Grant Abstract: Capacity building in chronic non-communicable diseases at the American University

Grant Number: 5D43TW009118-04
PI Name: Fuleihan
Project Title: Capacity building in chronic non-communicable diseases at the American University

Abstract: Vitamin D, a steroid hormone that controls over several hundreds of genes, amounts to around 3% of mouse and human genomes. A recent systematic review of 195 studies from 44 countries involving over 168,000 participants, revealed high prevalence of hypovitaminosis D worldwide, with considerable variation in mean 25 hydroxy-vitamin D 25 (OH)D levels, the preferred index of vitamin D nutritional status. Lifestyle factors modulate serum 25(OH)D levels, but recent studies have demonstrated that they are also under marked genetic influence. A limited number of involved genes along the vitamin D pathway have been identified, that, even when combined, only explain a small proportion of the variance in circulating vitamin D levels. Most studies conducted in relatively vitamin D replete, mostly Caucasian populations, and lacked a comprehensive approach. Hypovitaminosis D is most prevalent in the Middle East and Asia. Although concealed clothing, low sun exposure, dietary habits, and lack of government regulation, account for some variations in 25(OH)D levels, the genetic underpinnings are just beginning to be explored. High consanguinity rates in Lebanon, led collaborators to discover novel mutations/ genotype combinations related to classic phenotypes, such as clotting disorders. Hypovitaminosis D and rickets should be no exception.

In this proposal we will implement a comprehensive assessment of the genetics of the vitamin D pathway in the Lebanese, taking advantage of a completed one year randomized double blinded trial in elderly subjects investigating the effect of vitamin D, on 25(OH)D levels and indices of fuel and mineral metabolism. The proposal objectives are to:
1) Identify genetic variants in the vitamin D pathway that modulate total and free vitamin D levels at baseline in the trial cohort. 2) Identify genetic variants in the vitamin D pathway that affect the response to Vitamin D supplementation, in response to two vitamin D doses.
3) Characterize genetic variants the vitamin D pathway that influence surrogate markers of fuel and mineral metabolism that are linked to major health outcomes (osteoporosis, diabetes, and cardiovascular diseases). 4) Investigate the interaction of lifestyle factors with genotype on the ultimate phenotypic expression, be it baseline 25(OH) levels, levels in response to therapy, or surrogate markers. The group of collaborators on this project, experts in the conduct of clinical trials with vitamin D, in molecular biology and pharmacogenomics with insights into gene environment interaction, quantitative methods in genetics, and the availability of Next Generation Sequencing technology, all provide a unique opportunity for the proposed targeted investigations. This project addresses a common public health problem, It will lead to personalized strategies, with impact on Non-Communicable Diseases, of national, regional and possibly worldwide relevance.

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