Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jr^HS hypertensive rats

Abstract

Sex-specific differences in polygenic (essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating sex-common disease mechanisms in premenopausal women. However, emerging observations indicate sex-specific genetic susceptibility in various traits, thus requiring systematic study. Here we report a comparative analysis of independent total genome scans for salt-sensitive hypertension susceptibility quantitative trait loci (QTLs) in male and female F2 [Dahl R/jrHS x S/jrHS] intercross rats exposed to high-salt (8% NaCl) rat diets. Hypertension was phenotyped with three quantitative traits: blood pressure (BP) elevation associated with increased hypertensive renal disease [glomerular injury score (GIS)] and increased cardiac mass [relative heart weight (RHW)] obtained 8-12 wk after high-salt challenge; 24-h nonstress, telemetric BP measurements were used. Although sex-common QTLs were detected for BP [chromosome (chr) 1-144.3 Mbp; chr 1-208.8 Mbp], GIS (chr 1-208.8 Mbp), and cardiac mass (chr 5-150.3 Mbp), most QTLs across the three phenotypes studied are gender specific as follows: female QTLs for BP (chr 2-106.7 Mbp, chr 2-181.7 Mbp, chr 5-113.9 Mbp, chr 5-146.7 Mbp, chr 12-12.8 Mbp), GIS (chr 15-59.6 Mbp), and RHW (chr 2-31.5 Mbp, chr 5-154.7 Mbp, chr 5-110.9 Mbp); male QTLs for BP (chr 2-196.7 Mbp, chr 11-48.0 Mbp, chr 20-35.7 Mbp), GIS (chr 6-3.3 Mbp, chr 20-40.7 Mbp), and RHW (chr 6-3.3 Mbp, chr 20-40.7 Mbp). Furthermore, interacting loci with significant linkage were detected only in female F2 intercross rats for BP and hypertensive renal disease. Comparative analyses revealed concordance of BP QTL peaks with previously reported rat model and human hypertension susceptibility genes and with BP QTLs in previous Dahl S-derived F2 intercross studies and also suggest strain-specific genetic modifiers of sex-specific determinants. Altogether, the data provide key experimental bases for sex-specific investigation of mechanisms and intervention and prevention strategies for polygenic hypertension in humans.

Association of ATP1A1 and Dear Single-Nucleotide Polymorphism Haplotypes With Essential Hypertension

“…The investigation of potential association of ATP1A1 and Dear with hypertension susceptibility was based on cumulative evidence obtained in animal models of polygenic hypertension, in particular, our studies in the Dahl rat model linking ATP1A1 [3][4][5][6][7] and Dear 3,8 to salt-sensitive hypertension. Altogether, concordance of results validates findings in the Dahl rat model as paradigms for investigation in humans.…”

“…3 These 2 chr2 BP-QTLs correspond to 2 candidate genes supported by cumulative experimental evidence. Briefly, molecular genetic 4 -6 and transgenic 7 analyses demonstrate that a functionally significant Q276L variant of the ␣ 1 N,K-ATPase (ATP1A1), which exhibits abnormal K transport 4,5 and K affinities, 6 most likely underlies the chr2-196.…”

“…7 Mbp QTL of salt-sensitive hypertension in F2[Dahl RϫS] intercross male rats. 3 In parallel, molecular genetic studies show that a functionally significant Dear (dual endothelin [ET]-1/angiotensin II receptor) S44/M74 variant, located 20 Mbp from ATP1A1, is the likely candidate gene variant for the second chr2-181.7 Mbp QTL, exhibiting cosegregation with salt-sensitive hypertension in F2 intercross female rats. 3,8 Female-specific effects are corroborated in heterozygous Dear ϩ/Ϫ -deficient mice, which exhibit lower BP in adult females.…”

“…3 In parallel, molecular genetic studies show that a functionally significant Dear (dual endothelin [ET]-1/angiotensin II receptor) S44/M74 variant, located 20 Mbp from ATP1A1, is the likely candidate gene variant for the second chr2-181.7 Mbp QTL, exhibiting cosegregation with salt-sensitive hypertension in F2 intercross female rats. 3,8 Female-specific effects are corroborated in heterozygous Dear ϩ/Ϫ -deficient mice, which exhibit lower BP in adult females. 9 Although closely linked on rat chr2, analysis of corresponding syntenic regions in humans localize ATP1A1 and Dear to different chromosomes: ATP1A1 on chr1p21, spanning 30 Kb of genomic DNA with 22 exons; and Dear on chr4q31.3, encompassing Ϸ5 Kb of genomic DNA with 2 exons.…”

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

“…Contributing genetic factors have been documented in both human subjects 2-4 and animal models. [5][6][7][8][9] However, only recent investigations into the sexspecific 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.…”