Dataset Information

Race, common genetic variation, and therapeutic response disparities in heart failure.

ABSTRACT: 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.

SUBMITTER: Taylor MR

PROVIDER: S-EPMC4302116 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Race, common genetic variation, and therapeutic response disparities in heart failure.

Taylor Mathew R MR Sun Albert Y AY Davis Gordon G Fiuzat Mona M Liggett Stephen B SB Bristow Michael R MR

JACC. Heart failure 20141022 6

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 deg ...[more]

PMID: 25443111

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Project description:ObjectivesThis study sought to describe the health status of outpatients with heart failure and reduced ejection fraction (HFrEF) by sex, race/ethnicity, and socioeconomic status (SES).BackgroundAlthough a primary goal in treating patients with HFrEF is to optimize health status, whether disparities by sex, race/ethnicity, and SES exist is unknown.MethodsIn the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, the associations among sex, race, and SES and health status, as measured by the Kansas City Cardiomyopathy Questionnaire-overall summary (KCCQ-os) score (range 0 to 100; higher scores indicate better health status) was compared among 3,494 patients from 140 U.S. clinics. SES was categorized by total household income. Hierarchical multivariate linear regression estimated differences in KCCQ-os score after adjusting for 31 patient characteristics and 10 medications.ResultsOverall mean KCCQ-os scores were 64.2 ± 24.0 but lower for women (29% of sample; 60.3 ± 24.0 vs. 65.9 ± 24.0, respectively; p < 0.001), for blacks (60.5 ± 25.0 vs. 64.9 ± 23.0, respectively; p < 0.001), for Hispanics (59.1 ± 21.0 vs. 64.9 ± 23.0, respectively; p < 0.001), and for those with the lowest income (<$25,000; mean: 57.1 vs. 63.1 to 74.7 for other income categories; p < 0.001). Fully adjusted KCCQ-os scores were 2.2 points lower for women (95% confidence interval [CI]: -3.8 to -0.6; p = 0.007), no different for blacks (p = 0.74), 4.0 points lower for Hispanics (95% CI: -6.6 to -1.3; p = 0.003), and lowest in the poorest patients (4.7 points lower than those with the highest income (95% CI: 0.1 to 9.2; p = 0.045; p for trend = 0.003).ConclusionsAmong outpatients with HFrEF, women, blacks, Hispanics, and poorer patients had worse health status, which remained significant for women, Hispanics, and poorer patients in fully adjusted analyses. This suggests an opportunity to further optimize treatment to reduce these observed disparities.

Project description:ImportanceSequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated.ObjectiveTo assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction.Design, setting, and participantsThis was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020.Main outcomes and measuresOdds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes.ResultsThis study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]).Conclusions and relevanceAn increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.

Dataset Information

Race, common genetic variation, and therapeutic response disparities in heart failure.

Publications

Race, common genetic variation, and therapeutic response disparities in heart failure.

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