Thursday, January 24, 2008

Got TT? Stay away from "water pills"

In case you missed it. In the Journal of the American Medical Association a large retrospective analysis of the ALLHAT trial was done. What is the ALLHAT trial? It was an analysis of high blood pressure, treatments and outcomes. In the land of what us physician folk call Landmark Studies, this is a big study.

ALLHAT was a randomized, double-blind, multicenter clinical trial (623 clinical centers) with 42 418 hypertensive participants aged 55 years or older who had 1 or more additional risk factors for cardiovascular disease. ALLHAT was designed to determine if the incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction in high-risk hypertensive patients was lower with treatment using each of 3 antihypertensive drug classes: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an -adrenergic blocker (doxazosin) compared with treatment using a diuretic (chlorthalidone).

The posthoc analysis using genotypes was performed from 2004-2005. The results are just being published now. What did they genotype?

GenHAT genotyped variants in several hypertension-related genes in 39 114 ALLHAT participants with available DNA, making the study design a post hoc subgroup analysis of a randomized clinical trial. The goal of GenHAT was to understand gene-treatment interactions on CVD outcomes and blood pressure lowering.... There were 38 462 participants with data available for at least 1 variant.

The variant of interest is a gene called NPPA. Studies in animal models have shown that animals which have "minor alleles" for this gene end up with salt provoked hypertension. In addition and possibly more importantly, these patients showed higher risk of horrible disease such as stroke or heart attack.

I will not get into the physiology of high blood pressure today. But suffice it to say that there are several ways to lower the pressure in our arteries. Think of arteries like garden hoses. If there is alot of water in the hose, the pressure is up. If I take that same hose and that same amount of water, then I squeeze the hose. Guess what? The pressure goes up. So if I can lower the amount of water in the hose or dilate the hose to a bigger size, then I can lower the pressure. The "water pill" chlorthalidone removes water, the amlodipine dilates the hose. The Ace-inhibitor removes water indirectly.

Here's where we get a Landmark result for Personalized Medicine:
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.

What the hell does this mean? If you carry the TT pair of this NPPA gene, you shouldn't take the diuretic. Unless you want to have a higher risk of stroke.

The Sherpa Says: Despite being a modest elevation in risk, 126%. It is certainly easy enough to change a person's medications to avoid poor outcomes. This is what Personalized Medicine IS. The right diagnosis leading to the right drug for the right person. This is what we do at my offices. Does this come on the Illumina gene chips? SNP database ID rs5065. To my firend Brandon, check this one out!


Anonymous said...

Was ths the big news you were going to announce?

cariaso said...

On chip Affy GenomeWide 6
On chip Affy500k
On chip Illumina Human 1M
On chip Illumina Human 1
On chip Illumina Human Hap550
On chip Illumina Human Hap650Y
On chip Illumina Human NS12

rs5065 is literally on every known chip.

Steve Murphy MD said...

Can 23andMe write me a new prescription for amlodipine?

No the news I am going to announce is much bigger than that.


Tepi said...

interesting stuff. seems you've got a very forward-thinking thing going on here.

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