Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. Those population effects extend to differences in frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data for genetic variation between AA and EA populations. Data indicate that: 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents; 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA compared with EA individuals; and 3) in many cases, these differences likely play a role in observed racial differences in drug or device response.
Key Words
genetic polymorphisms
heart failure
pharmacogenetics
racial ancestry
Abbreviations and Acronyms
AA
African ancestry
ACEI
angiotensin-converting enzyme inhibitor
ACM
all-cause mortality
ARB
angiotensin-receptor blocker
CCDS
consensus coding sequence
CRT
cardiac resynchronization therapy
Del
deletion
EA
European ancestry
HF
heart failure
HFH
heart failure hospitalization
HFrEF
heart failure with reduced left ventricular ejection fraction
ICD
implantable cardioverter-defibrillator
Ins
insertion
MRA
mineralocorticoid receptor antagonists
NF
non-heart failure
RAAS
renin-angiotensin-aldosterone system
RES
relative effect size
SNP
single-nucleotide polymorphism
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This study was supported by National Heart, Lung, and Blood Institute grants R01 HL7701 (Dr. Liggett) and 2R01 HL48013 (Dr. Bristow) and the Veterans’ Affairs Cooperative Studies Program. Dr. Taylor has received research grants and clinical trial support from Sanofi Therapeutics; and clinical trial support from Amicus Therapeutics and Array Biopharma. Dr. Sun is a consultant for St. Jude Medical; and has received research support from Medtronic Inc. Drs. Davis and Bristow are employees of and stock shareholders in ARCA biopharma, which is developing the beta-blocker/sympatholytic agent bucindolol. Dr. Liggett holds stock options in ARCA biopharma. Dr. Fiuzat has reported that she has no relationships relevant to the contents of this paper to disclose.