رسائل دكتوراة
English
2023
Genome-Wide Association Study of Vitamin D Deficiency in the Middle East With a Relevant Characterization of the Novel SDR42E1 Gene
Georges M. Nemer, Nagham Nafiz Ahmad Hendi
كلية العلوم الصحية والحيوية-جامعة حمد بن خليفة · قطر
Epidemiological studies have revealed that Middle Eastern countries have the highest incidence of Vitamin D deficiency with severe complications. However, the impact of Vitamin D polymorphisms and the performance of polygenic models have been studied primarily in European populations, with little knowledge in the Middle Eastern. A nonsense variant in the uncharacterized SDR42E1 gene has been identified recently as a potential contributor to Vitamin D deficiency through genomic research.
Methods
I conducted the first genome-wide association study to identify genetic determinants of Vitamin D levels in Middle Eastern populations using whole-genome and whole-exome sequencing approaches in 6,047 and 199 discovery subjects from Qatar and Lebanon, respectively. I also functionally and structurally characterized the novel SDR42E1 by generating stable CRISPR/Cas9-mediated genome editing in the selected HaCat and HCT116 human cell models.
Results
I discovered a novel variant, rs2298850 (P-value = 1.71 × 10-08, effect size (Beta) = -0.1285), in a known locus of the group-specific component gene (GC) in the Qatari population. I confirmed the association of Vitamin D to several variants, including rs11723621 (P-value = 1.93 × 10-08, Beta = -0.12574) and rs4588 (P-value = 8.06 × 10-08, Beta = -0.1188) in the GC. I further identified a novel suggestive variant, rs141064014 on chromosome 7 in the MGAM gene (P-value of 4.40 × 10−06) and rs7036592, on chromosome 9 in the PHF2 gene (P-value of 8.43 × 10−06). A GWAS meta-analysis combining results from the previous European data and Qatari cohort identified novel variants in known loci, including rs67609747 and rs1945603 on chromosome 11. Many variants were replicated through combining elderly Lebanese data and the largest European GWAS from the UK Biobank, including rs2725405 on chromosome 17 in the SLC38A10 gene (P-value of 3.73 x 10-08). Finally, a low predictive performance of European ancestry-derived polygenic scores was observed when applied to the Middle East individuals. I determined a cytoplasmic localization of SDR42E1 protein in the cutaneous HaCat and intestinal HCT116 cells. Significant gene associations between the SDR42E1 and genes involved in Vitamin D pathways were identified, including alkaline phosphatase, placental type (ALPP), ATP-binding cassette C1 (ABCC1), solute carrier 7A5 (SLC7A5). Gene regulators of cellular senescence and cancer prognosis were found to be significantly affected after the knockout and knockout of SDR42E1 in HaCat and HCT116 cells. Significant alterations in Vitamin D metabolites, including 24R-24,25-Dihydroxyvitamin D, and lipid membrane components, including phosphatidylcholine, were observed in the absence of SDR42E1 from the HaCat cells. Cellular viability also decreased significantly after the knockout of SDR42E1 in the HCT116 cells.
Conclusion
These results emphasize the diversity in the genetic architecture and its impact on preventive and precision medicine across different populations. My findings offer novel perspectives on the physiological mechanisms and genetic factors contributing to the variation of Vitamin D levels in Middle Eastern populations. The comprehensive understanding of the molecular mechanisms underlying Vitamin D metabolism and associated health conditions garnered from my study of the novel SDR42E1, and its variant constitutes a foundation for future research and translational applications in clinical precision medicine.
