Wang Ying, O'Connell Jeffrey R, McArdle Patrick F, Wade James B, Dorff Sarah E, Shah Sanjiv J, Shi Xiaolian, Pan Lin, Rampersaud Evadnie, Shen Haiqing, Kim James D, Subramanya Arohan R, Steinle Nanette I, Parsa Afshin, Ober Carole C, Welling Paul A, Chakravarti Aravinda, Weder Alan B, Cooper Richard S, Mitchell Braxton D, Shuldiner Alan R, Chang Yen-Pei C
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31. doi: 10.1073/pnas.0808358106. Epub 2008 Dec 29.
Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10(-6)). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na(+) excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.
高血压给个人和公共健康带来了沉重负担，但这种复杂疾病的遗传基础却知之甚少。我们对阿米什人进行了一项关于收缩压和舒张压（SBP和DBP）的全基因组关联研究，发现丝氨酸/苏氨酸激酶基因STK39中的常见变异与强烈的关联信号。我们在一个独立的阿米什人群以及包括糖尿病遗传计划、弗雷明汉心脏研究、GenNet和哈特派在内的4个非阿米什白人样本中证实了这种关联（所有研究合并的荟萃分析：n = 7125，P < 10^(-6)）。与血压升高相关的等位基因频率> 0.09，在阿米什人中分别与SBP/DBP升高3.3/1.3 mmHg相关，在非阿米什研究中虽影响较小但具有一致性。基于细胞的功能研究表明，STK39与WNK激酶和阳离子 - 氯离子共转运体相互作用，这些蛋白的突变会导致单基因形式的血压调节异常。我们证明，在体内，STK39在远端肾单位表达，在那里它可能与这些蛋白相互作用。虽然所有相关的单核苷酸多态性（SNP）都不会改变蛋白质结构，但我们鉴定并通过实验证实了一个具有等位基因特异性体外转录活性的高度保守内含子元件，作为这种关联的功能候选者。因此，STK39中的变异可能通过增加STK39的表达从而改变肾脏钠排泄来影响血压，从而将罕见和常见的血压调节等位基因统一在同一生理途径中。
