The “Double” Paradox of Atrial Fibrillation in Black Individuals

Atrial fibrillation (AF) affects more than 33 million people worldwide and is associated with increased risks for stroke, heart failure, and death.^1,2 One explanation for the increasing incidence and prevalence of arrhythmia may relate, in part, to the aging of the population in Western countries. However, the recent identification of novel risk factors for AF such as race, obstructive sleep apnea, metabolic syndrome, and obesity may also play a role in the growing AF epidemic.³ Despite a greater burden of well-established risk factors, black individuals are less prone to develop AF than white individuals of European ancestry for reasons that are not completely clear. Possible etiologies of this AF paradox include the differential impact of ethnic-specific risk factors and an underlying genetic basis for the reduced incidence and prevalence of AF among black individuals.⁴

We examined the race- and sex-specific influences of demographic, lifestyle, anthropometric, and medical factors on the development of AF in more than 8000 participants in the Southern Community Cohort Study.⁵ Although the prevalence of AF was significantly lower among black individuals (11%) than white individuals (15%), the patterns of AF risk were similar between the 2 racial groups. However, associations with well-established risk factors such as hypertension, diabetes, and stroke were somewhat stronger among black individuals. Of note, this study⁵ showed that traditional risk factors for AF were responsible for 58% of the burden of AF among black individuals, in contrast to 44% in white individuals, which is consistent with other studies demonstrating that only 50% of people with AF in the population can be explained by well-established risk factors. Although this study⁵ included a large cohort of black individuals and white individuals of similar socioeconomic status, extensive baseline data, and systematic and unbiased follow-up data on evaluations of participants for AF, novel risk factors for AF were not examined. Nonetheless, the findings of our study emphasize that approximately 50% of the burden of AF among black individuals was not explained by well-established risk factors implicating other etiologies for the AF paradox.

Another possible explanation for the AF paradox among black individuals may relate to an underlying genetic basis, with Marcus et al⁶ showing that the proportion of European ancestry in African American individuals was associated with an increased risk for AF in individuals enrolled in the Cardiovascular Health Study and the Atherosclerosis Risk in Communities Study. In 2011, Delaney et al⁷ examined the role of 3 loci of AF risk at chromosomes 1q21, 4q25, and 16q22 in European-descent populations. Genetic ancestry was estimated, and single-nucleotide polymorphisms (SNPs) at the genomic loci were tested for associations with AF in African American individuals. This study⁷ demonstrated that the European index SNPs from the 3 regions associated with AF were not the index SNPs associated with AF in black individuals. Furthermore, European admixture at any of the genomic regions tested did not modulate AF risk. While these findings contrasted with those obtained by Marcus et al,⁶ different study designs, especially the choice of ancestry-informative markers vs region-specific and sample-size differences, may be responsible for the conflicting data. The major limitation of the study by Delaney et al⁷ is related to the modest sample size.

The study by Roberts et al⁸ in this issue of JAMA Cardiology examined the role of 9 common AF-associated SNPs in mediating the AF paradox in black individuals and sought to identify novel genetic loci by conducting admixture mapping. This approach is particularly suitable for populations of mixed ancestry. Admixture mapping is a modified version of the genome-wide association study (GWAS) and has been used to map loci and genetic variants for various phenotypes in black individuals, including chronic kidney disease and prostate and breast cancer. Candidate SNP and genome-wide admixture mapping was performed in the Cardiovascular Health Study (n = 3969), the Atherosclerosis Risk in Communities Study (n = 12 341), and the Health, Aging and Body Composition Study (n = 1015). The investigators identified a previously known AF-associated SNP (rs10824026) on chromosome 10q22 (near MYOZ1) that partially mediated a higher risk for AF in white individuals compared with black individuals. The minor allele of the SNP, which is known to be protective against AF, was not only more common in black individuals but also accounted for 11.4% to 31.7% of the reduced risk of AF in black individuals. Despite using the 3 largest population-based cohort studies involving black individuals, surprisingly, the admixture mapping meta-analysis failed to identify any AF-associated loci that met the prespecified genome-wide significance level.

The findings of the study by Roberts et al⁸ provide some insights into the role of common genetic variants in mediating the AF paradox in black individuals. However, it also highlights some of the challenges associated with defining the etiologic basis for the differential racial risk of AF. First, one potential explanation for the failure to identify any AF-associated alleles with admixture mapping may relate to inadequate power. But it is important to note that the meta-analysis involved nearly 5000 black individuals and constitutes the largest African American cohort that has undergone GWAS analysis. The practicalities of recruiting tens of thousands of black individuals with or without AF are daunting and cost prohibitive. Second, while positional cloning and candidate gene approaches and GWASs have shown that both common and rare genetic variants contribute to the genetic architecture of AF, collectively less than 10% of the heritability of the arrhythmia is explained.⁹ The findings of Roberts et al⁸ suggest that some of this missing heritability may be related to multiple low-level genetic variants that cannot be uncovered by current approaches or by gene-gene and/or gene-environment interactions. Support for the gene-gene interaction comes from a recent study by Huang et al¹⁰ that shows that an interaction between AF GWAS loci (rs210626 in ZFHX3 and rs2200733 near PITX2c) may be responsible for some of the missing heritability of AF. Alternatively, it is possible that the findings of this study⁸ may focus more attention on identifying rare genetic variants using next-generation sequencing as one explanation for the missing heritability. Third, the finding that the minor allele of the rs10824026 SNP is protective is perhaps not surprising by itself, but the fact that the minor allele frequency of the 3 strongest AF-associated SNPs at chromosomes 4q25, 1q21, and 16q22 are more frequent in black individuals relative to white individuals is worth mentioning. It is certainly possible that gene-gene interactions are complex and harbor different AF susceptibility SNPs, not all of which increase susceptibility to AF. It is certainly possible that different cis- and trans-acting regulatory elements may be protective and reduce the likelihood of developing AF in black individuals.

Another study¹¹ in this issue of JAMA Cardiology presents research from the Atherosclerosis Risk in Communities Study. This is a community-based cohort study designed to evaluate determinants of cardiovascular disease in the general population. This biracial study enrolled 15 792 black individuals and white individuals during the period from 1987 through 1989, with periodic longitudinal follow-up occurring through 2013. The current analysis was designed to assess the age-specific association of AF with stroke, heart failure, coronary artery disease, and all-cause mortality.

Magnani and colleagues¹¹ found that the incidence of AF was less among black individuals than among white individuals, with AF conferring an increase in the risk of all outcomes assessed. The absolute risk of developing stroke, heart failure, coronary artery disease, or all-cause mortality in AF patients was greater for black individuals than white individuals. The relative risk of the development of an adverse outcome, however, was similar. This occurred as a result of the black population appearing to be a higher risk cohort, with a worse outcome compared with white individuals for not only those who developed AF but also those who did not.

The strengths of the study¹¹ are many. Whereas a number of studies have evaluated the prevalence of AF among black individuals and white individuals,^12,13 this is one of the few studies providing data on the incidence of disease, along with an assessment of the resulting cardiovascular outcomes. This study¹¹ includes a large number of patients followed up over many years. Unlike many of the randomized clinical trials of AF, this study¹¹ did include large numbers of black individuals (n = 3831). Magnani and colleagues¹¹ correctly point out the limitations, including the reliance of International Classification of Diseases, Ninth Revision (ICD-9) codes for identification of patients with AF, the inability to include the impact of subclinical AF, and the lack of adjustment for variation in treatment.

Magnani and colleagues¹¹ importantly add to the literature another in the long list of studies showing cardiovascular disorders with either an increase in incidence or worse outcome in black individuals compared with white individuals, including patients with heart failure,¹⁴ stroke,¹⁵ or coronary artery disease.¹⁶ The reason for these disparities remains unclear. Despite an intense search over the last decade, no consistent genetic cause has been identified.¹⁷ What is known is that there are a number of socioeconomic factors found more commonly among black individuals that strongly correlate with worse cardiovascular outcomes.¹⁸ There are many studies demonstrating the influence of neighborhood social environment and the risk of adverse health events.¹⁹ The possibility that these social determinants of health are playing a direct causative role through an epigenetic mechanism is an interesting, but still unproven theory.²⁰

The studies by Roberts et al⁸ and Magnani et al¹¹ add to our understanding of the racial differences associated with AF, which is less common but results in worse outcomes among black individuals. They also highlight the need for additional investigation regarding the possible social, environmental, and genetic causes for these findings.

Corresponding Author: Dawood Darbar, MD, Division of Cardiology, University of Illinois at Chicago, 840 S Wood St, 920S (MC 715), Chicago, IL 60612 (darbar@uic.edu).

Published Online: June 22, 2016. doi:10.1001/jamacardio.2016.1259.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.