Hypertension and Related Diseases Center, Azienda Ospedaliero Universitaria-Università di Sassari, Sassari, Sardinia, Italy.
Physiol Genomics. 2011 Nov 7;43(21):1219-25. doi: 10.1152/physiolgenomics.00012.2011. Epub 2011 Aug 23.
Essential hypertension is highly prevalent in the elderly population, exceeding 70% in people older than 60 yr of age, and remains a leading risk factor for heart disease, stroke, and chronic renal disease. Elucidation of genetic determinants is critical but remains a challenge due to its complex, multifactorial pathogenesis. We investigated the role DEspR promoter variants, previously associated with male essential hypertension susceptibility, in blood pressure (BP) regulation. We detected a single nucleotide polymorphism within the DEspR 5'-regulatory region associated with increased BP in a male Sardinian cohort accounting for 11.0 mmHg of systolic BP (P<10(-15)) and 9.3 mmHg of diastolic BP (P<10(-15)). Sequence analysis of three normotensive subjects homozygous for the rs6535847 "normotension-associated T-allele" identified a canonical TATAAAA-box in contrast to a CATAAAA-motif in three hypertensive subjects homozygous for the rs6535847 "hypertension-associated C-allele." In vitro analysis detected decreased transcription activity with the CATAAAA-motif promoter-construct compared with the canonical TATAAAA-box promoter-construct. Although BP did not differ between DEspR+/- knockout male mice and wild-type littermates at 6 mo of age, radiotelemetric BP measurements in 18 mo old inbred DEspR+/- knockout male mice known to have decreased DEspR RNA and protein detected higher systolic, mean, and diastolic BPs in DEspR+/- mice compared with littermate wild-type controls (P<0.05). Our results demonstrate that promoter variants in DEspR associated with hypertension susceptibility and increased BP in Sardinian males affect transcription levels, which then affect BP in an age-dependent and male-specific manner. This finding is concordant with the late-onset and sex-specific characteristics of essential hypertension, thus reiterating the mandate for sex-specific analyses and treatment approaches for essential hypertension.
原发性高血压在老年人群中患病率很高，60 岁以上人群中超过 70%患有原发性高血压，仍然是心脏病、中风和慢性肾病的主要危险因素。阐明遗传决定因素至关重要，但由于其复杂的多因素发病机制仍然是一个挑战。我们研究了先前与男性原发性高血压易感性相关的 DEspR 启动子变异在血压（BP）调节中的作用。我们在一个撒丁岛男性队列中检测到 DEspR 5'-调控区的一个单核苷酸多态性与 BP 升高相关，该多态性可导致收缩压升高 11.0mmHg（P<10(-15))和舒张压升高 9.3mmHg（P<10(-15))。对三个同型纯合子携带 rs6535847“正常血压相关 T-等位基因”的正常血压受试者的序列分析，与三个同型纯合子携带 rs6535847“高血压相关 C-等位基因”的高血压受试者的 CATAAAA-基序相比，发现了一个典型的 TATAAAA-盒。体外分析检测到，与典型的 TATAAAA-盒启动子构建体相比，CATAAAA-基序启动子构建体的转录活性降低。尽管在 6 个月大时，DEspR+/- 敲除雄性小鼠与野生型同窝仔鼠的 BP 没有差异，但在已知 DEspR RNA 和蛋白水平降低的 18 个月大的近交 DEspR+/- 敲除雄性小鼠中进行的无线电遥测 BP 测量显示，DEspR+/- 小鼠的收缩压、平均压和舒张压均高于同窝仔鼠的野生型对照组（P<0.05）。我们的结果表明，与撒丁岛男性原发性高血压易感性和 BP 升高相关的 DEspR 启动子变异影响转录水平，进而以年龄依赖和男性特异性的方式影响 BP。这一发现与原发性高血压的迟发性和性别特异性特征一致，因此再次强调了对原发性高血压进行性别特异性分析和治疗方法的必要性。
