Efficacy of Hypertension Drugs Modified by Gene Variants

By Michael Smith
BIRMINGHMAM, Ala., Jan. 22 -- The goal of a genetic scan to narrow the choice of a hypertension drug to the need of an individual patient, beyond trial and error, is a bit closer to reality.
In an analysis of more than 39,000 hypertension patients, gene variations appeared to play a role in which patients responded best to different hypertension drugs, found Donna Arnett, Ph.D., of the University of Alabama at Birmingham, and colleagues.
The finding "moves us one step closer toward the ultimate goal of providing individualized treatment guided by genetic information," Dr. Arnett and colleagues said in the Jan. 23 issue of the Journal of the American Medical Association.
But they cautioned that the research -- predicated on a post hoc substudy of a large randomized clinical trial -- is not yet ready for prime time.
Before the findings can be used by clinicians, Dr. Arnett and colleagues said, essential further research includes replicating the findings, exploring gene-gene and gene-environment interactions, and conducting cost-benefit analyses.
The research built on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which randomized 42,418 hypertensive participants 55 or older from February 1994 through January 1998 and then followed them until March 2002.
Participants were randomized to a diuretic, a calcium antagonist, an angiotensin-converting enzyme inhibitor, or an alpha-blocker and the primary endpoint was fatal coronary heart disease or nonfatal myocardial infarction.
For the substudy -- dubbed Genetics of Hypertension Associated Treatment or GenHAT -- the researchers looked at a range of cardiovascular outcomes for the 39,114 participants with DNA available for study.
The GenHAT study became possible in 2003, when a test became available for single nucleotide polymorphisms (SNPs) in a gene called atrial natriuretic precursor A (NPPA), from which atrial natriuretic polypeptide (ANP) is derived.
Animal studies have shown that low levels of ANP, the diuretic that controls extracellular fluid volume and electrolyte homeostasis, lead to hypertension, while enhanced levels lead to hypotension.
Dr. Arnett and colleagues looked at two SNPs in NPPA that appeared likely to have functional consequences -- a guanine-adenine switch dubbed rs5063 and a thymine-cytosine switch dubbed rs5065.
The goal was to see whether having the different alleles of the gene had any effect on which of the four drugs was more efficacious.
In fact, analysis showed that rs5063 was not associated with any variations in effect, but the C alleles of the second SNP were associated with a better outcome if patients carrying them were randomized to the diuretic.
When comparing the diuretic and the calcium antagonist, for instance, lower event rates were found in univariate analyses for the C allele carriers than for the TT homozygous individuals.
Specifically:
Those with two copies of the C allele had a relative risk for coronary heart disease of 0.86, compared with 0.90 for those with one copy, and 1.09 for those with two T alleles. The differences were significant at P=0.03.
The corresponding relative risks for stroke were 1.18, 0.82, and 1.26, which was significant at P=0.01 when the two groups with a C allele were combined into one.
For all-cause mortality, having two C alleles led to a risk of 0.87, one copy to a risk of 0.98, and two T alleles to a risk of 1.12, which was significant at P=0.05.
In accord with the clinical findings, six-month changes in systolic blood pressure for those with the CC genotype were larger with the diuretic than with the other medications, while the majority (with the TT genotype) had a smaller range of variation. Results were similar for diastolic blood pressure.
After correction for multiple comparisons, none of the findings retained statistical significance, the researchers noted, but the consistency of associations remained in five of seven outcomes and "lends some credibility to the findings."
The study was supported by the National Heart, Lung, and Blood Institute and the NIH.
The researchers reported no financial conflicts.
Primary source: Journal of the American Medical Association Source reference:Lynch AI, et al "Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension" JAMA 2008; 299: 296-307.