Sickle Cell Trait Status Research Articles

The Risk of Pregnancy Related Hypertension Disorder Associated with Sickle Cell Trait in U.S. Service Women.

The health impact of the heterozygous (Hb Ss) Sickle Cell Trait (SCT) among the estimated one million females of reproductive age in the United States on pregnancy related hypertensive disorders (PRHD) including preeclampsia is not as well understood or researched as Sickle Cell Disease (SCD). This retrospective cohort study included 25,020 U.S. enlisted, active duty service women during 1992 to 2013. Race within the sample is primarily black (84%) given that blacks have the highest prevalence of SCT. All 5,004 SCT positive individuals and a matched sample of 20,016 from those considered SCT negative were followed while on active duty for PRHD outcomes including gestational hypertension (GHTN), preeclampsia and eclampsia. The adjusted incidence rate ratio (IRR) for any PRHD in SCT positive compared to negative individuals was 1.46 (95% CI 1.32 - 1.62). SCT positive versus negative subjects had higher health care utilization rates and utilization rate ratios (URR) for all PRHD diagnoses combined 2.03 (95%CI: 1.97 - 2.10) and for each specific PHRD diagnosis. The prevalence of preeclampsia or eclampsia did not vary by SCT status. The overall PRHD attributable risk due to SCT was 30.4% (95% CI 23.1-37.1%) and the overall number needed to screen to detect a case of PRHD was 156 (95% CI 117-220). The results of this study indicate that being SCT positive is a risk factor for PRHD and provides evidence that SCT status may have an adverse effect on reproductive health. Future research needs to include other known risk factors for PRHD to include gravity and parity history, BMI, past history of PRHD prior to enlistment as well as to examine the association with maternal/child pregnancy outcomes.

Incidence, demographic characteristics, and geographic distribution of sickle cell trait and sickle cell anemia births in Michigan, 1997-2014.

BackgroundThis study describes the incidence, demographic characteristics, and geographic distribution of sickle cell anemia (SCA) and sickle cell trait births in Michigan.MethodsMichigan newborn screening records and birth certificates (1997–2014) were used to identify sickle cell trait and SCA births, as well as demographic characteristics and mother's residential address. Incidence was calculated overall and by county.ResultsDuring the study period, there were 592 SCA births and 33,404 sickle cell trait births in Michigan. The majority of SCA (86.3%) and trait (80.2%) cases were among children who were black. Children with SCA were born in 23% of Michigan counties; children with trait were born in 93%.ConclusionCompared to SCA, sickle cell trait births occur at 50‐fold greater incidence and have a substantially expanded geographic distribution. Further research is necessary to understand the most appropriate and impactful use of resources to increase the proportion of families and adults that are aware of their sickle cell trait status.

Sickle cell trait and risk of cognitive impairment in African-Americans: The REGARDS cohort

BackgroundSickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. MethodsThe Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0–6; ≤4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. FindingsAmong 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). InterpretationIn this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. FundingNational Institutes of Health, American Society of Hematology.

APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults.

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status (Pinteraction=0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus.

Association of Sickle Cell Trait With Ischemic Stroke Among African Americans

African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Incident ischemic stroke. This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.

Identifying Factors Underlying the Decision for Sickle Cell Carrier Screening Among African Americans Within Middle Reproductive Age.

Guidelines recommend that African Americans know their sickle cell trait status to inform reproductive health decisions. Few studies have applied a behavioral theory to identify factors associated with sickle cell trait screening to inform intervention targets to increase this behavior. We applied a Sickle Cell Trait Screening Framework to identify factors associated with African Americans' intention to ask for sickle cell trait screening. Participants (N = 300), ages 18 to 35, completed a cross-sectional survey. A three-step sequential ordinary least squares regression analysis identified factors influencing intention. Results indicated socio-demographic factors (age, education), knowledge and fear beliefs (screening knowledge, perceived threat), and reasoned action approach (RAA) constructs were associated with intention. RAA constructs influenced intention over knowledge and fear beliefs with an increase in R2 of .468. Perceived behavioral control was more predictive of intention (β = .576, p < .001). Attitude and perceived norm also had significant weights (β = .325 and β = .192, both p < .001, respectively). Findings from this study can inform strategies (e.g., eliminating costs associated with screening, reducing fear of painful tests) to increase sickle cell trait screening among African Americans. Ultimately, more sickle cell carriers will become aware of their trait status and be able to make informed reproductive health decisions.

The Association Between Sickle Cell Trait in U.S. Service Members with Deployment, Length of Service, and Mortality, 1992-2012.

Sickle cell trait (SCT) affects an estimated 5.02% of non-Hispanic blacks, 1.08% of Hispanics, and 0.1% of Whites in the U.S. military. Policies for SCT screening and occupational restrictions vary by service. Population-based studies of SCT with quantification of military-relevant outcomes are lacking. The study design was a retrospective cohort of 15,081 SCT-positive versus 60,320 SCT-negative U.S. active duty personnel enlisted from 1992 to 2012 and followed through 2013. Military-relevant outcome included number and days of deployment, length of service, and cause of death. SCT-positive versus SCT-negative service members experienced more deployments (p < 0.01) and longer number of days deployed for all services, especially the Army (p < 0.001). The median length of service was longer for SCT-positive service members stratified by service and by gender (p < 0.05). The adjusted risk of length of service greater than 5 yr by SCT status was 1.37 (95% confidence interval 1.31-1.43) with greater than a three-fold higher risk in the Navy and Air Force compared with the Army. Crude mortality rate was not significantly different by SCT status, although deaths due to suicide, self-directed violence, and other non-specific causes were more common in SCT-positive service members. We found that SCT-positive service members deployed more frequently, for greater lengths of time, and remained in service longer. No significant difference in crude mortality ratio was discovered. Additional research on military-relevant outcomes and a cost-effectiveness analysis of SCT screening practices are needed to inform evidence-based SCT enlistment policies.

Sickle cell trait knowledge and health literacy in caregivers who receive in-person sickle cell trait education.

BackgroundDespite universal screening that detects sickle cell trait (SCT) in infancy, only 16% of Americans with SCT know their status. To increase SCT status awareness, effective education for patients and their families is needed. The objective of this study was to assess caregivers’ SCT knowledge before and after an in‐person SCT education session.MethodsA trained educator provides in‐person SCT education to caregivers of referred infants with SCT at Nationwide Children's Hospital. From August 2015 to July 2016, primarily English‐speaking caregivers of infants with hemoglobin S‐trait were recruited and completed a health literacy assessment and a SCT knowledge assessment (SCTKA) before and after receiving education. Caregivers repeated the SCTKA again after ≥6 months, if they could be contacted.ResultsThirty‐eight (38.1%) percent of 113 caregivers had high SCTKA scores (≥75%) before education but 90.3% achieved high scores after education. Caregivers with low SCTKA scores after education had significantly lower health literacy (P = 0.029) and baseline SCTKA scores (P = 0.003) compared to those with higher scores after education. At ≥6 months, caregivers’ scores were significantly higher (P = 0.014) than baseline, but only 73.3% scored ≥75%.ConclusionOur results suggest that caregivers’ baseline SCT knowledge is low, improves with in‐person education but may decline with time. Caregivers who do not achieve high SCT knowledge after education had lower health literacy and baseline knowledge. Future studies should determine if adapting in‐person education to caregivers’ health literacy and knowledge levels results in high and sustained SCT knowledge among all caregivers and more individuals who know their SCT status.

Blood Pressure and Arterial Stiffness in Kenyan Adolescents With the Sickle Cell Trait.

The potential association between sickle cell trait (SCT) and increased arterial stiffness/blood pressure (BP) has not been evaluated in detail despite its association with stroke, sudden death, and renal disease. We performed 24-hour ambulatory BP monitoring and arterial stiffness measurements in adolescents raised in a malaria-free environment in Kenya. Between December 2015 and June 2016, 938 randomly selected adolescents (ages 11–17 years) who had been continuous residents of Nairobi from birth were invited to participate in the study. Standard clinic BP measurement was performed, followed by 24-hour ambulatory BP monitoring and arterial stiffness measurement using an Arteriograph24 (TensioMed Ltd., Budapest, Hungary) device. SCT status was determined using DNA genotyping in contemporaneously collected blood samples. Of the 938 adolescents invited to participate, 609 (65%) provided complete data for analysis. SCT was present in 103 (15%). Mean 24-hour systolic and diastolic BPs were 116 (standard deviation (SD), 11.5) mm Hg and 64 (SD, 7) mm Hg, respectively, in children with SCT and 117 (SD, 11.4) mm Hg and 64 (SD, 6.8) mm Hg, respectively, in non-SCT children. Mean pulse wave velocity (PWV) was 7.1 (SD, 0.8) m/second and 7.0 (SD, 0.8) m/second in SCT and non-SCT children, respectively. We observed no differences in PWV or in any clinic or ambulatory BP-derived measures between adolescents with and without SCT. These data suggest that SCT does not independently influence BP or PWV.

Perspectives and Practices of Athletic Trainers and Team Physicians Implementing the 2010 NCAA Sickle Cell Trait Screening Policy.

Sickle cell trait (SCT) is usually benign. However, there are some conditions that may lead to SCT-related problems and put athletes with the trait at particular risk. In 2010 the National Collegiate Athletic Association (NCAA) issued a policy that required all Division I (DI) student-athletes to confirm their SCT status or sign a liability waiver to opt out of testing. Athletic trainers and team physicians play key roles in the policy implementation and we examined their perceptions and practices. Between December 2013 and March 2014 we interviewed 13 head athletic trainers and team physicians at NCAA Division I colleges and universities in North Carolina. We used an interview guide with open-ended questions covering knowledge of SCT, historical screening and education practices, current implementation, and policy benefits and challenges. Participants were knowledgeable about SCT and thought the policy was beneficial in providing SCT health information to and for student-athletes. Schools varied in provision of genetic counseling, offering the waiver, SCT tests administered, and other aspects. Challenges included: insufficient guidance from the NCAA; financial considerations; and misunderstanding of the relationships of race and ancestry to SCT risk. Athletic staff found the policy valuable, but felt it needs clarity and standardization.

Awareness of Sickle Cell Trait Status: A Cross-Sectional Survey of Antenatal Women in Ghana.

This study was conducted to evaluate pregnant women's awareness of sickle cell disease and sickle cell trait and the factors that contribute to it. Two hundred and six pregnant women with at least 20 weeks gestation answered a questionnaire regarding awareness of their trait status and questions to test their knowledge of sickle cell disease. Although the majority of patients were aware of their trait status (87.4%), only 29% of knowledge questions were answered correctly; patients who self-identified as having sickle cell trait did not do better. Patients who responded that they knew a good deal about sickle cell disease scored an average of 3.5 points (number of correct responses to nine questions) more than individuals who responded that they knew nothing (P < 0.001). Individuals who knew they had been tested for the sickle cell trait scored approximately 2 points higher than those who did not know whether they had been tested (P = 0.004). Respondents with at least secondary education scored on average 1 point higher on the knowledge test than those with less education (P = 0.004). Knowing someone with sickle cell disease was associated with a mean score of 1.25 points higher than individuals who did not know any affected individual (P = 0.000).There is a deficit in the knowledge of sickle cell disease among Ghanaian pregnant women. Therefore, there is the need for public education on sickle cell disease.

Abstract P023: Association of Sickle Cell Trait with Common Electrocardiographic Abnormalities in The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study

Introduction: Sickle cell disease (SCD) arises from an autosomal recessive mutation that leads to progressive vascular obstruction and early death. Sickle cell trait (SCT), the carrier status, is present in ~8% of African-Americans (AA) and is thought to be a benign condition, although evidence now suggests an association with worse cardiovascular and renal outcomes. Electrocardiogram (ECG) changes have been documented in SCD patients; however, similar studies in SCT individuals are lacking. We hypothesized that left ventricular hypertrophy (LVH), atrial fibrillation (AF) and QTc prolongation would be more common in SCT carriers than non-carriers. Methods: SCT was genotyped in 10,731 AA participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Baseline risk factors were recorded from 2003-7. LVH was determined using Sokolow-Lyon criteria for all participants, and Cornell criteria in those with 12 lead ECGs (n = 8,690). AF was based on both self-report and ECG criteria. We assessed the association of SCT with LVH, AF, and QTc using multivariable logistic regression adjusting for age, sex, income, education, self-reported history of stroke, myocardial Infarction, diabetes, hypertension, and chronic kidney disease. Results: Among AA participants with ECG data and genotyping, 787 of 10,553 were SCT carriers (7.5%). AF was present in 814 (7.8%), LVH in 1,556 (14.7%) and QTc prolongation in 357 (3.4%). SCT status was associated with AF with an adjusted OR of 1.36 (95% CI 1.05, 1.76). SCT was not associated with LVH by Cornell criteria or Sokolow-Lyon (OR 1.16; 95% CI 0.94, 1.42). There was a significant age (continuous) by SCT interaction (p=0.02) with SCT associated with increased risk of LVH in younger but not older individuals. When stratified by the mean age of the cohort (65 years), younger individuals with SCT had an OR of 1.50 (95% CI 1.14, 1.97) for LVH, an association not seen in older individuals (OR 0.86; 95% CI 0.63-1.18). QTc prolongation was not associated with SCT (OR 0.97, 95% CI 0.64-1.47). Conclusions: SCT was associated with increased prevalence of AF in all individuals and with LVH in younger but not older individuals and was not associated with QTc prolongation. These data suggest SCT is not benign, and for the first time report the association of SCT with common ECG abnormalities. The association with AF and LVH is concerning with respect to increased stroke risk, especially the increased prevalence of LVH seen at younger ages in SCT. These data raise the question of whether individuals with SCT need more intensive monitoring and/or hypertension control than the general population.

‘It means everyone should know their status’: exploring lay conceptions of sickle cell trait and sickle cell trait screening among African Americans within middle reproductive age

ABSTRACTObjective: This study examined the meaning of sickle cell trait and sickle cell trait screening from the lay perspective of African Americans.Design and Methods: African Americans (N = 300), ages 18–35 and unaware of their sickle cell trait status, completed two open-ended questions from a larger survey. One question asked for their understanding of sickle cell trait; the other asked for their understanding of sickle cell trait screening. Content analysis occurred in two phases: (1) In vivo and holistic coding; and (2) focused coding.Results: Four categories emerged illustrating lay conceptions of sickle cell trait; (1) Perceived as an illness; (2) Perceived recognition of the inheritance pattern of sickle cell trait; (3) Perceived lack of knowledge of sickle cell trait; and (4) Perceived importance of sickle cell trait. Five categories emerged illustrating lay conceptions for sickle cell trait screening: (1) Perceived recognition that screening means getting tested for sickle cell trait; (2) Perceived lack of knowledge of sickle cell trait screening; (3) Perceived health benefit of sickle cell trait screening; (4) Perceived importance of sickle cell trait screening; and (5) Perceived barriers to sickle cell trait screening.Conclusions: Sickle cell trait and sickle cell trait screening are concepts that are both regarded as important among this high-risk population. However, there is still misunderstanding concerning the hereditary nature and reproductive implications of sickle cell trait. Interventions seeking to improve communication on the need for sickle cell trait screening should begin by identifying what the population at large understands, knows and/or believes to improve their ability to make informed health decisions.

Association among sickle cell trait, fitness, and cardiovascular risk factors in CARDIA

AbstractThe contribution of sickle cell trait (SCT) to racial disparities in cardiopulmonary fitness is not known, despite concerns that SCT is associated with exertion-related sudden death. We evaluated the association of SCT status with cross-sectional and longitudinal changes in fitness and risk for hypertension, diabetes, and metabolic syndrome over the course of 25 years among 1995 African Americans (56% women, 18-30 years old) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Overall, the prevalence of SCT was 6.8% (136/1995) in CARDIA, and over the course of 25 years, 46% (738/1590), 18% (288/1631), and 40% (645/1,611) of all participants developed hypertension, diabetes, and metabolic syndrome, respectively. Compared with participants without SCT, participants with SCT had similar baseline measures of fitness in cross-section, including exercise duration (535 vs 540 seconds; P = .62), estimated metabolic equivalent of tasks (METs; 11.6 vs 11.7; P = .80), maximum heart rate (174 vs 175 beats/min; P = .41), and heart rate at 2 minutes recovery (44 vs 43 beats/min; P = .28). In our secondary analysis, there was neither an association of SCT status with longitudinal changes in fitness nor an association with development of hypertension, diabetes, or metabolic syndrome after adjustment for sex, baseline age, body mass index, fitness, and physical activity. SCT is not associated with reduced fitness in this longitudinal study of young African American adults, suggesting the increased risk for exertion-related sudden death in SCT carriers is unlikely related to fitness. SCT status also is not an independent risk factor for developing hypertension, diabetes, or metabolic syndrome.

NCAA Football Off-Season Training: Unanswered Prayers… A Prayer Answered.

Off-season training in year-round collegiate football is purported to be performance enhancing. Absent principles of exercise physiology, excesses in sport-training regimens pose risk to the participant athletes. Since 2000, 33 National Collegiate Athletic Association (NCAA) football players have died in sport: 27 nontraumatic deaths and 6 traumatic deaths, a ratio of 4.5 nontraumatic deaths for every traumatic death. On average, 2 NCAA football players die per season. Best practices, consensus guidelines, and precautions are ignored, elevating the risk. However, standards exist that will, if heeded, prevent nontraumatic death in athletes training for sport. Sickle cell trait status knowledge and tailored precautions are preventing deaths from exertional collapse associated with sickle cell trait. Adherence to established principles of exercise physiology and best-practice training standards, which is long overdue, will help to prevent not only deaths from exertional collapse associated with sickle cell trait but also sudden cardiac, exertional heat stroke, and asthma deaths.

Association of Sickle Cell Trait with Risk of Coronary Heart Disease in African Americans

BackgroundThe incidence of and mortality from coronary heart disease (CHD) is significantly higher among African Americans (AAs) compared to Whites, even after adjusting for traditional CHD risk factors. Studies suggests that the unexplained excess risk might be the result of genetic modifiers associated with African ancestry conferring a higher risk of CHD. One such gene variant is the sickle cell mutation. The heterozygous state, or sickle cell trait (SCT), with a prevalence of 8 - 12% among AAs, was previously deemed clinically benign; however, recent evidence indicates that SCT is associated with increased risk of chronic kidney disease venous thromboembolism and sudden death following exertion. Individuals with SCT have higher circulating levels of C-reactive protein, fibrinogen, prothrombin fragment 1.2 and D-dimer. We hypothesized that AAs with SCT have a higher risk for myocardial infarction (MI) and coronary heart disease (CHD) than AAs who are homozygous for wild-type hemoglobin.MethodsWe obtained genotype and phenotype data from the Women's Health Initiative (WHI) REasonsfor Geographic and Racial Differences in Stroke (REGARDS), Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS) and Atherosclerosis Risk In Communities (ARIC) cohorts. The outcomes were incident MI or CHD. Incident MI was defined as adjudicated non-fatal or fatal MI, while incident CHD was defined as 1) adjudicated non-fatal MI, 2) fatal MI, 3) documented coronary revascularization procedures or 4) non-MI CHD death. SCT status was determined by either direct genotyping or imputation for rs334 using the 1000Genome reference panel. Homozygous individuals and those with a prior history of CHD were excluded. Individuals with incident “micro MI”, only defined in REGARDS, were also excluded from the analysis. Analysis was performed separately in each cohort using a Cox proportional hazard models to estimate the hazard ratio (HR) for incident MI or CHD comparing SCT carriers to non-carriers. Models in each cohort were adjusted for age, sex, study site or region of residence, hypertension or systolic blood pressure, diabetes, serum LDL or HDL or total cholesterol, and population stratification (using principal components of global ancestry). The results from each cohorts were then meta-analyzed using a random effect model due to significant heterogeneity between studies (I2 = 39.1%, p = 0.02 for MI meta-analysis and I2 = 56%, p = 0.01 for CHD meta-analysis).ResultsA total of 20,053 African American men and women were included in the combined sample; 1503 with SCT (7.5% prevalence). Average ages in years at baseline were: 65.0±6.0 in WHI (N = 2248), 62.0 ± 9.2 in REGARDS (N = 10573); 62.2±10.2 in MESA (N = 1556); 50.0 ± 11.9 in JHS (N = 2133); and 54.0 ± 6.0 in ARIC (N = 3543). There were no statistically significant differences in the distribution of traditional cardiovascular risk factors by SCT status within cohorts, except that atrial fibrillation was more prevalent among REGARDS participants with SCT compared to those without SCT (9.9% vs. 7.8%, p = 0.03). The crude incidence rate of MI per 1000 person years in those with SCT compared to those without SCT was: 4.0 vs. 5.2 in WHI; 5.7 vs. 5.0 in REGARDS; 5.8 vs 4.3 in MESA, 2.0 vs 2.1 in JHS; and 4.1 vs 5.9 in ARIC. For CHD, the crude incidence rate was: 5.8 vs. 7.2 in WHI, 8.9 vs. 7.4 in REGARDS; 15.4 vs. 6.4 in MESA; 3.4 vs. 3.4 in JHS; and 10.5 vs. 9.5 in ARIC.The HR (95% CI) for MI was: 0.96 (0.49 - 1.89) in WHI; 1.27 (0.8 - 2.0) in REGARDS; 1.84 (0.74 - 4.60) in MESA; 1.24 (0.28 - 5.44) in JHS; and 0.68 (0.42 - 1.10) in ARIC. And that for CHD was: 1.05 (0.63 - 1.74) in WHI; 1.49 (1.01 - 2.18) in REGARDS; 2.82 (1.48 - 5.38) in MESA; 1.45 (0.50 - 4.19) in JHS; and 1.10 (0.80 - 1.50) in ARIC. Meta-analysis showed that, while SCT status was not significantly associated with incident MI (1.10 [0.73 - 1.64]), it was significantly associated with incident CHD (1.42 [1.02 - 1.98] Figures 1a and 1b).ConclusionsThis study showed a significant association between SCT and incident CHD, but not MI. Our conclusion is limited by the significant heterogeneity that existed between studies. Since SCT status was not associated with MI, but was associated with CHD, further work is needed to confirm these findings, determine which CHD component(s) explain the observed association and elucidate the possible mechanism(s) involved. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers

BackgroundStudies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions.MethodsWe used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers.ResultsThere was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P=0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P=0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P=0.008).ConclusionsSickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.)

A Comparative Study of Solubility Based Sickle Cell Screening Versus Genomic Method in Blood Donors

Background:Sickle cell trait (SCT) is more common in minority African-Americans (AA) and Hispanic blood donors. Screening donors for Sickle Hemoglobin (HbS) carrier status (SCT) can be useful, especially in managing the transfusion needs of neonates and patients with sickle cell disease. Currently, the Sickledex test, based on the principle of relative insolubility of HbS in phosphate buffers, is routinely used for HbS donor screening. However, there are several limitations including the inability to perform high-throughput testing by automation as donor centers target larger numbers of minority blood donors. False positives results due to hyperlipidemia, dysglobulinemia and higher peripheral blood hematologic counts have also been reported. Hence alternative methods to identify SCT donors are highly desirable in blood centers. The purpose of this study was to validate testing, and to identify rates of False Positive (FP) and False Negative (FN) sickledex screening in blood donors by verifying the presence or absence of the most common mutation seen with HbS production using molecular methods. The comparison could offer evidence to use molecular methods as a test of record to manage HbS carriers at blood centers.Methods and ResultsBetween Jan 2012 till Dec 2014, 200 sickledex screening tests were done daily, totaling approximately 90,000 donors self-identifying as Caucasians and 60,000 donors identifying as African American or Hispanic tested during the study period. Amongst Caucasians tested, 154 had a positive sickledex screen result. Since the prevalence of SCT is less common in the Caucasian population, we hypothesized several of these Caucasian donors could have a false positive screening test. All 154 sickledex positive Caucasian donor samples were prospectively tested for the HbS mutation detection with molecular methods. BioArray Human Erythrocyte Antigen (HEA) Bead Chip DNA assay with PCR multiplex based technology was used to detect the HbS mutation (β-globin change -173 A>T, more commonly designated 20A>T). Of the 154 sickledex + Caucasians, 108 (70%) donors tested negative (FP Screen) and 46 (30%) tested positive for the HbS mutation. A retrospective review of sickledex results in our electronic database for minority donors (n-3431) who also had HEA BeadChip assay was performed to determine concordance. Of 3431 minority donors tested, only 2 (0.0006%) had a positive sickledex screening and were negative by HEA, with the remaining negative by both the sickledex screen and HEA tests. Among minority donors (n= 254) testing + for HbS by HEA, 3% (8/254) were negative by sickledex screening. To establish concordance of HEA assay with high performance liquid chromatographic (HPLC) assay, two separate cohorts were evaluated. Initially 12 sickle screen and HEA positive donors was subject to HPLC analysis, which confirmed SCT status in all 12 samples. Subsequently sickledex screen positive but HEA negative samples (n= 40), were subject to HPLC. All 40 showed absence of SCT by HPLC. Finally, 58 random sickledex + samples had gene sequencing and HEA performed in parallel. Out of 58 samples, 54 showed a positive HbS mutation by HEA with A>T (SCT) nucleotide change noted with gene sequencing. In the remaining 4 samples, HEA was negative with gene sequencing showing (3 T>T and in 1C>T) change at nucleotide 163 associated with Hemoglobin Okayama.Conclusion:The HEA bead chip assay testing for the HbS mutation showed 100% concordance with HPLC and gene sequencing in samples studied. Molecular methods can process multiple samples in a single setting to detect SCT. FP sickledex screening results in Caucasians needs confirmatory testing for the HbS mutation to avoid unnecessary donor notification and deferral. The association, if any, of false positive sickledex screening in Caucasian donors with the Hgb Okayama mutation is under further investigation. DisclosuresNo relevant conflicts of interest to declare.

Reproductive Attitudes and Behaviors in People With Sickle Cell Disease or Sickle Cell Trait: A Qualitative Interpretive Meta-Synthesis

Sickle cell disease (SCD) is a serious and life threatening disorder. The literature on informed reproductive decisions among people with SCD is limited, suggesting that there is a lack of awareness about SCD and Sickle cell trait status (SCT) among high-risk populations. The purpose of this qualitative interpretive meta-synthesis (QIMS) is to examine the reproductive attitudes and behaviors in people with SCD or SCT to create effective genetic counseling programs to inform reproductive decision making. Three studies were included in the QIMS for a total sample of 79 participants. The majority of the sample was African American, ages 16 to 63. Other demographic characteristics of the study populations and data collection methods used in these studies varied. Seven themes on reproductive attitudes and behaviors among people with SCD or SCT emerged: lack of awareness or education about SCD and SCT; men who deny having SCT; attitudes toward learning one's SCT status; rationales for learning a partner's SCT status prior to commencing a relationship; valuing relationships over SCD risk; learning one's own and partner's SCT status; and the consequences of not asking about partners' SCT status. Implications for prevention programming involving improved education and awareness about the disease and reproduction are discussed.

Would sickle cell trait influence the metabolic control in sub-Saharan individuals with type 2 diabetes?

To determine the prevalence and effects of sickle cell trait on metabolic control in a Cameroonian diabetic population in a tertiary care setup. This was a cross-sectional study involving 73 consecutive outpatients with Type 2 diabetes recruited from the Yaounde National Diabetes and Obesity Centre. Sickle cell trait status was based on haemoglobin electrophoresis. Metabolic control was assessed by plasma glucose and HbA(1c), and comparisons made between participants with and without sickle cell trait, with adjustment for confounders through linear regressions models. The prevalence of sickle cell trait was 19%, without sex difference, and comparable with figures in individuals without diabetes in this setting. Participants with diabetes and sickle cell trait were older than the non-trait participants (66 vs. 58 years, P = 0.02). Otherwise, clinical and biological profile including indicators of metabolic control were similarly distributed between trait and non-trait participants (all P >0.08). After adjustment for confounders, sickle cell trait was unrelated to fasting glucose (β = 0.02; 95% confidence interval -37.68-43.30) and HbA(1c) (β = -0.03, 95% confidence interval -1.18-0.93), and did not affect the relationship between the two markers of diabetes control (β = -0.03, 95% confidence interval -1.18-0.89). Sickle cell trait was as frequent in this subgroup of patients with Type 2 diabetes as in the general population, suggesting no specific association with diabetes. It does not affect the metabolic control of diabetes. However, how this translates into long-term outcome needs to be fully elucidated in this setting, with an increasing population with both sickle cell trait and diabetes mellitus.