JAMA：降压药效力与基因变异有关

根据1月23日《美国医学协会期刊》（JAMA）上的一则研究显示，罹患高血压并具有某些基因变异的患者对某些降压药会体验到不同的治疗效果，这提示将病人的基因型与某些降压药进行匹配可能会产生更好的结果。

美国明尼苏达大学的Amy  I.  Lynch及其同僚开展了一项研究，旨在调查具有次要NPPA（心房利钠素前体A）基因型（NPPA  G664A  及  NPPA  T2238C）的高血压病患在随机接受利尿药氯噻酮（chlorthalidone）治疗与随机接受其它类别降压药治疗时，在心血管疾病（CVD）的测试上是否会有不同的结果。

该项研究包括38462名参与者，他们是来自ALLHAT试验（Antihypertensive  and  Lipid  Lowering  Treatment  to  Prevent  Heart  Attack  Trial，即抗高血压及降脂治疗以预防心脏病发作的试验）中的高血压患者。该试验是在美国和加拿大开展的一项多中心的随机临床试验。在2004年2月到2005年1月间，这些病患接受了基因型检查。这些参加试验者被随机分配到一个利尿药（氯噻酮，1万3860人  ）组、一个钙通道阻滞剂（氨氯地平  [Amlodipine]，  8174人）组、一个血管紧张素转化酶（ACE）抑制剂  （赖诺普利  [Lisinopril],  8233人）组，或一个阿尔法-阻滞剂（多沙唑嗪  [doxazosin]，  8195人）组。对这些病人的随访时间平均为4.9年。

研究人员发现，当氯噻酮（利尿药）组与氨氯地平  （钙通道阻滞剂）组进行比较时，NPPA  T2238C  变异与冠心病（CHD）、中风、全因死亡、混合型CHD及混合型CVD存在着遗传药理方面的关联；当氯噻酮组与氨氯地平组或赖诺普利（ACE抑制剂）组进行比较时，NPPA  T2238C  变异与中风之间也存在着遗传药理方面的关联。这种关联性在所有的结果中都是始终如一的，那些具有至少一份拷贝的次要C等位基因（一种基因的备选形式）者如果被分配到氯噻酮组的话，他们与分配到氨氯地平组（以及对中风进行比较的氨氯地平组加上赖诺普利组）的患者相比较具有较低的罹患疾病及/或死亡的风险，而那些具有TT基因型的氯噻酮组的病患，他们比分配到氨氯地平组的病患具有更高的患病及/或死亡的风险。（来源：EurekAlert!中文版）

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This Week in JAMA
JAMA. 2008;299(3):253.
Vol. 299 No. 3, January 23, 2008

Pharmacogenetic Association of the NPPA T2238C Genetic Variant With Cardiovascular Disease Outcomes in Patients With Hypertension

Amy I. Lynch, PhD; Eric Boerwinkle, PhD; Barry R. Davis, MD, PhD; Charles E. Ford, PhD; John H. Eckfeldt, MD, PhD; Catherine Leiendecker-Foster, MS; Donna K. Arnett, PhD

JAMA. 2008;299(3):296-307.

Context The NPPA gene codes for the precursor of atrial natriuretic polypeptide, suggesting that NPPA may modulate the efficacy of some antihypertensive drugs.

Objective To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (BP) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications.

Design, Setting, and Patients Post hoc analysis of 38 462 participants with hypertension from ALLHAT, a multicenter randomized clinical trial conducted in the United States and Canada. Genotyping was performed from February 2004 to January 2005.

Intervention Participants were randomly assigned to receive a diuretic (chlorthalidone; n = 13 860), a calcium antagonist (amlodipine; n = 8174), an angiotensin-converting enzyme inhibitor (lisinopril; n = 8233), or an {alpha} -blocker (doxazosin; n = 8195).

Main Outcome Measure The primary outcome measure was coronary heart disease (CHD), defined as fatal CHD or nonfatal myocardial infarction (mean follow-up, 4.9 years). Secondary outcomes were stroke, all-cause mortality, combined cardiovascular disease outcomes, and 6-month systolic and diastolic BP changes. Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly.

Results Depending on genotype, the event rates per 1000 person-years were 15.3 to 19.7 for CHO, 9.6 to 15.4 for stroke, and 27.4 to 30.7 for all-cause mortality. For the NPPA T2238C variant, lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine (CHD: CC = 0.86; TC = 0.90; TT = 1.09; P = .03 [dominant model]; stroke: CC = 1.18; TC = 0.82; TT = 1.26; P = .01 [additive and dominant models]; all-cause mortality: CC = 0.87; TC = 0.98; TT = 1.12; P = .05 [dominant model]). Combined end points yielded similar results. Consistent with these clinical findings, 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone (–6.5 mm Hg) than with amlodipine (–3.8 mm Hg), lisinopril (–2.4 mm Hg), or doxazosin (–3.8 mm Hg). Among those with the TT genotype, systolic BP differences between drugs were less (range, –5.4 to –7.5 mm Hg; P value, <.001 to .003 for interaction); diastolic BP showed similar results. We found no pharmacogenetic associations with the NPPA G664A variant.

Conclusions The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP. Minor C allele carriers experienced more favorable cardiovascular disease outcomes when randomized to receive a diuretic, whereas TT allele carriers had more favorable outcomes when randomized to receive a calcium channel blocker.

Author Affiliations: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (Drs Lynch and Eckfeldt and Ms Leiendecker-Foster); Human Genetics Center, University of Texas Health Science Center at Houston (Dr Boerwinkle) and University of Texas School of Public Health (Drs Davis and Ford), Houston; and Department of Epidemiology, University of Alabama at Birmingham (Dr Arnett).