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Will race matter in the era of personalized medicine?
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In the May 2008 issue of Nature Medicine, a report by Liggett et al brought the field of medicine another step closer to uncovering the potential of genomics in our everyday practice. On the heels of a landmark clinical trial (COUMA-GEN) using individual genotypes to guide medical therapy (warfarin dosing), Liggett and colleagues provided data to suggest that in some patients with systolic dysfunction CHF, beta-blockers (a first-line therapy) may be superfluous. The investigators identified a novel polymorphism (GRK5-Leu41) that appears to offer a cardio-protective, beta-blocker-like effect, both in transgenic mouse models and in their human observational studies. The Leu41 variant was present in less than 5% of the white cohort and thus did not allow for statistical analysis in this group. However, in the black cohort, 35% had the beta-blocker-like Leu41 variant.
Of 375 black patients followed for an average of 30 months, 61 (16%) were not taking beta-blockers. Of the 65% black study participants without the protective Leu41 variant, the survival was markedly better in those who were taking beta-blockers (HR 0.22, P<.001). However, there was no additional improvement in survival from beta-blocker use among the patients carrying the Leu41 variant.
Indeed, the favorable survival curve for the 27 Leu41 individuals not taking beta-blockers was statistically no different from the survival curve of the 182 non-Leu41 individuals taking beta-blockers. The authors suggest that this genetic beta-blocker effect may explain the “disappointing results” seen in black cohorts of earlier clinical trials evaluating beta-blockers in CHF (as well as hypertension). It is not certain if these variable results seen in trials using first- or second-generation nonvasodilating beta-blockers (ie, metoprolol, bisoprolol, atenolol) will also be seen with third-generation beta-blockers, which have vasodilating properties, (ie, carvedilol, nebivolol).
Although none of the beta-blocker CHF trials have had a large enough enrollment of black participants to accurately measure true racial differences in response to therapy, most have reported favorable survival benefit among blacks; the exception being the BEST study with bucindolol (Gencaro, Arca Biopharama Inc.). Failure of bucindolol to show survival benefit in the entire BEST cohort was initially explained by race, 18% improvement in survival among whites and a nonsignificant 17% decrease in survival in blacks. Liggett, Bristow and others later showed that a SNP in the beta-1 adrenergic receptor (B1-389Arg/Gly) explained the observations better and demonstrated mortality benefit across racial boundaries within a specific genotype.
 Shawn W. Robinson |
 Elijah Saunders |
As the information related to this intriguing study filtered down through the medical and lay press, there was misplaced emphasis on the beta-blocker-like, protective Leu41 variant being more common in blacks, as opposed to the fact that such a protective variant exists at all. Ironically, the investigators performed elegant biochemical and physiologic studies in cells and mice to demonstrate the potential clinical impact a simple genetic variation might have in humans (skin/hair color of the mice was not specified). Potentially, the same Leu41 variant could be protective in white patients with HF as well, and 4% to 5% of white patients with congestive HF in the United States is not an insignificant number.
The potential harm in allowing the beta-blocker-like Leu41 variant to be viewed as a “black variant” is the possibility that life-saving beta-blocker therapy may be withheld from black patients with congestive HF inappropriately. A similar misinterpretation of a race-based report out of the SOLVD trial cohort generated so much concern that blacks may stop receiving life-saving ACE therapy that a number of follow-up articles were published highlighting the mortality benefit of ACE in blacks with systolic congestive HF.
The notion that ACE therapy is less effective in blacks with hypertension is also potentially harmful. The AASK study showed that blacks had a slower progression of their chronic kidney disease with ACE therapy than with calcium channel blocker therapy, even though ACE drugs are considered to be less effective than calcium channel blockers in lowering BP in blacks. Ultimately, genetic variants will be identified that explain these differences across racial boundaries as well.
Most would agree that race is more of a social, geographic and even political construct than a genetic surrogate. With more than 200 years of the United States’ “melting pot” experience, cultural identity is becoming more relevant than the old construct of race. As a result, those who self-identify as African-American may possess varying amounts of genetic markers associated with African ancestry. Liggett et al tried to control for this by looking at 15 such markers in their population, but several more markers exist, and there is no agreement on which ones are sufficient and/or necessary to “quantify” African ancestry. With such powerful molecular tools available to get at the actual biochemistry underlying some of the physiologic differences we see, is use of skin color or cultural identity appropriate on which to base pharmacologic treatment or research design?
To be clear, race, ethnicity and cultural heritage still need to be acknowledged as potent forces that influence disease severity, and disparities in medical procedures, resource allocation and clinical outcomes. This line of research must continue as significant gaps in equality of care for racial and ethnic minorities still exist. The findings of the Liggett study offer a glimpse into the future of personalized medicine, when the best therapy can be tailored to the appropriate genotype. Perhaps, then, we can stop turning to race to explain biochemistry.
Shawn W. Robinson, MD, is Assistant Professor of Medicine and Medical Director of the Coronary Care Unit, Division of Cardiology, University of Maryland School of Medicine, Baltimore.
Elijah Saunders, MD, FACC, FACP, FAHA, is Professor of Medicine in the Division of Cardiology and Section Head of Hypertension, University of Maryland School of Medicine, Baltimore and is a member of the Vascular Medicine/Intervention Section of the Cardiology Today Editorial Board.
For more information:
- Dries DJ, Yancy CW, Strong MA, Drazner MH. Congest Heart Fail. 2004;(1):30-3. Review.
- Exner DV, Dries DL, Domanski MJ, Cohn JN. N Engl J Med. 2001;344(18):1351-7.
- Liggett SB, Cresci S, Kelly RJ, et al. Nat Med. 2008;14(5):510-7.
- Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al.. Proc Natl Acad Sci USA. 2006;103(30):11288-93.