Del-Aguila J L, Beitelshees A L, Cooper-Dehoff R M, Chapman A B, Gums J G, Bailey K, Gong Y, Turner S T, Johnson J A, Boerwinkle E
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD, USA.
Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.
氢氯噻嗪（HCTZ）是处方最为广泛的抗高血压药物之一。尽管众所周知HCTZ与高血糖和高甘油三酯血症有关，但其不良反应的潜在机制尚未完全明确。我们对两项不同临床试验（抗高血压反应的药物基因组学评估和抗高血压反应的遗传流行病学研究）中HCTZ治疗后空腹血糖和甘油三酯变化进行了全基因组关联研究和荟萃分析。位于NELL1基因11p15.1的两个单核苷酸多态性（rs12279250和rs4319515（r² = 0.73））在非裔美国人中与空腹血浆甘油三酯变化的关联达到全基因组显著性水平，每个变异等位基因与甘油三酯变化增加28mg/dl相关。NELL1编码一种含有表皮生长因子样重复序列的细胞质蛋白，已被证明可抑制脂肪生成分化。这些发现可能代表了HCTZ诱导不良代谢效应的一种新机制。
