American Heart Association, Inc.

Go Red Original Articles

Systematic, Genome-Wide, Sex-Specific Linkage of Cardiovascular Traits in French Canadians

Ondrej Seda; Johanne Tremblay; Daniel Gaudet; Pierre-Luc Brunelle; Alexandru Gurau; Ettore Merlo; Louise Pilote; Sergei N. Orlov; Francis Boulva; Milan Petrovich; Theodore A. Kotchen; Allen W. Cowley, Jr; Pavel Hamet

From the Centre de Recherche (O.S., J.T., P-L.B., A.G., S.N.O., F.B., P.H.), Centre Hospitalier de l’Université de Montréal–Technôpole Angus, Montreal, Quebec, Canada; Complexe Hospitalier de la Sagamie (D.G.), Chicoutimi, Quebec, Canada; École Polytechnique de Montreal (E.M.), Montreal, Quebec, Canada; McGill University Health Center (L.P.), Montreal, Quebec, Canada; and the Medical College of Wisconsin (T.A.K., A.W.C.), Milwaukee, Wis.

Correspondence to Pavel Hamet, Research Centre, Centre Hospitalier de l’Université de Montréal–Technôpole Angus, 4th Floor, Room 401-F, 2901 Rachel St East, Montreal, Quebec, Canada H1W 4A4. E-mail pavel.hamet{at}umontreal.ca


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The sexual dimorphism of cardiovascular traits, as well as susceptibility to a variety of related diseases, has long been recognized, yet their sex-specific genomic determinants are largely unknown. We systematically assessed the sex-specific heritability and linkage of 539 hemodynamic, metabolic, anthropometric, and humoral traits in 120 French-Canadian families from the Saguenay-Lac-St-Jean region of Quebec, Canada. We performed multipoint linkage analysis using microsatellite markers followed by peak-wide linkage scan based on Affymetrix Human Mapping 50K Array Xba240 single nucleotide polymorphism genotypes in 3 settings, including the entire sample and then separately in men and women. Nearly one half of the traits were age and sex independent, one quarter were both age and sex dependent, and one eighth were exclusively age or sex dependent. Sex-specific phenotypes are most frequent in heart rate and blood pressure categories, whereas sex- and age-independent determinants are predominant among humoral and biochemical parameters. Twenty sex-specific loci passing multiple testing criteria were corroborated by 2-point single nucleotide polymorphism linkage. Several resting systolic blood pressure measurements showed significant genotype-by-sex interaction, eg, male-specific locus at chromosome 12 (male-female logarithm of odds difference: 4.16; interaction P=0.0002), which was undetectable in the entire population, even after adjustment for sex. Detailed interrogation of this locus revealed a 220-kb block overlapping parts of TAO-kinase 3 and SUDS3 genes. In summary, a large number of complex cardiovascular traits display significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. Many of these would have been missed in a traditional, sex-adjusted setting.


Key Words: sex dimorphism • genetic linkage • single nucleotide polymorphisms • cardiovascular disease


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The sexual dimorphism of many physiological traits, as well as susceptibility to a wide variety of diseases, including hypertension, has long been recognized.1 Both social and environmental factors, as well as biological influences, contribute to this dimorphism, yet their relative relevance is not well appreciated. Contributing genetic factors have been documented in both human subjects2–4 and animal models.5–9 However, only recent investigations into the sex-specific genetic architecture of complex traits led to the hypothesis that even the determinants of common conditions like hypertension, such as humoral regulation of volume,10 and reaction to outcome events, such as myocardial infarction,11 may have both unisex and sex-specific genetic determinants.4 If that is the case, adjustment for sex during the analysis and interpretation of data may actually hide a significant portion of genome-driven physiology unique for men or women. Recent investigation found that less than one quarter of 628 recently published clinical cardiovascular studies reported sex-specific results.12 There is a potentially sizeable impact of the genetically driven, sex-specific pathophysiology on clinical management of the above-mentioned conditions. Women have been shown to be more prone to adverse effects of, eg, angiotensin-converting enzyme inhibitors or antiarrhythmic drugs,13 and the beneficial effects of aspirin therapy were reported to be attributed to reduction in the risk of ischemic stroke, but not myocardial infarction, in women, with the opposite observation in men.14

The sex-specific genetic architecture has been described for blood pressure (BP),15–20 triglycerides, high-density lipoprotein cholesterol,21 fasting insulin,22 type 2 diabetes,23 body mass index,24,25 percentage of body fat,26 bone mineral density,27 serotonin28 and cortisol29 levels, asthma,30 autism,31 stuttering,32 and several other complex phenotypes in various geoethnic groups. We previously reported the largest set of loci significantly linked to hypertension and its metabolic components in the founder population of French Canadians from the Saguenay-Lac-St-Jean region of Quebec.33,34 Because we noted that sex explained a significant portion of variation in several cardiovascular phenotypes,34 we decided to harness the wealth of gathered phenotypic data by systematic analysis of sex-specific heritability and microsatellite- and single nucleotide polymorphism (SNP)–based linkage of 539 direct and derived anthropometric, metabolic, hemodynamic, and humoral traits, which have not been reported to date.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
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Extended Methods and Results sections can be found in the online data supplement, available at http://hyper.ahajournals.org.

Cohort and phenotyping were described previously.34–37 Details may be found in the online data supplement. The study was approved by the ethics committees of Complexe Hospitalier de la Sagamie, Université du Québec à Chicoutimi, and the Centre Hospitalier de l’Université de Montréal. All of the subjects gave their informed consent. All of the phenotyping was performed by trained personnel who followed standard operating procedures, as described previously.34–37

Genotyping
Genotyping with microsatellite markers has been described previously.34 SNP genotypes were assessed in the Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, with the GeneChip Human Mapping 50K Array Xba240 (Affymetrix).

Linear Regression
To evaluate the correlation between a trait and sex, we used a linear regression model: trait=f (age, sex), where age was an additional covariate, implemented in the GNU R statistical package, version 2.1.1. This test reports a P value and a correlation coefficient R2, which indicate the proportion of variance because of age and sex.

Estimation of Narrow-Sense Heritability
We estimated narrow-sense heritability (h2N) by a variance-components approach implemented in SOLAR, version 2.1.1. Phenotypes were first adjusted for covariates, age and sex (in the combined sample), only when appropriate. A model containing environmental and additive variance components was then created with a constraint being that they sum to 1 (h2r+e2=1) and was computed separately for each sex.

Linkage Analyses
Multipoint and 2-point linkage analyses were performed by the variance components approach implemented in SOLAR, version 2.1.1, in 3 settings, including the entire sample and then separately in men and women. The genetic information was represented by 437 microsatellite markers uniformly distributed throughout the whole genome and GeneChip Human Mapping 50K Array Xba240-derived SNPs. Age and sex were considered as covariates in linkage analyses of the combined (male+female) set. When significant (P<0.05), the covariates were retained in the final models. Sex-specific linkage was accomplished by representing the other sex phenotype data as missing.

Linkage disequilibrium analysis was performed using Haploview 4.0.38 The default algorithm of generation of linkage disequilibrium blocks was CIs, according to Gabriel et al.39


*    Results
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 up arrowAbstract
 up arrowIntroduction
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 *Results
down arrowDiscussion
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Sex and Age Dependence of Analyzed Traits
In the first step, we performed linear regression analysis of 539 phenotypes with sex and age (Table 1). We found 47.3% phenotypes to be age and sex independent, 14.5% phenotypes to be specifically age dependent, 13.8% phenotypes to be sex dependent only, and 24.4% phenotypes to be both age and sex dependent after correction for multiple comparisons. Figure 1 illustrates the frequency of sex, age, sex and age, and independent traits in major cardiovascular-related categories. Details on each category are shown in Table S1. In the group of sex-only dependent variables, the most significant trait was the amount of body fat measured by skinfolds (P=7.2x10–108), followed by obesity-related anthropometric and body composition measures (eg, volume of extracellular water measured by bioimpedance, P=3.9x10–98) and biochemical traits (eg, hematocrit, P=5.6x10–67). Among traits with exclusive age-specific distribution, various measures of systolic BP (SBP) but not diastolic BP were most prominent, eg, SBP by ambulatory blood pressure measurement (P=2.8x10–44). Both sex and age mainly affected the variability of several body composition traits and height, followed by mostly diastolic BP measures. Because the present study is focused on sex-specific features, the analysis hereafter considers only sex-related features of the genetic architecture of the studied traits.


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  		Table 1. Number of Phenotypes for Which Sex and/or Age Are Significant Covariates in a Linear Regression Model


Figure 1
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  		Figure 1. Distribution of sex, age and sex, and age-related traits in major phenotype categories. Relative frequencies of phenotypes for which sex ({blacksquare}), age ({square}), and sex and age (Figure 1) are significant covariates in the linear regression model after correction for multiple testing (P<9.3x10–5). The percentage of traits in each major phenotype category not passing the threshold is indicated as independent (IND., Figure 1). BP/HR indicate cardiac indices; HUMORAL/BCH, humoral and biochemical measures.

Sex-Specific Heritability
We identified a substantial gradient along the comparison of estimates of h2N between the sexes (Figure S1). Among the traits, where single-sex h2N was higher than that of the combined sample, there were almost twice as many traits showing 20%, 40%, and 60% h2N sex difference in the male than in the female subsets. The most contrasting observations are summarized in Table 2. One-thousand permutations performed on 13 of the most contrasting phenotypes indicate that the larger heritability differences between men and women correspond on average with lower P values (Pearson correlation coefficient r=–0.57) and are, thus, more likely to represent genuine heritability differences. Nevertheless, because heritability computed by SOLAR is not robust to the addition of even a few individuals, especially in small groups, we proceeded to much more robust linear regression and linkage analysis.


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  		Table 2. Comparison of h2N of Traits Where Single-Sex h2N Was Higher Than That of the Combined Sample and the Between-Sex Difference Was >50%

Linkage
We identified 270 loci showing >2.0 logarithm of odds (LOD) point differences between the linkage signals found in the respective sexes. Then, we performed 10 000 permutation tests, and after adjusting for multiple comparisons (P<9.3x10–5), we retrieved 31 sex-specific quantitative trait loci (QTLs) based on the microsatellite map (Table S2). Focusing on 1-LOD drop support intervals under the linkage peaks, we subsequently carried out 2-point linkage with SNPs (n=90 to 1662 SNP per QTL). On 20 occasions, we were able to confirm the presence of a sex-specific signal, depicted in Figure S2. Table 3 contains detailed information on the 10 male-specific and 10 female-specific loci. Four observations mapping to the same region of chromosome 12 pertain to related phenotypes and putatively represent 1 biological signal, reducing male-specific QTLs to 7. The supine SBP showed male-specific linkage on chromosome 12 with a single SNP exceeding LOD 4 (Figure 2A). This region belongs to the 220-kb haplotype block encompassing most of the TAO-kinase 3 gene and part of the suppressor of the defective silencing 3 homolog SUDS3 gene (Figure 2B). We then analyzed the impact of the alleles of relevant SNPs on supine SBP in both sexes. As illustrated in Figure 2C, there was a significant opposite impact on SBP of rs575121 male GG homozygotes having the highest BP (131±4 mm Hg), whereas the same allele in women resulted in the lowest BPs (113±4 mm Hg; sex*rs575121 interaction, P=0.03). Heart rate (HR) under varying physiological circumstances also displayed significant sex-specific linkage in 6 distinct loci constituting the most frequent dimorphic feature (Figure S3). The majority of identified sex-specific signals mapped to intergenic regions. Two of them resided within recently reported copy number variants (http://projects.tcag.ca/variation/): HR change during norepinephrine infusion on chromosome 11 (rs566797) and cAMP on chromosome 19 (rs10500275), both representing female-specific QTLs in our cohort (Table 3).


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  		Table 3. Summary of Sex-Specific Linkage Signals Significant in Genome-Wide Multipoint Linkage, Using Microsatellites and Peak-Wide 2-Point Linkage With SNPs


Figure 2
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  		Figure 2. A, Male-specific linkage of supine SBP on chromosome 12 by microsatellite-based multipoint linkage and 2-point linkage with SNPs. B, Detailed view of linkage disequilibrium at the peak of 2-point linkage is shown using Haploview 4.0-generated linkage disequilibrium blocks as described in the Methods section. The values of D' are indicated in number and by color (for LOD ≥2: bright red: D'=1, shades of red/pink: D'<1; for LOD <2: white), with indication of gene tracks in the region. C, SBP (age-adjusted mean±SE) in the supine position according to sex and genotype of rs575121. Only significant results of Tukey’s posthoc tests between women and men of identical genotypes are shown. ***P<0.001.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The sexual dimorphism of physiological traits and even diseases is historically recognized, as well as its impact on cardiovascular outcomes (cardiovascular disease),40–42 contrasting with therapeutic guidelines, which suggest generally the same medication choices for both sexes. Over the last decade, several candidate genes for specific traits were explored for their dimorphism, such as a sex-specific impact of the tumor necrosis factor-{alpha} gene on abdominal obesity in men and the thigh region in women.2 Then, genome-wide search for sex-specific determinants of single phenotypes ensued.15–32 In 2000 subjects from the Framingham study, plasma natriuretic peptide (ANP) levels disclosed different degrees of heritability in men and women, but only suggestive linkage was found at 2 chromosomes.10 In the present study, the physiological relevance of ANP, cGMP, and urinary sodium pathway43 demonstrated a consistent heritability pattern, particularly in the standing position, in females only. For plasma renin activity, significant heritability (66%) was detected previously only in the male subgroup.44 This is in concordance with our observation of several renin measurements showing disproportionately larger heritability in men (Table 2). In 1 of the first systematic approaches to evaluating sex-specific genetic architecture of complex traits, Weiss et al4 have assessed heritability and linkage of 17 quantitative traits in Hutterites, 3 of them reaching the criteria for genome-wide significance.

Here, we report the results of sex-specific scans applied to 539 phenotypes based on our past thorough exploration of dense phenotyping in French-Canadian subjects,34 revealing 20 significant QTLs with consistent sex-specific linkage to various hemodynamic, anthropometric, humoral, and metabolic traits. If we had implemented the commonly used sex-adjustment, all of these potentially important genomic variants would have been missed.

Our most relevant results point to a region of chromosome 12, specifically to the TAOK3 gene. Indeed, this member of the mitogen-activated protein kinase cascade will deserve further exploration, because sexual dimorphism has been demonstrated in many studies of heart remodeling, including that after myocardial infarction.11 Actually, 3 other genes containing intronic SNPs significantly linked to BP and HR measures in this study have a common feature with TAOK3: they are all involved in fundamental cellular signaling pathways. Furthermore, as the homozygotes of the minor allele (GG) of the above-mentioned chromosome 12 variant rs575121 represented 16% to 25% of whites, the potential importance of the TAOK3 variation may well reach beyond the specific Saguenay-Lac-St-Jean population.

SNP rs1360005, showing significant male-specific linkage to insulin level during the glucose tolerance test, is located in the immediate vicinity of 5'-untranslated region of the SORBS1 gene. This is a member of a phosphatidylinositol 3-kinase–independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4.45 Despite this positive role of SORBS1 in glucose uptake, it has been shown recently that deletion of the gene protects against high-fat diet–induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduction of markers of inflammation.46 Nevertheless, no sex-dependent physiological effects were reported for SORBS1 polymorphisms so far in humans or animal models.

HR is recognized as an independent predictor of cardiac events, especially in the male sex,47 particularly at rest.48 In the present study, intronic SNP in thyroid hormone receptor-β was linked uniquely to HR in women. This observation is of interest, because thyroid hormone receptor-β is the predominant isoform in the liver, whereas T3 effects on HR are mediated mostly by thyroid hormone receptor-{alpha}.

In comparison to reported studies of sex-specific linkage, we noted several possible overlapping signals but none for the identical phenotype. The female-specific locus for sodium excretion quantity overlaps with suggestive linkage reported for fasting insulin in African-American women from the Hypertension Genetic Epidemiology Network Study.22 The male-specific locus for trunk:extremity ratio may actually overlap with male-specific suggestive serotonin level linkage in Hutterites.4 We can speculate that, within the framework of a recently proposed systemic view of complex conditions, the Human Diseasome,49 certain nodes and pathways shared among distinct common diseases may be preferentially frequented by one or the other sex.

Sex is a biological status determined by sex chromosomes and their interactions with autosomes, X-chromosome inactivation, sex hormones, and related determinants. Gender is in part determined by the above, but also submitted to sociocultural and educational shaping, eg, in some societies, fat in women is praised, whereas other geoethnic groups value slenderness. In this context, the observable traits in humans are subject to both sex and gender influences, even in the presence of a strong genetic component.50 Here, we further report its wide-range relevance, in fact, similar in extent to that of age. One of the potential limitations of this study is a possible geoethnic specificity of the findings, which requires validation in sex-specific analyses in additional cohorts. However, even concordance between human populations in the sex dependency of some phenotypes does not resolve the sex versus gender impact, because the expression of a given phenotype can indeed be modulated by sociocultural influences. A systematic search for the sex dimorphism in syntenic regions for the corresponding biological function in rodent models7,8,51 will have to be undertaken to help to distinguish between sex and gender as physiological determinants.

Perspectives
The clinical implications of the presented results are well in term with several empirical observations,52 like the Medical Research Council trial in >17 000 patients, where benefit was associated with active treatment only in men considering all-cause mortality, whereas the opposite effect was found in women.53 The results of this and other studies indicate the possibility of genetically, rather than empirically driven,13,14 sex-specific clinical management of complex conditions, a more tangible concept before the implementation of a full-blown personalized medicine based on pharmacogenomics. We conclude that a significant portion of complex cardiovascular traits displays significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. These results underline the weakness of sex adjustment used in many linkage studies and underscore the need for sex-specific evaluations.


*    Acknowledgments
 
Sources of Funding

This work was supported by funds from the National Institutes of Health Specialized Center of Research HL-54998, Canadian Institutes of Health Research (Cardiogene Consortium, MT-11463 and MT-14654), and by a grant from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada to the Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond (GENESIS) intercapacity enhancement team on gender and sex determinants of cardiovascular diseases.

Disclosures

None.

Received November 19, 2007; first decision December 17, 2007; accepted December 31, 2007.


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