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: Sickle cell trait; Mean corpuscular hemoglobin

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