The Y Chromosome Effect on Blood Pressure in Two European Populations

Charchar, Fadi J.; Tomaszewski, Maciej; Padmanabhan, Sandosh; Łacka, B; Upton, Mark; Inglis, G. C.; Anderson, Niall; McConnachie, Alex; Żukowska-Szczechowska, E; Grzeszczak, W; Connell, John; Watt, Graham; Dominiczak, Anna F.

doi:10.1161/hy0202.103413

Cited by 82 publications

(66 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Proof of the concept will rest with demonstration of a combination of molecular or genetic variations acting together to increase risk for hypertension. That such a pairing of genes can affect BP was suggested in an association study in which individuals with a HindIII restriction site on the Ychromosome were at increased risk for hypertension if they were also carriers of a variant in the aldosterone synthase gene (14).…”

Section: Enac's Pivotal Position Lends Itself To a "Two-hit Model" Fomentioning

confidence: 99%

Central Role for ENaC in Development of Hypertension

Pratt¹

2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Na؉ reabsorption by the epithelial Na ؉ channel (ENaC) in cortical collecting duct provides the final renal adjustment to Na A n increase in Na ϩ and water retention is required for the development of most forms of hypertension as was proposed by Guyton years ago (1) and to this day has never really been refuted. In instances in which the mechanism for the hypertension is known, in which an identified gene mutation defines it, generally speaking an increase in the function of the epithelial Na ϩ channel (ENaC) leads to the Na ϩ retention and elevation in BP (2). The bigger question and the issue addressed in the current review is the extent to which ENaC participates in the development of common forms of hypertension. A strong case can be made for the fact that ENaC is pivotally positioned, both anatomically and physiologically, to convey a dominant influence on the prevalence of hypertension. Studies of hypertension in relation to ENaC and its major regulator, aldosterone, are reviewed here, and a general mechanism for development of hypertension is formulated. Finally, a clinical trial of the effectiveness of ENaC inhibition to lower BP in patients with hypertension is described. Common Molecular Variations in ENaC and Risk for HypertensionThe discovery of mutations in ␤-and ␥-subunits of ENaC to explain Liddle syndrome (3,4), a severe form of low-renin hypertension (5), was soon followed by a search for common genetic variants in ENaC subunits that affect susceptibility in less rare forms of hypertension. Of course variants were identified, and they were almost universally more common in black individuals, which fit nicely with the higher prevalence of low-renin hypertension in black individuals. After a number of years of study by several investigative groups, however, it remains unestablished that a given variant influences the risk for hypertension.The first molecular variant to show an association with hypertension was T594M in the C-terminus of ␤-ENaC (Figure 1) in a study of black individuals who lived in London (6) (the variant is rare in white individuals). Frequencies of the variant were found to be 8.3% in hypertensive individuals and 2.4% in normotensive individuals. In addition, plasma renin activity was lower in carriers of T594M. Subsequent studies by others have for the most part failed to replicate the same relationship to hypertension (7,8). In another study, seven molecular variants, all in ␤-ENaC, with overall allele frequencies of 44% in black individuals and 1% in white individuals, showed no association with hypertension and showed no effect on function using two different in vitro techniques (7). In our own laboratory, we found a G442V variant in the extracellular loop (Figure 1) in ␤-ENaC (again occurring almost exclusively in black individuals) significantly associated with an index of ENaC activity, the urinary aldosterone/K ϩ ratio, in normotensive young people, but it did not associate with hypertension in a study of adults (8). We also found that the A663T variant inPublished onli...

show abstract

Section: Enac's Pivotal Position Lends Itself To a "Two-hit Model" Fomentioning

confidence: 99%

Central Role for ENaC in Development of Hypertension

Pratt¹

2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…HindIII restriction fragment length polymorphism (12) is one of the most widely studied variants of the Y chromosome. Australian men negative for the HindIII restriction site have been shown to have significantly higher DBP than HindIII positive men (13), whereas a study based on Polish and Scottish men reported an association between the presence of the HindIII restriction site and elevated levels of SBP and DBP (14). The presence of the HindIII restriction site was more prevalent among hypertensive than normotensive subjects (15).…”

Section: Introductionmentioning

confidence: 96%

Effects of the Y Chromosome on Cardiovascular Risk Factors in Japanese Men

et al. 2008

View full text Add to dashboard Cite

“…In addition, there have been reports indicating that there exist associations between Y chromosome haplogroups and male infertility (Kuroki et al, 1999;Krausz et al, 2001;Lu et al, 2007;Yang et al, 2008;Puzuka et al, 2011;Ran et al, 2013;Sato et al, 2013), semen parameters (Sato et al, 2014), and prostate cancer (Ewis et al, 2006;Lindstr€ om et al, 2008;Wang et al, 2012) in some populations, including the Japanese. The Y chromosome haplogroup is also associated with several phenotypes other than male characteristics, including cardiovascular risk (Hiura et al, 2008;Bloomer et al, 2013;Kostrzewa et al, 2013), coronary artery disease (Charchar et al, 2012), lipids (Charchar et al, 2004;Russo et al, 2008), and blood pressure (Charchar et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men

et al. 2015

View full text Add to dashboard Cite

SUMMARYThe association between the Y chromosome haplogroup D2 and risk of azoospermia and low sperm motility has been previously studied, and it was indicated that haplogroups DE (YAP lineage) are associated with prostate cancer risk in Japanese males. Our assumption had been that Y chromosome haplogroups may be associated with sex hormone levels, because sex hormones have been deemed responsible for spermatogenesis and carcinogenesis. In this study, we assessed the association between Y chromosome haplogroups and sex hormone levels, including those of testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin-B, and calculated free testosterone (cFT), in 901 young men from the general Japanese population (cohort 1) and 786 Japanese men of proven fertility (cohort 2). We found that the haplogroup D2a1 was significantly associated with high LH levels in a combined analysis involving two cohorts (b = 0.068, SE = 0.025, p = 0.0075), following correction for multiple testing. To date, this result is the first evidence that implicates Y chromosome haplogroups in an association with sex hormone levels.

show abstract

The Y Chromosome Effect on Blood Pressure in Two European Populations

Cited by 82 publications

References 26 publications

Central Role for ENaC in Development of Hypertension

Central Role for ENaC in Development of Hypertension

Effects of the Y Chromosome on Cardiovascular Risk Factors in Japanese Men

Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men

Contact Info

Product

Resources

About