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الأبحاث

Research Title :Rare-Variant Genome-Wide Association and Polygenic Score Assessment of Vitamin D Status in a Middle Eastern Population

Authors : Nagham Nafiz Hendi, Umm-Kulthum Umlai, Omar Albagha & Georges Nemer

Abstract :Vitamin D deficiency is highly prevalent in the Middle East despite abundant sunlight; however, most genetic studies have focused on common variants in Europeans only. We analyzed whole-genome sequences from 13,808 Qatar Biobank participants, evaluating rare variants (minor allele frequency 0.01–0.0001) for associations with serum 25-hydroxyvitamin D (25(OH)D) levels and deficiency risk (≤20 ng/mL) in independent discovery (n = 5885) and replication (n = 7767) cohorts, followed by meta-analyses. In quantitative analyses, the discovery cohort identified 41 genome-wide significant signals, including CD36 rs192198195 (p = 2.48 × 10−8), and replication found 46, including SLC16A7 rs889439631 (p = 2.19 × 10−8), implicating lipid metabolism pathways. In binary analyses, replication revealed POTEB3 rs2605913 (p = 2.8 × 10−8), while meta-analysis (n = 13,652) uncovered SLC25A37 rs952825245 (p = 5.15 × 10−12), a locus associated with cancer and vitamin D signaling. Rare-variant polygenic scores derived from discovery significantly predicted continuous (R2 = 0.146, p = 9.08 × 10−12) and binary traits (AUC = 0.548, OR = 0.99, p = 9.22 × 10−6) in replication. This first rare-variant GWAS of vitamin D in Middle Easterners identifies novel loci and pathways, underscores the contribution of ancestry-specific rare alleles, and supports integrating rare and common variants to guide precision management in high-burden populations.”

Keywords : Vitamin D, Rare variants, GWAS, Polygenic score, Middle Eastern population

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Research Title : SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model

Authors :Nagham Nafiz Hendi & Georges Nemer

Abstract :Introduction: Vitamin D is a pleiotropic hormone essential for bone health and overall physiological function. Despite its significance, vitamin D deficiency remains widespread and is often influenced by genetic factors. Methods: This study investigates the role of SDR42E1, a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. Using CRISPR/Cas9 gene-editing, we generated an SDR42E1 knock-in model in HCT116 colorectal cells, which exhibit high endogenous SDR42E1 expression, harboring a nonsense variant associated with vitamin D deficiency. Results: Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, P = 0.007) and cancer-related signaling pathways (FC = −1.7, P = 0.02). Notably, key differentially expressed genes included upregulated LRP1B and ABCC2, alongside downregulated WNT16 and SLC7A5. Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = −0.37, P = 0.0005). Functionally, SDR42E1 deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient SDR42E1 overexpression with restoring ABCC2 expression. Conclusion: These findings establish SDR42E1 as a key modulator of vitamin D-related pathways and highlight its potential as a therapeutic target for addressing vitamin D deficiency and associated pathologies, including cancer

Keywords : SDR42E1; endocrine disorders; genetics in endocrinology; precision medicine; vitamin D regulation

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Research Title :Functional Characterization of the SDR42E1 Reveals Its Role in Vitamin D Biosynthesis

Authors : Nagham Nafiz Hendi, M.-T. Bengoechea-Alonso, J. Ericsson, & Georges Nemer

Abstract :Vitamin D deficiency poses a widespread health challenge, shaped by environmental and genetic determinants. A recent discovery identified a genetic regulator, rs11542462, in the SDR42E1 gene, though its biological implications remain largely unexplored. Our bioinformatic assessments revealed pronounced SDR42E1 expression in skin keratinocytes and the analogous HaCaT human keratinocyte cell lines, prompting us to select the latter as an experimental model. Employing CRISPR/Cas9 gene-editing technology and multi-omics approach, we discovered that depleting SDR42E1 showed a 1.6-fold disruption in steroid biosynthesis pathway (P-value = 0.03), considerably affecting crucial vitamin D biosynthesis regulators. Notably, SERPINB2 (P-value = 2.17 × 10−103), EBP (P-value = 2.46 × 10−13), and DHCR7 (P-value = 8.03 × 10−09) elevated by ∼2–3 fold, while ALPP (P-value <2.2 × 10−308), SLC7A5 (P-value = 1.96 × 10−215), and CYP26A1 (P-value = 1.06 × 10−08) downregulated by ∼1.5–3 fold. These alterations resulted in accumulation of 7-dehydrocholesterol precursor and reduction of vitamin D3 production, as evidenced by the drug enrichment (P-value = 4.39 × 10−06) and total vitamin D quantification (R2 = 0.935, P-value = 0.0016) analyses. Our investigation unveils SDR42E1's significance in vitamin D homeostasis, emphasizing the potential of precision medicine in addressing vitamin D deficiency through understanding its genetic basis”

Keywords :CRISPR/Cas9; HaCaT; multi-omics; SDR42E1; steroidogenesis; vitamin D biosynthesis

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Research Title :In Silico Characterization of the Novel SDR42E1 as a Potential Vitamin D Modulator

Authors :Nagham Nafiz Hendi & Georges Nemer

Abstract :“The short-chain dehydrogenase/reductase (SDR) superfamily encompasses enzymes that play essential roles in the metabolism of steroid hormones and lipids. Despite an enigmatic function, recent genetic studies have linked the novel SDR 42 extended-1 (SDR42E1) gene to 25-hydroxyvitamin D levels. This study investigated the potential SDR42E1 functions and interactions with vitamin D using bioinformatics and molecular docking studies. Phylogenetic analysis unveiled that the nucleotide sequences of human SDR42E1 exhibit high evolutionary conservation across nematodes and fruit flies. Molecular docking analysis identified strong binding affinities between SDR42E1 and its orthologs with vitamin D3 and essential precursors, 8-dehydrocholesterol, followed by 7-dehydrocholesterol and 25-hydroxyvitamin D. The hydrophobic interactions observed between the protein residues and vitamin D compounds supported the predicted transmembrane localization of SDR42E1. Our investigation provides valuable insights into the potential role of SDR42E1 in skin vitamin D biosynthesis throughout species. This provides the foundation for future research and development of targeted therapies for vitamin D deficiency and related health conditions

Keywords :Bioinformatics; Evolutionary conservation; Molecular docking; SDR42E1; Vitamin D skin biosynthesis

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Research Title :5. Genetic Determinants of Vitamin D Deficiency in the Middle Eastern Qatari Population: A Genome‑Wide Association Study

Authors : Nagham Nafiz Hendi, Yasser Al-Sarraj, Umm-Kulthum Umlai, Karsten Suhre, Georges Nemer, & Omar Albagha

Abstract :Introduction: Epidemiological studies have consistently revealed that Vitamin D deficiency is most prevalent in Middle Eastern countries. However, research on the impact of genetic loci and polygenic models related to Vitamin D has primarily focused on European populations. Methods: We conducted the first genome-wide association study to identify genetic determinants of Vitamin D levels in Middle Easterners using a whole genome sequencing approach in 6,047 subjects from the Qatar Biobank (QBB) project. We performed a GWAS meta-analysis, combining the QBB cohort with recent European GWAS data from the UK Biobank (N = 345,923). Additionally, we evaluated the performance of European-derived polygenic risk scores (PRS) using UK Biobank data in the QBB cohort. Results: Our study identified an association between a variant in a known locus for the group-specific component gene (GC), specifically rs2298850 (p = 1.71×10⁻⁸, Beta = –0.1285), and Vitamin D levels. Furthermore, our GWAS meta-analysis identified two novel variants at a known locus on chromosome 11: rs67609747 and rs1945603. Notably, we observed a heritability of Vitamin D estimated at 18% in this cohort—higher than previous European estimates. Despite the lower predictive performance of European-derived PRS in the Qatari cohort, the scores were significantly linked to Vitamin D deficiency risk. Conclusion: This novel study reveals the genetic architecture contributing to Vitamin D deficiency in the Qatari population, emphasising the genetic heterogeneity across different populations”

Keywords :Middle Eastern; Vitamin D deficiency; genetic predispositions; genome-wide association study; polygenic risk score

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Research Title :6. The Genetic Architecture of Vitamin D Deficiency among an Elderly Lebanese Middle Eastern Population: An Exome‑Wide Association Study

Authors : Nagham Nafiz Hendi, Marlene Chakhtoura, Yasser Al-Sarraj, Dania Saleh Basha, Omar Albagha, Ghada El Hajj Fuleihan, & Georges Nemer

Abstract :The Middle East region experiences a high prevalence of hypovitaminosis D, yet most genetic studies on vitamin D have focused on European populations. Furthermore, there is a lack of research on the genomic risk factors affecting elderly people, who are more susceptible to health burden. We investigated the genetic determinants of 25-hydroxyvitamin D concentrations in elderly Lebanese individuals (n = 199) through a whole-exome-based genome-wide association study. Novel genomic loci displaying suggestive evidence of association with 25-hydroxyvitamin D levels were identified, including rs141064014 in MGAM (p = 4.40 × 10⁻⁶) and rs7036592 in PHF2 (p = 8.43 × 10⁻⁶). A meta-analysis of the Lebanese data and the largest European GWAS confirmed consistency replication of numerous variants, including rs2725405 in SLC38A10 (p = 3.73 × 10⁻⁸). Although the PRS model derived from European populations exhibited lower performance than European estimations, it still effectively predicted vitamin D deficiency among our cohort. Our findings provide novel insights into the genetic mechanisms underlying vitamin D deficiency among elderly Middle Eastern populations, facilitating the development of personalised approaches for more effective management of hypovitaminosis D. Additionally, we demonstrated that whole-exome-based genome-wide association study is an effective method for identifying genetic components associated with phenotypes.”

Keywords :Middle Eastern population; exome-wide association study; genetic determinants; polygenic risk score; vitamin D deficiency.

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Research Title :7. Patient Characteristics Associated with Pegylated Interferon Alfa-2a Induced Neutropenia in Chronic Hepatitis C Patients

Authors : Nagham N. Hindi & Mohammad I. Saleh

Abstract :Neutropenia is a haematologic disorder commonly reported in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon alfa-2a (PEG-IFN α-2a). The objective of the present project is to identify patient characteristics associated with neutropenia in hepatitis C patients. Demographic, clinical, and genetic data from 715 patients with chronic HCV infection treated with PEG-IFN α-2a and ribavirin were analysed. The outcome variable was the development of grade 3 or 4 neutropenia, defined as the decrease in neutrophil counts below 1×10⁹/L anytime during study. Predictors of neutropenia were identified using a 2-stage approach. First, univariate analysis was performed to identify possible predictors of neutropenia. T-test was used for continuous variables and Fisher’s exact test for categorical variables. Second, multiple logistic regression with stepwise addition was then applied using predictors identified in the univariate analysis step to produce a final model containing independent predictors at P < .05. Logistic regression identified female gender, absolute neutrophil counts, and cholesterol level as the main predictors of neutropenia. Female gender increases the odds of experiencing neutropenia by 86 % compared to male gender. A 1-unit (mmol/L) increase in cholesterol level decreases the odds of developing neutropenia by 13 %. A 55 % reduction in the likelihood of developing neutropenia for a 1-unit (10⁹/L) increase in the absolute neutrophil counts. Patients with high risk of developing neutropenia can be identified. Identification of this cohort allows early intervention to prevent neutropenia. Possible intervention is to administer drugs that raise neutrophil count such as filgrastim before neutropenia occurs

Keywords :Hepatitis C; interferon; neutropenia; pegylated interferon alfa-2a; predictors

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