Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension

JAMA. 2008 Jan 23;299(3):296-307. doi: 10.1001/jama.299.3.296.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Amlodipine / therapeutic use
  • Antihypertensive Agents / therapeutic use*
  • Atrial Natriuretic Factor / genetics*
  • Blood Pressure
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / genetics*
  • Chlorthalidone / therapeutic use
  • Diuretics / therapeutic use*
  • Doxazosin / therapeutic use
  • Female
  • Genotype
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / genetics*
  • Lisinopril / therapeutic use
  • Male
  • Middle Aged
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide


  • Antihypertensive Agents
  • Diuretics
  • NPPA protein, human
  • Amlodipine
  • Atrial Natriuretic Factor
  • Lisinopril
  • Doxazosin
  • Chlorthalidone