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

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

doi:10.1161/hypertensionaha.107.105247

Cited by 47 publications

(36 citation statements)

References 52 publications

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“…We have previously described that a significant portion of cardiometabolic phenotypes has a sex-dependent penetrance in families with hypertension on Quebec founder population. 35 Regardless, the sex difference in the BP phenotype of the KO mice is true and significant, according to analysis with a mixed-effects linear model (Figure 2c). Nakayama et al 36 reported that smooth muscle-specific deletion of EFNB2 using SM22Δ-Cre results in lower body weight, reduced VSMC proliferation, thinner arterial vessel wall and enlarged arterial diameter.…”

Section: Discussionmentioning

confidence: 94%

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

et al. 2016

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Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3′ region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans. European Journal of Human Genetics (2016) 24, 1817-1825; doi:10.1038/ejhg.2016.105; published online 17 August 2016 INTRODUCTION Erythropoietin-producing hepatocellular kinases (EPH) are the largest family of receptor tyrosine kinases. In the basis of sequence homology, they are divided into A and B subfamilies. 1 Their ligands, called ephrins (EFNs), are also cell surface molecules. 2 EFNs are also divided into A and B subfamilies, based on the way they anchor on the cell surface: the A subfamily anchors on the cell surface through glycophosphatidylinositol, and the B subfamily, through a transmembrane domain. 2 The interactions between EPH kinases and EFNs are promiscuous, but EPHA kinases preferably interact with EFNA ligands, and EPHB kinases with EFNB ligands, which have three members, EFNB1, EFNB2 and EFNB3. 2 Although EPH members and EFN members share homology with their respective members, each member has its distinct function in different cellular processes. [3][4][5][6][7] In general, the EPH kinases interact with their EFN ligands on neighboring cells, because EPHs and EFNs are all cell surface molecules. 2 These molecules could be cleaved from the cell surface by enzymes such as ADAM10, 8,9 an unspecified matrix metalloproteinase, 10 or γ-secretase; 11 therefore, it is possible that the shed soluble fragments of EPH and EFN might be able to influence cells and tissues at a distance by blocking the interaction of EPHs and EFNs there.

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Section: Discussionmentioning

confidence: 94%

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

et al. 2016

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“…29 This FTO SNP is a SNP on the array that is closest to the FTO SNP genotyped in adolescents. The rs9302652 genotype distribution in the adult cohort was following: CC, 9.7%; CT, 40.6%; and TT, 49.7%.…”

Section: Adultsmentioning

confidence: 99%

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Pausová

Syme

Abrahamowicz

et al. 2009

Circ Cardiovasc Genet

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Background-FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results-The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions-These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone. (Circ Cardiovasc Genet. 2009;2:260-269.)

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“…[1][2][3][4][5] The high heritability of gene expression variation indicates that it may serve as an intermediate phenotype for the identification of genomic determinants of complex traits, such as essential hypertension. We initiated this approach by exploring the pleiotropic regulation of heat stress genes mapping the mRNA accumulation after heat stress and using recombinant inbred strains (RIS) developed by inbreeding the F 2 generation of normotensive Brown-Norway (BN-Lx) and spontaneously hypertensive rats (SHR).…”

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Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

et al. 2013

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N umerous quantitative trait loci for blood pressure (BP) elevation have been identified in essential hypertension in the last decade, followed by genome-wide association studies. [1][2][3][4][5] The high heritability of gene expression variation indicates that it may serve as an intermediate phenotype for the identification of genomic determinants of complex traits, such as essential hypertension. We initiated this approach by exploring the pleiotropic regulation of heat stress genes mapping the mRNA accumulation after heat stress and using recombinant inbred strains (RIS) developed by inbreeding the F 2 generation of normotensive Brown-Norway (BN-Lx) and spontaneously hypertensive rats (SHR). 6 We discovered a common regulator of heat stress genes, the rat heat stress transcription factor. 7 Subsequently, Hubner et al 8 undertook integrated gene expression profiling in the adipose tissue and kidneys of 6-week-old male animals from the same RIS. Dmitrieva et al 9 adopted this strategy for comparative analysis of common differentially-expressed genes in the kidneys of 4-, 8-, 12-, and 18-week-old males of 3 distinct SHR lines versus normotensive Wistar-Kyoto (WKY) rats. The renal transcriptomes of 2-week-old SHR and WKY females 10 and 9-week-old rats of both sexes 11 were compared by other research teams. However, results generated by these studies cannot serve to identify genes involved in the age-dependent development of hypertension. In the present investigation, we compared whole genome expression profiles in kidneys isolated from 12-, 40-, and 80-week-old male and female SHR and 4 RIS (HXB3, 13, 17, and 23) with different temporal patterns of hypertension development. Among the genes significantly correlating with increasing mean systolic and diastolic blood pressures, we noted the augmented mRNAs levels of Scnn1b and Scnn1g genes encoding β-and γ-epithelial Na channel (ENaC) subunits. The present study is thus focusing on the expression and activity of these genes in relation to age-dependent increase of blood pressure.Abstract-Elevation of blood pressure with age is one of the hallmarks of hypertension in both males and females. This study examined transcriptomic profiles in the kidney of 12-, 40-, and 80-week-old spontaneously hypertensive rats and 4 recombinant inbred strains in search for functional genetic elements supporting temporal dynamics of blood pressure elevation. We found that both in males and females of spontaneously hypertensive rats and hypertensive recombinant inbred strains age-dependent blood pressure increment was accompanied by 50% heightened expression of epithelial sodium channel β-and γ-subunits. Epithelial sodium channel subunit expression correlated positively with blood pressure but correlated negatively with renin expression. Increased epithelial sodium channel activity was observed in cultured epithelial cells isolated from the kidney medulla of 80-week-old spontaneously hypertensive rats but not in agematched normotensive Wistar Kyoto. This difference remained evident after ...

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

Cited by 47 publications

References 52 publications

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

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