Abstract
Vitamin D is important in multiple aspects of health and its effects are mediated through the Vitamin D Receptor (VDR). We wanted to test the hypothesis that specific haplotypes of the VDR gene are associated with markers of disease severity, inflammation and bone health in Sickle Cell Disease (SCD). Genotyping was performed on DNA specimens from 1141 study participants in the NIH-funded Silent Infarct Transfusion (SIT) trial. We used the clinical and laboratory data to create separate endothelial dysfunction, vaso-occlusive severity scores and phenotype variables. Seventy-nine Single Nucleotide Polymorphisms (SNP) in the VDR gene and three associated genes—CYP27B1, VD binding protein, retinoid X receptor, were evaluated. The discovery cohort individuals had VDR haplotype information from a prior Genome-Wide Association Study (GWAS). The validation cohort was analyzed for SNPs that were significant in the discovery cohort. The pheno-type data were obtained from the demographic and clinical information of the participants, and were used to create the severity scores, vaso-occlusive score, endothelial dysfunction severity, and overall severity score. Potential gene-gene interactions were analyzed for prediction of disease severity within each severity score. Two SNPs were associated with the overall severity score, 3 SNPs with the endothelial dysfunction severity score and 4 SNPs with the vaso-occlusive severity score. After permutation testing to correct for multiple comparisons, only one of the associations remained significant. SNP rs7965281 was found to be associated with the endothelial dysfunction severity score and remained significant after correcting for multiple comparisons using permutation testing. In the validation cohort, that SNP was again tested for association with each of the severity scores. There was no association with the endothelial or the overall severity score but a trend towards association with the vaso-occlusive severity score (p = 0.02). None of the known functional polymorphisms in the VDR gene were found to have an association with severity in sickle cell disease. Further work analyzing for gene-gene interaction using the same significant SNPs remains to be done in association with inflammatory markers and measure of bone health. Those studies may provide insight on the contribution of VDR polymorphisms to sickle cell disease severity.
Highlights
Sickle Cell Disease (SCD) is a hereditary disorder primarily affecting people of African ancestry [1]
Vitamin D deficiency has been studied in sickle cell disease to some extent, the polymorphisms in the Vitamin D Receptor (VDR) gene have not been explored in sickle cell disease or in Africans or African Americans [8]
We evaluated 79 Single Nucleotide Polymorphisms (SNPs) in the VDR gene, three associated genes: CYP27B1, VD binding protein, retinoid X receptor, and tagging SNPs from the African American population from Hap map (Appendix 1)
Summary
Sickle Cell Disease (SCD) is a hereditary disorder primarily affecting people of African ancestry [1]. SCD is a single gene disorder and the complications of this disease affect every organ of the body including the vascular and immune systems along with bone metabolism. Vitamin D deficiency is commonly seen in patients with sickle cell disease especially those with SCD-SS [2] [3]. Because of the presence of the VDR on cells in endothelial, inflammatory and bone systems, polymorphisms in this gene may be associated with disease manifestations in these organ systems in SCD. Our hypothesis is that specific VDR polymorphisms are associated with disease severity in sickle cell disease. Some of the variation in the severity of sickle cell disease can be explained by differing polymorphisms in the VDR gene
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