Abstract
Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL) detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004) and D11S1346 (at 10.6 Mb, P = 0.00000004), suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR), and adrenomedullin (ADM) are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs) within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57–0.94]). For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13–1.84]). Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension.
Highlights
Essential hypertension is a highly prevalent disorder and remains a major risk factor for the most common causes of mortality, including coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease [1,2]
Genomewide association studies have failed to detect major hypertension susceptibility genes that may contribute greater than 5 mmHg to the blood pressure (BP) effect [6,7,8,9]
These studies reported that several loci were significantly associated with increased BP by analyzing tens of thousands of patients in a multi-center, meta-analysis paradigm with BP effects ranging from 0.5–1 mmHg [6,7,8,9]
Summary
Essential hypertension is a highly prevalent disorder and remains a major risk factor for the most common causes of mortality, including coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease [1,2]. Genomewide association studies have failed to detect major hypertension susceptibility genes that may contribute greater than 5 mmHg to the blood pressure (BP) effect [6,7,8,9] These studies reported that several loci were significantly associated with increased BP by analyzing tens of thousands of patients in a multi-center, meta-analysis paradigm with BP effects ranging from 0.5–1 mmHg [6,7,8,9]. This implies that either hundreds of hypertension susceptibility genes exist that account for essential hypertension in humans, with each locus contributing a small fraction of the increase in BP (0.5–1 mmHg effect), or the studies have failed to detect major hypertension susceptibility loci due to major confounders, such as inherent genetic heterogeneity of human populations, great variability in trait measurements, the existence of several factors that are not accounted for, and factors in the analytical paradigm (e.g., sex-specific effects, gestational risk factors, and presence of hypertension subtypes with unique pathogenetic mechanisms)
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