DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males
DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males
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DOI：
10.1152/physiolgenomics.00012.2011
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发表时间：
2011-11-01
影响因子：
4.6
通讯作者：
Ruiz-Opazo, Nelson
中科院分区：
文献类型：
--
作者：
Glorioso, Nicola;Herrera, Victoria L. M.;Ruiz-Opazo, Nelson
Glorioso N、Herrera VLM、Didishvili T、Argiolas G、Troffa C、Bulla P、Bulla E、Ruiz-Opazo N。DEspR T/CATAAAA-box 启动子变体降低 DEspR 转录，并与撒丁岛男性血压升高相关。 Physiol Genomics 43: 1219-1225, 2011。首次发表于 2011 年 8 月 30 日； doi:10.1152/Physolgenomics.00012.2011.-原发性高血压在老年人群中非常普遍，在 60 岁以上的人群中超过 70%，并且仍然是心脏病、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。我们研究了之前与男性原发性高血压易感性相关的 DEspR 启动子变体在血压 (BP) 调节中的作用。我们在撒丁岛男性队列中检测到 DEspR 5' 调节区内的单核苷酸多态性与血压升高相关，收缩压为 11.0 mmHg (P < 10(-15))，舒张压为 9.3 mmHg (P < 10(-15))。对 rs6535847“正常血压相关 T 等位基因”纯合的三名正常血压受试者的序列分析鉴定出典型的 TATAAAA 盒，与 rs6535847“高血压相关 C 等位基因”纯合的三名高血压受试者中的 CATAAAA 基序相反。体外分析检测到，与典型的 TATAAAA-box 启动子构建体相比，CATAAAA-motif 启动子构建体的转录活性降低。虽然 6 月龄 DEspR(+/-) 敲除雄性小鼠和野生型同窝小鼠之间的血压没有差异，但对已知 DEspR RNA 和蛋白质减少的 18 个月近交 DEspR(+/-) 敲除雄性小鼠进行放射遥测血压测量，发现与同窝野生型对照小鼠相比，DEspR(+/-) 小鼠的收缩压、平均血压和舒张压更高（P < 0.05）。我们的结果表明，与撒丁岛男性高血压易感性和血压升高相关的 DEspR 启动子变异会影响转录水平，从而以年龄依赖性和男性特异性的方式影响血压。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，从而重申了对原发性高血压进行性别特异性分析和治疗方法的要求。
Glorioso N, Herrera VLM, Didishvili T, Argiolas G, Troffa C, Bulla P, Bulla E, Ruiz-Opazo N. DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males. Physiol Genomics 43: 1219-1225, 2011. First published August 30, 2011; doi:10.1152/physiolgenomics.00012.2011.-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.