Is Sickle Cell Trait Associated with Incident Cardiovascular Outcomes in African Americans?
Authors: Hyacinth Hyacinth Idu , Carty Cara , Burke Gregory L. , Naik Rakhi P. , Adams Robert J. , Gee Beatrice E. , Longstreth Will , Egede Leonard , Lackland Daniel T. , Greenberg Charles S. , Hunt Kelly J. , Kindy Mark M. , Taylor Herman , Manson JoAnn E. , Allison Mattthew , James Wilson G. , Reiner Alexander 
Published: October 2019

Abstract
Background
African Americans experience higher rates of cardiovascular disease (CVD) and mortality from stroke and coronary heart disease. It is possible that genetic modifiers associated with African ancestry may confer higher risk of CVD. The sickle cell mutation results from a functional single nucleotide polymorphism (SNP) involving the substitution of GTG (valine) for a GAG (glutamic acid) in the gene encoding beta globin. Heterozygosity for the mutation (rs334) results in sickle cell trait (SCT) which is prevalent among 8% of African Americans, while homozygosity produces sickle cell anemia. Sickle cell trait has been deemed clinically benign yet recent evidence shows that it is associated with increased risk of chronic kidney disease, a 2 times increased risk for venous thromboembolism and a 4 times increased risk for pulmonary embolism. Further, there is evidence that individuals with SCT have higher serum levels of C-reactive protein, Fibrinogen 2.1 fragments and D-dimers. We hypothesized that African Americans with SCT have a higher risk for cardiovascular outcomes than those without SCT (homozygous wild-type hemoglobin).
Methods
Data were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS) and Women’s Health Initiative (WHI). Incident myocardial infarction (MI) was defined as adjudicated non-fatal or fatal MI, coronary heart disease (CHD) was defined as a composite endpoint including adjudicated non-fatal MI, fatal CHD, or documented coronary revascularization procedure. Sickle cell trait was identified either by direct genotyping or imputation for rs334. Individuals who were homozygous for the sickle mutation or had a prior history of CHD events were excluded. Cox proportional hazards models were used to estimate a hazard ratio (HR) of incident MI or CHD comparing sickle cell trait carriers to non-carriers. Models were adjusted for age, sex and principal component of global ancestry. Analysis was performed separately in each cohort and the results were subsequently meta-analyzed using a fixed effect inverse variance weighted method.
Results
A total of 11,128 African American men and women were included in the pooled data base. The average age at baseline were 62.2 ± 10.1, 49.8 ± 11.8 and 61.4 ± 7.0 years for MESA, JHS and WHI respectively, with JHS participants significantly younger than the other two cohorts (p <0.001). Unlike the MESA and JHS cohorts that included both genders, the WHI cohort was exclusively female. Additionally, the percentage African ancestry was significantly higher among those with SCT compared to those without SCT (82 ± 12% vs. 78 ± 14% for MESA, 84 ± 6% vs. 82 ± 9% for JHS and 79 ± 12% vs. 76 ± 15% for WHI), further the percentage African ancestry was significantly lower among WHI subjects irrespective of carrier status, p <0.01. There was no significant difference between cohorts in the prevalence of diabetes or hypertension, mean blood pressure levels, or proportion of smokers (table 1). The HR for incident MI was 1.56 (0.66 – 3.68) in MESA, 1.04 (0.32 – 3.39) in JHS and 0.97 (0.68 – 1.39) in WHI, but was not statistically significant. Further, the HR for incident CHD was 2.73 (1.52 – 4.89) in MESA, 1.14 (0.46 – 2.89) in JHS and 0.97 (0.68 – 1.17) in WHI, although the HR only achieved statistical significance in MESA (p<0.001). Overall, sickle cell trait was not significantly associated with incident MI (1.04 [0.76 – 1.43]) or CHD (1.11 [0.85 – 1.43] figure 1).
Limitation/Recommendations and Conclusion
The overall result from this study did not demonstrate a significant association between SCT and CHD. This may reflect inadequate power due to the relatively small number of CHD events and differences in study design. This study suggests the need for a well powered study to test this hypothesis, the result of which could have significant impact on the approach to risk factor modification for African Americans.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
Naik: NHLBI: Research Funding.