Grand Rounds

Is there a Link Between Sickle Cell Trait and Increased Risk for Coronary Heart Disease?

BACKGROUND AND PURPOSE:

African American individuals are more likely to experience coronary heart disease and related mortality than are Non-Hispanic White individuals
- Genetic factors such as sickle cell trait (SCT) may contribute to this unexplained excess risk
Hyacinth et al. (JAMA Network Open, 2021) assessed whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals

Cohort study
Data sources
- Women’s Health Initiative (WHI) study (follow up 1993 and 1998 to 2014)
- Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (follow up 2003 to 2014)
- Multi-Ethnic Study of Atherosclerosis (MESA) (follow up 2002 to 2016)
- Jackson Heart Study (JHS) (follow up 2002 to 2015)
- Atherosclerosis Risk in Communities (ARIC) study (follow up 1987 to 2016)
Participants
- African American individuals
- Exclusion: Sickle cell disease (homozygous for variant) or a history of CHD
Exposure
- Sickle cell trait status: Determined by determining presence of rs334 (the sickle cell single nucleotide variant)
Study design
- Definitions
  - MI: adjudicated nonfatal or fatal MI
  - CHD: 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 (HR) for incident MI or CHD comparing SCT carriers with noncarriers
- Covariate adjustments: Age | Sex (except for the WHI study) | Study site or region of residence | Hypertension | Diabetes | Serum lipids | Global ancestry (using genome-wide genotyping data)
Primary outcome
- Incident MI
- Incident CHD

23,197 African American individuals
- Women: 70.2%
- Median age range: 53.2 to 64.0 years
- There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts
- Incidence of SCT: 7.7%
Incidence of outcomes
- Incident MI: 1034 individuals (76 with SCT)
- Incident CHD: 1714 individuals (137 with SCT)
The meta-analyzed crude incidence rate of MI did not differ by SCT status
- With SCT: 3.8 per 1000 person-years (95% CI, 3.3 to 4.5)
- Without SCT: 3.6 per 1000 person-years (95% CI, 2.7 to 5.1)
Crude incidence rate of composite CHD also did not differ by SCT status
- With SCT: 7.3 per 1000 person-years (95% CI, 5.5 to 9.7)
- Without SCT: 6.0 per 1000 person-years (95% CI, 4.9 to 7.4)
Meta-analysis of all 5 studies: SCT status was not significantly associated with either MI or composite CHD
- MI: HR 1.03 (95% CI, 0.81 to 1.32)
- Composite CHD: HR 1.16 (95% CI, 0.92 to 1.47)

Among African American individuals, there was no link between sickle cell trait and increased risk of myocardial infarction or coronary heart disease
The lack of independent association was consistent between crude and adjusted data

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