Abstract
The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
Highlights
60% of this disparity is associated with the excess burden of classical factors associated with cardiovascular disease (CVD) among African American individuals compared with non-Hispanic White individuals.[3,4,6,7,8,9,10]
We examined whether African American individuals with sickle cell trait (SCT), compared with those without SCT, had a higher risk of myocardial infarction (MI) or coronary heart disease (CHD) after adjustment for traditional factors associated with CHD
Of the total 23 197 participants, 1781 had SCT; the prevalence of SCT in our study ranged from 6.4% to 9.1% across cohorts, with a mean of 7.7%, which is consistent with the reported range of population prevalence of SCT in the US.[17,47,48]
Summary
The burden of cardiovascular disease (CVD) in general and coronary heart disease (CHD) in particular is disproportionately high among African American individuals,[1,2] resulting in a substantial health disparity.[3,4,5] Approximately 60% of this disparity is associated with the excess burden of classical factors associated with CVD among African American individuals compared with non-Hispanic White individuals.[3,4,6,7,8,9,10] The associations of hypertension with CHD11 and of the apolipoprotein L1 (APOL1 [RefSeq ID NG_023228]) risk gene variant (ie, G1 [rs73885319 and rs60910145] and/or G2 [rs71785313]) with excess burden of hypertensive kidney disease among African American individuals[12,13,14] have raised the question of a possible association between genetic variation and some of the observed excess and unexplained burden of CHD among African American individuals compared with non-Hispanic White individuals. Ito et al[15] reported that possession of 2 APOL1 risk alleles was associated with higher overall risk for CVD and with early age at onset among African American individuals. There have been inconsistent findings for the association between APOL1 genotypes and CVD,[16] there is a rationale that genetic variation is possibly associated with the observed disparities in the incidence and prevalence of CVD in general and CHD in particular among African American individuals. Several studies have reported that in addition to the APOL1 gene variant, heterozygosity for the sickle cell variant (sickle cell trait [SCT]) was associated with the incidence and progression of chronic kidney disease (CKD) and albuminuria,[17,18,19] a factor associated with CVD.[20,21]
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