Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery. For cognitive assessments, we used fully corrected T scores adjusted for age, sex, race, and education. Based on the diagnostic and statistical manual 5 criteria, we defined mild and major cognitive impairment as T scores with a 1 or 2 standard deviation (SD) and >2 SD below the mean on at least 1 test, respectively. Forty-two patients were enrolled, with 36 completing MRIs. SCI was present in 50% of the patients (18), of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs 27.7%; P = .026), including major cognitive impairment (50% vs 5.6%; P = .010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment (odds ratio [OR] 10.5 [95% confidence interval (95% CI), 1.45-76.63]; P = .020) and major cognitive impairment (OR 7.98 [95% CI, 1.11-57.27]; P = .039) after adjusting for history of stroke and Beck depression inventory scores. MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these silent infarcts are neither silent nor innocuous.

Alpha Globin Gene Copy Number Is Associated with Prevalent Chronic Kidney Disease and Incident End-Stage Kidney Disease among Black Americans.

BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic-mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P<0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P=0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P=0.005). CONCLUSIONS: Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review.

Immune checkpoint blockade has demonstrated durable clinical benefits in a variety of malignancies. These immune checkpoint inhibitors (ICIs) produce unwanted autoimmune reactions due to an impaired self-tolerance. Hematologic immune-related adverse events (heme-irAEs) have been increasingly reported in the literature with a reported fatality rate of 12%. In this review, we illustrate 3 cases treated at Johns Hopkins Hospital for ICI-induced agranulocytosis, aplastic anemia, and thrombocytopenia. We then summarize the available evidence regarding the incidence and prevalence of heme-irAEs. We identified immune thrombocytopenia and hemolytic anemia as the most commonly reported heme-irAEs which are more commonly observed with nivolumab therapy. Median time to onset of heme-irAEs varies between patients but occurs earlier with CTLA-4 inhibitors than with anti-PD-L1/PD-1 agents. We also describe the current challenges regarding the recurrence of heme-irAEs despite immune checkpoint blockade termination. We provide the available evidence supporting a mixed T-cell and B-cell immune-mediated response. Finally, we review the treatment algorithm of these complications and provide treatment alternatives to steroid-refractory cases.

Factors mediating cancer risk in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at an elevated risk for certain cancers compared to the population at large. Cancers seen at higher rates in the SLE population include hematologic malignancies, such as non-Hodgkin lymphoma, and cancers of the lung and thyroid. SLE patients also have a decreased risk for certain malignancies, such as breast cancer, melanoma, and prostate cancer. We review the literature on risk factors for malignancy in patients with SLE and discuss the exogenous and innate factors that are thought to contribute to the unique pattern of cancer risk observed in this patient population. These risk factors are important for providers of SLE patients to understand in order to maintain high clinical suspicion and detect malignancy as soon as possible. Further research is needed to determine the most effective guidelines on counseling patients on cancer screening and prevention.

The Cancer Risk Profile of Systemic Lupus Erythematosus Patients.

ABSTRACT: Systemic lupus erythematosus (SLE) patients have a well-established increased risk for cancer. Research from the past 2 decades has identified the specific malignancies that afflict SLE patients at disproportionate rates. Systemic lupus erythematosus patients are at heightened risk for several hematologic malignancies as well as for certain solid tumors, including lung, thyroid, and hepatobiliary cancers. They are at decreased risk for several cancers as well, including prostate and melanoma. Improved understanding of the unique cancer risk profile of SLE patients has led some professional societies to recommend specialized cancer screening and prevention measures for these patients and has enabled clinicians to better serve the SLE patient population.

Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and ß-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and ß-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.

APOL1 Nephropathy Risk Alleles and Mortality in African American Adults: A Cohort Study.

RATIONALE & OBJECTIVE: APOL1 nephropathy risk alleles are associated with the development of chronic kidney disease (CKD) in African Americans. Although CKD is an established risk factor for mortality, associations of APOL1 risk alleles with mortality are uncertain. STUDY DESIGN: Prospective cohort. SETTINGS & PARTICIPANTS: 10,380 African American and 17,485 white American participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. EXPOSURES: APOL1 nephropathy risk alleles. OUTCOMES: All-cause and cause-specific mortality. ANALYTICAL APPROACH: Cox proportional hazards models were used to examine the association of APOL1 high-risk genotypes (2 risk alleles) versus APOL1 low-risk genotypes (0/1 risk allele) with all-cause and cause-specific mortality in African Americans and examine the risk for all-cause mortality in African Americans with high-risk genotypes versus African Americans with low-risk genotypes and white Americans. RESULTS: APOL1 high-risk participants were younger and had a higher prevalence of albuminuria than low-risk participants. There was no statistically significant association of APOL1 high- versus low-risk genotypes with all-cause mortality in models adjusted for sociodemographic variables, comorbid conditions, and kidney function (HR, 0.88; 95% CI, 0.77-1.01). After further adjustment for genetic ancestry in a subset with available data, a statistically significant association emerged (HR, 0.81; 95% CI, 0.69-0.96). Associations differed by CKD status (Pinteraction=0.04), with African Americans with high-risk genotypes having lower risk for mortality than those with low-risk genotypes in fully adjusted models (HR, 0.78; 95% CI, 0.62-0.99) among those with CKD, but not those without CKD (HR, 0.84; 95% CI, 0.66-1.05). Compared with white Americans, African Americans with high-risk genotypes had a similar rate of mortality, whereas African Americans with low-risk genotypes had a higher rate of mortality (HR, 1.07; 95% CI, 1.00-1.14) in fully adjusted models. LIMITATIONS: Lack of follow-up measures of kidney function. CONCLUSIONS: African Americans with high-risk APOL1 genotypes had lower mortality than those with low-risk genotypes in multivariable-adjusted models including genetic ancestry.

The current state of sickle cell trait: implications for reproductive and genetic counseling.

Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.

The molecular basis for the prothrombotic state in sickle cell disease.

The genetic and molecular basis of sickle cell disease (SCD) has long since been characterized but the pathophysiological basis is not entirely defined. How a red cell hemolytic disorder initiates inflammation, endothelial dysfunction, coagulation activation and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a history of VTE. Here, we thoroughly review the molecular basis for the prothrombotic state in SCD, specifically highlighting emerging evidence for activation of overlapping inflammation and coagulation pathways, that predispose to venous thromboembolism. We share perspectives in managing venous thrombosis in SCD, highlighting innovative therapies with the potential to influence the clinical course of disease and reduce thrombotic risk, while maintaining an acceptable safety profile.

APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

BACKGROUND: Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.

Metabolic syndrome among adults living with sickle cell disease.

Metabolic syndrome (MetS) is a key risk factor for cardiovascular disease (CVD) incidence and all-cause mortality. MetS prevalence among adults with sickle cell disease (SCD) is not well known. We report initial findings from a cross-sectional study that examined MetS risk factors within a cohort of adults living with SCD. 50 adult SCD participants (ages 21-66 years; 72% female) completed demographic and health behavior surveys, health-related family and personal histories, and anthropometric and laboratory measurements. Descriptive and inferential statistics were used to summarize and compare CVD risk factors, stratified in separate analyses by SCD genotype and sex. Triglyceride, blood pressure, and fasting glucose levels were within normal limits. 78% of the cohort reported moderate to high physical activity. However, 46% of this cohort was overweight and dietary saturated fat intake exceeded both the national average (11%) and US Dietary Guidelines (<10%). 14.3% of the cohort fulfilled criteria for MetS with large waist circumference and reduced HDL levels prominently accounting for this status. We evaluated the prevalence of MetS in a cohort of adults living with SCD. Our findings suggest that increased attention to eating habits and physical activity may generate new approaches for decreasing cardiovascular morbidity in SCD.

A case-control analysis of hyperhemolysis syndrome in adults and laboratory correlates of complement involvement.

BACKGROUND: Hyperhemolysis syndrome (HS) is a poorly understood, severe hemolytic anemia provoked by transfusion. Both host and donor RBCs are destroyed in HS; thus, transfusion paradoxically worsens anemia. Risk factors and mechanism of HS are unknown. STUDY DESIGN AND METHODS: A retrospective case-control analysis was performed on adults with HS. Patients with HS were matched 1:1 with matched, transfused controls, and HS risk factors were analyzed with multivariable logistic regression. HS samples were analyzed for complement deposition by flow cytometry, and an in vitro model of bystander hemolysis was developed. RESULTS: Forty-one patients with 54 episodes of HS were identified in a 26-year period from 1992 to 2018. Of the HS episodes, only 18.5% were associated with a new alloantibody, and such patients were more tolerant of additional transfusion in the acute episode (p = 0.005). Thirteen percent of episodes were fatal, and HS recurred in 52.6%. Alloimmunization (odds ratio [OR], 17.3), non-B blood type (OR, 9.8), D antigen (OR, 9.1), and infection (OR, 5.5) were associated with HS on multivariable analysis. Hyperbilirubinemia was predictive of fatal HS (OR, 33.6). Increased complement was observed on RBCs during HS episodes, and the in vitro model of bystander hemolysis recapitulated complement decoration of sickled RBCs. CONCLUSIONS: HS is associated with significant morbidity, mortality, and recurrence. Risk factors such as known alloimmunization, blood group, and infection predispose to HS. Bystander complement activation may drive HS. These factors may help physicians refine risk-benefit assessments for transfusion and guide further therapeutic development.

Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review.

Background: Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes. Purpose: To evaluate associations between SCT and clinical outcomes in children and adults. Data Sources: English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles. Study Selection: Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality. Data Extraction: A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus. Data Synthesis: Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low. Limitation: Publication bias was possible, and high-quality evidence was scant. Conclusion: Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT. Primary Funding Source: National Human Genome Research Institute.

Association of sickle cell trait with atrial fibrillation: The REGARDS cohort.

BACKGROUND: Sickle cell trait (SCT), sickle cell disease's (SCD) carrier status, has been recently associated with worse cardiovascular and renal outcomes. An increased prevalence of atrial fibrillation (AF) is documented in SCD patients; however, studies in individuals with SCT are lacking. OBJECTIVES: To determine the association of SCT with AF. METHODS: Among African-American participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study we assessed the association of SCT (by ECG or medical history) with prevalent AF using logistic regression adjusting for age, sex, income, education, history of stroke, myocardial infarction, diabetes, hypertension, and chronic kidney disease. A second evaluation was performed a mean of 9.2 years later among available participants, and the same model was used to test the association of SCT with incident AF. RESULTS: In 10,409 participants with baseline ECG data and genotyping, 778 (7.5%) had SCT and 811 (7.8%) had prevalent AF. After adjusting for age, sex, education and income, SCT was associated with AF, OR 1.32 (95% CI 1.03-1.70). The association with incident AF assessed at the second in-home visit with the same adjustments was similar; OR 1.25 (95% CI 0.77-2.03). CONCLUSIONS: SCT was associated with a higher prevalence of AF and a non-significantly higher incident AF over a 9.2 year period independent of AF risk factors. SCT remained associated with prevalent AF after adjusting for potential factors on the causal pathway such as hypertension and chronic kidney disease suggesting alternate mechanisms for the increased risk.

D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study.

OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, ß=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (ß=0.373, P=9.06×10-13) than among men (ß=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (ß=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

Sickle Cell Trait and the Risk of ESRD in Blacks.

Blacks, compared with whites, have an increased risk of progression to end-stage renal disease (ESRD). Emerging evidence suggests that, in addition to APOL1 high-risk genotypes, hemoglobin variants, including sickle cell trait (SCT) and hemoglobin C trait, have a role in kidney disease in blacks. However, the association between these hemoglobin traits and ESRD remains unknown. In a large population-based cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we evaluated 9909 self-reported blacks (739 with SCT and 243 with hemoglobin C trait). Incident ESRD occurred in 40 of 739 (5.4%) individuals with SCT, six of 243 (2.5%) individuals with hemoglobin C trait, and 234 of 8927 (2.6%) noncarriers. The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT and 4.0 per 1000 person-years for noncarriers. Compared with individuals without SCT, individuals with SCT had a hazard ratio for ESRD of 2.03 (95% confidence interval, 1.44 to 2.84). Hemoglobin C trait did not associate with prevalent CKD or ESRD. The incidence rate for ESRD among participants with APOL1 high-risk genotypes was 6.6 per 1000 person-years, with a hazard ratio for ESRD of 1.77 (95% confidence interval, 1.31 to 2.38) for participants with, compared with those without, APOL1 high-risk genotypes. In this cohort, SCT strongly associated with risk of progression to ESRD in blacks, and this degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes. These results may have important public policy implications for genetic counseling of SCT carriers.

Association of Sickle Cell Trait With Hemoglobin A1c in African Americans.

Importance: Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective: To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants: Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures: Presence of SCT. Main Outcomes and Measures: Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results: The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance: Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.