Association of Hemoglobin S and C Traits with Kidney Disease in African Americans in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Naik Rakhi P. , Irvin Marguerite R. , Judd Suzanne , Gutierrez Orlando , Zakai Neil A , Derebail Vimal K. , Peralta Carmen , Lewis Michael , Zhi Degui , Arnett Donna , McClellan William , Wilson James G. , Reiner Alexander , Kopp Jeffrey , Winkler Cheryl , Cushman Mary 
Published: October 2019

Abstract
Background: Sickle cell trait (SCT) and hemoglobin C trait are two of the most common inherited hemoglobin mutations in the world due to their malarial protective effects. APOL1 renal risk variants, which confer resistance to trypanosomal infection, are prevalent in African-ancestry populations and are associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). While an increased risk of CKD in SCT carriers has been demonstrated; there are conflicting data on SCT and the risk of ESRD, and the association between hemoglobin C trait and kidney disease remains unknown. Furthermore, whether co-inheritance of hemoglobin S or C and APOL1 gene risk variants contributes to the risk of CKD has not been established.
Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 12,514 African-Americans age ≥ 45 years from the contiguous United States between 2003-2007. All participants consenting to genetic research were genotyped for hemoglobin S and hemoglobin C traits. Individuals with hemoglobin SS, SC, or CC genotypes were excluded from analysis. APOL1 high-risk genotypes were defined as the presence of two renal risk variants, G1/G1, G2/G2, or G1/G2. Prevalent CKD was defined as a baseline eGFR < 60mL/min/1.73 m2 and/or the presence of albuminuria ≥ 30mg/g based on spot urine albumin/creatinine ratio (ACR) measurements. Logistic regression was used to calculate odds ratios (OR) of prevalent CKD for hemoglobin S/C, and Cox regression was used to estimate risk of incident ESRD. All analyses were adjusted for age, sex, smoking, hypertension, diabetes, APOL1 high-risk genotype status, and baseline eGFR (for incident ESRD). A genetic interaction analysis of hemoglobin S/C variants and APOL1 high-risk genotypes on prevalent CKD was also performed.
Results: A total of 10,481 African American participants, 7.5% with SCT and 2.5% with hemoglobin C trait, had available genetic data for analysis. As shown in table 1, prevalent CKD was significantly more common in SCT carriers than non-carriers, with an OR for CKD of 1.86 [95% CI 1.57-2.20]). In addition, individuals with SCT had a 1.5-fold increased hazard of incident ESRD compared to non-carriers, although this was not statistically significant. Hemoglobin C trait was not associated with prevalent CKD or incident ESRD, but the numbers were small. On genetic interaction analysis, co-inheritance of hemoglobin C and APOL1 high-risk genotypes significantly increased the risk of prevalent CKD (p-interaction=0.003), while co-inheritance of SCT and APOL1 high-risk genotypes did not appear to interact to increase CKD risk.
Conclusions: In this large cohort of over 10,000 African Americans, SCT was associated with an increased risk of prevalent CKD and demonstrated a trend of association with incident ESRD. Hemoglobin C trait was not associated with prevalent CKD but may interact with APOL1 high-risk genotypes to potentiate the risk of CKD. Future studies are needed to further examine these gene-gene interactions and to establish the relationship between hemoglobin S/C traits and ESRD.
Table 1. Association of Hemoglobin S and C Traits with Prevalent CKD and Incident ESRD Outcome Non-carriers Heterozygous Hgb S (Hgb AS) Heterozygous Hgb C (Hgb AC) Prevalent CKD N (%) 2212 (24.5) 266 (35.7) 63 (25.7) Adjusted OR (95% CI) 1.00 (ref) 1.86 (1.57-2.20) 0.98 (0.72-1.33) Incident ESRD N (%) 110 (1.17) 18 (2.30) 5 (1.95) Incidence rate (N/1000 person-years) 2.95 6.04 5.06 Adjusted HR (95% CI) 1.00 (ref) 1.52 (0.91-2.52) 2.30 (0.93-5.65)

Disclosures
No relevant conflicts of interest to declare.