Search

Introduction: People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene ( HBA) deletion would be associated with reduced risk of incident ischemic stroke., Methods: We evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke., Results: Four-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years' follow-up. HBA copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66., Conclusions: Although a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Background: Some but not all African-Americans (AA) who carry APOL1 nephropathy risk variants ( APOL1 ) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene-gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study., Methods: Genotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL 1 * SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1 * SNP interactions that met the threshold of 1.0 × 10 -5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study., Results: Two APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1 -SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold ( P interaction = 3.4 × 10 -8 ), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with P interaction < 1.0 × 10 -5 ), a variant ( rs2181251 ) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, P interaction =5.3 × 10 -6 ) but the association was not replicated (GenHAT study, P interaction = 0.07, BioVU study, P interaction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes., Conclusion: In a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaudhary, Armstrong, Hidalgo, Gutiérrez, Hellwege, Limdi, Reynolds, Judd, Nadkarni, Lange, Winkler, Kopp, Arnett, Tiwari and Irvin.)