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

• DOI: 10.1371/journal.pgen.1007293
• Publication Date: 2018-03-28T17:33:47Z
• Authors: Laura M. Raffield; Jacob C. Ulirsch; Rakhi P. Naik; Samuel Lessard; Robert E. Handsaker; Deepti Jain; Hyun M. Kang; Nathan Pankratz; Paul L. Auer; Erik L. Bao; Joshua D. Smith; Leslie A. Lange; Ethan M. Lange; Yun Li; Timothy A. Thornton; Bessie A. Young; Goncalo R. Abecasis; Cathy C. Laurie; Deborah A. Nickerson; Steven A. McCarroll; Adolfo Correa; James G. Wilson; ; Guillaume Lettre; Vijay G. Sankaran; Alex P. Reiner
• Keywords: Adult; 0301 basic medicine; 570; Heredity; DNA Copy Number Variations; Hemoglobin, Sickle; 610; Erythrocytes, Abnormal; Anemia, Sickle Cell; QH426-470; Biochemistry; Sickle Cell Trait; Cohort Studies; Young Adult; 03 medical and health sciences; alpha-Globins; alpha-Thalassemia; Animal Cells; Red Blood Cells; Chronic Kidney Disease; Medicine and Health Sciences; Genome-Wide Association Studies; Genetics; Ethnicities; Humans; Hemoglobin; African American people; Glycated Hemoglobin; 0303 health sciences; Blood Cells; Biology and Life Sciences; Proteins; Computational Biology; Human Genetics; Anemia; Cell Biology; Genomics; Hematology; Population groupings; Genome Analysis; Globins; 3. Good health; Black or African American; Phenotype; Nephrology; Cellular Types; People and places; Research Article; Glomerular Filtration Rate

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 β-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 β-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.