Abstract
In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10-8), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57x10-7), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2x10-5). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5’ CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.
Highlights
Sickle cell disease (SCD) is an inherited hemoglobin disorder affecting approximately 1 in 600 individuals of African American ancestry in the United States [1]
Genome-wide single SNP association Genome-wide association and meta-analysis was performed for systolic blood pressure (SBP) in 1,617 subjects (843 males, 774 females) from the Silent Infarct Transfusion (SIT) Trial and Cooperative Study of Sickle Cell Disease (CSSCD) cohorts
The observed suggestive genetic signals of dopamine receptor D2 subtype (DRD2) region SNPs and the prediction of MIR4301 binding to DRD2 as a potential target, suggests the plausible involvement of DRD2 region in the regulation of SBP in SCD cohorts
Summary
Sickle cell disease (SCD) is an inherited hemoglobin disorder affecting approximately 1 in 600 individuals of African American ancestry in the United States [1]. Previous studies have demonstrated that the arterial blood pressure in steady state patients with SCD is significantly lower than that of age, sex and race matched controls [4,5,6,7,8,9]. These findings are counterintuitive in view of the well-known vascular and renal abnormalities associated with SCD and the high prevalence of hypertension in African American adults [10,11,12]. Identifying genetic factors associated with systolic blood pressure (SBP) may help define both pathophysiological mechanisms, as well as identify patients at increased risk for SCI
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