Gene Expression

Racial differences & heart attacks

If you don’t like the word “racial,” just substitute “population.” In any case, Many African-Americans Have A Gene That Prolongs Life After Heart Failure:

About 40 percent of African-Americans have a genetic variant that can protect them after heart failure and prolong their lives, according to research conducted at Washington University School of Medicine in St. Louis and collaborating institutions.

“By mimicking the effect of beta blockers, the genetic variant makes it appear as if beta blockers aren’t effective in these patients,” he explains. “But although beta blockers have no additional benefit in heart failure patients with the variant, they are equally effective in Caucasian and African-American patients without the variant.”

The researchers…found that 41 percent of African-Americans have a variant GRK5 gene that more effectively suppresses the action of adrenaline than the more common version of the gene. People with the variant gene could be said to have a natural beta blocker, Dorn says. The variant is extremely rare in Caucasians, accounting for its predominant effects in African-Americans.

Here’s the original paper, A GRK5 polymorphism that inhibits bold ?-adrenergic receptor signaling is protective in heart failure:

?-adrenergic receptor (?AR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize ?ARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological ?AR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and ?-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced ?AR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a ‘genetic ?-blockade’ that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of ?-blocker clinical trials in this population.

The key here is that you can’t assume all genetic backgrounds are the same; something that should be obvious to you if you’ve been reading for the past generation about how Africans exhibit more extant genetic variation than all other human populations combined. The medical regime which encouraged the prescription of beta blockers presupposed a white treatment population, which makes sense since most Americans are white (greatest good for the greatest number and all). Against that genetic background beta blockers exhibit a great deal of efficacy; but against an African American genetic background far less so. Why? In this case the answer seems rather clear in that there is an allele of this locus whose polymorphism has a direct causal relationship to a biochemical pathway implicated in the production of the relevant enzyme. These sorts of data are the rationales for attempting to make sure you have a diverse populations against which you perform medical trials; humans are mostly the same, but differences on the margins are not trivial (you won’t think so when you get sick!). Varied genetic backgrounds and their biomedical importance are one of the primary reasons behind research endeavours such as the International HapMap Project.

Obviously I’m really interested in evolution and humans, and how the two relate. But research with basic science yield is funded ultimately due to interest in proximate human well being; in other words, evolutionary biological implications are a side effect of the quest for medically salient data. Why establish a rigorous taxonomy of human populations? Why develop genetic analyses which can smoke out cryptic population substructure? Why map out as many QTLs as possible for a host of assorted molecular genetic processes? Knowledge is power, and hopefully power which those in medical disciplines will use to craft the regime most well suited to the host of priors any given individual brings to the table. Of course, I would also make the case that an acknowledgment of the ubiquity of evolution in shaping where we start out in life (or end up) is essential to extracting maximum insight from these data.

Note: Take a closer look at the SNP yourself. “A” codes for the non-protective variant.

Comments

  1. #1 Abel Pharmboy
    April 21, 2008

    Razib, this is fascinating – thanks for posting. Your point about “population” instead of race makes good sense in that we are already using pharmacogenomics to determine which patient populations might respond better to some drugs and/or experience more or less of certain side effects.

    The race issue in pharmacology, however, is extremely polarized as evidenced by the flop of BiDil, a formulation of two old drugs that proved effective in heart failure only with patients of African American ancestry. Some saw it as a race-based drug and others felt it was an exploitation of the race issue since the two generic drugs could be given independently, and cheaper, than this patented formulation.

  2. #2 razib
    April 21, 2008

    Some saw it as a race-based drug and others felt it was an exploitation of the race issue since the two generic drugs could be given independently, and cheaper, than this patented formulation.

    well, i hope they hashed out the conflicts of interest. i wouldn’t be surprised if the future because of economies of scale ‘majority populations’ may have access to cheaper drugs. but when it comes to health, price doesn’t matter, right?

  3. #3 ringo
    April 21, 2008

    I wonder if this will also speak to the higher rate of asthma in the african-descended population vs the european-descended one. Beta blockers can actually make asthma worse (anyone who’s ever taken adrenaline to open an airway can probably appreciate the mechanism).

  4. #4 keil
    April 21, 2008

    Hey Razib, are you familiar with melanotan? I’m a fair skinned redhead and I’m considering trying it. I love beaches, but hate skin cancer.

  5. #5 Alicia P
    April 21, 2008

    I did my dissertation work on the genetic susceptibility of African Americans, compared to Caucasians, to hypertension based on the prevalence of certain SNPs. When I first began in the lab it took me awhile to wrap my mind around ethnic subpopulations.

    There has been so much momentum to suppress any idea of race since the civil rights movement that I think it will make gene-based therapeutics difficult to supply to a particular group that needs them.

  6. #6 max
    April 22, 2008

    I don’t think you’d disagree with this, but instead of “more diverse” studies, we need larger subgroups of haplotype-specific populations. When those populations are racial, all the easier for visual recruitment.

    But the point is that a population-blind study would decrease the apparent effect of beta blockers for whites, while increasing the apparent effect for blacks (neither good for accurate science). Theoretically we want to stratify by as many factors as possible, to get be able to describe a theoretical patient as closely as possible. Personalized medicine, the future of the medical enterprise, requires studies with populations that are very alike (genotype-wise, ideally) to the patient.

  7. #7 The Urban Scientist
    April 22, 2008

    Thanks for this information. I posted a link on my sight, too. And it hints at something important for people to understand about research, clinical research in particular – we need to know more. Regrettably, most African-Americans are completely leery of research and think ANY research that looks at sub-pops of Black people or poor black people is a plot to destroy them — Tuskeegee throwback.

    I think important info like this and how you remind everyone of the evolutionary context is an important point to helping people understand.

    Thanks for the update.