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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Public Health

Year Degree Awarded

2018

Month Degree Awarded

May

First Advisor

Richard J. Wood

Second Advisor

Zhenhua Liu

Third Advisor

Jing Qian

Subject Categories

Biochemical Phenomena, Metabolism, and Nutrition | Genetic Structures | Maternal and Child Health | Public Health | Women's Health

Abstract

Lifestyles have been dynamically changing in the past few years in Saudi Arabia, and the prevalence of non-communicable diseases (NCDs), such as obesity, diabetes, hypertension, high cholesterol, and other cardiovascular diseases (CVD), is notably increasing. In fact, NCDs are affecting a growing number of people in SA, especially women of childbearing age. Vitamin D deficiency has also become pandemic and a major public health concern among the Saudi population despite the abundance of sunlight. The most vulnerable groups are pregnant women and their newborns. Previous studies have correlated low vitamin D status with a higher risk of adverse short- and long-term health consequences for both mother and child. Therefore, identification of novel genetic markers in women at risk of adverse pregnancy outcomes could lead to earlier identification of at-risk pregnancies and inform possible interventions to reduce adverse health outcomes.

The fact that vitamin D receptors (VDR) are present in almost every tissue of the human body has led to a debate about the extra-skeletal functions of vitamin D. To date, numerous studies have associated VDR gene polymorphisms to serious chronic illnesses. One candidate gene that has attracted interest in the literature is FokI VDR polymorphisms. FokI VDR, is capable of altering the protein structure and produces two structurally different variants: a longer (f allele) and a shorter (F allele), which is more effective and has higher transcriptional activity than the long variant (f allele).

Since there is scarce research regarding the potential association between FokI VDR polymorphism and adverse metabolic health outcomes in pregnant Saudi women, we hypothesized that Saudi mothers with poorer vitamin D status plus expression of the longer, less effective f version of the VDR protein would be at greatest risk of any adverse effects, such as vitamin D deficiency, gestational diabetes mellitus (GDM), and metabolic syndrome (MS).

We carried out a cross-sectional study in pregnant Saudi women and compared the association between the FokI VDR genotype and different metabolic health outcomes. The participants were randomly selected from primary health care centers and governmental hospitals scattered around the city of Riyadh during their first and second trimesters check-up between December 2013 and January 2016. The FokI VDR genotype was assessed, and its association with different variables, including vitamin D status, GDM, and MS and its components, were also analyzed.

In the first study, we investigated the association between FokI VDR gene polymorphism and serum 25-hydroxyvitamin D (25(OH)D) levels in 345 pregnant Saudi women (273 with vitamin D deficiency and 72 non-deficient subjects) in their first trimester. About 79% of the women studied were vitamin D deficient (25(OH)D < 50 nmol/L). Our findings indicated that the Ff genotype and the combined variant genotype (Ff+ ff) showed a significant decrease in the risk of developing vitamin D deficiency (FF vs. Ff, OR = 0.44, 95% CI = 0.200.94, P = 0.035, FF vs. Ff+ff, OR = 0.42, 95% CI = 0.200.88, P = 0.022), after adjusting for confounding factors that had significant effect on altering vitamin D status.

In the second study, we examined whether there was a difference in the risk of having GDM among the various FokI VDR genotypes in 108 GDM patients and 260 healthy pregnant women in their second trimester. We found no significant difference in risk. However, within the group of patients carrying the minor ff genotype, we found that serum 25(OH)D was significantly and inversely associated with fasting serum glucose and hemoglobin A1C. Vitamin D deficiency was highly prevalent among study participants amounting to 85.3%. It was also significantly associated with GDM (P=0.016) and glucose indices such as fasting insulin, HOMA_IR and HOMA_b.

In the third study, we investigated the association of the FokI VDR genotype as a risk factor for MS and its components in 368 pegnant Saudi women (44 with MS and 324 without MS) in their second trimester. We found that the minor ff genotype was a significant risk factor for MS (P = 0.039; OR = 2.91; 95% CI, 1.05–8.1).

Together, the results of the previous studies suggest that FokI VDR gene polymorphism could be a risk factor for vitamin D deficiency, poorer glucose homeostasis, and MS in the Saudi population.

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