Association between vitamin d deficiency, vitamin d receptor gene polymorphisms and selected mRNA gene expression markers in Malaysian women with gestational hypertension

Vitamin D deficiency is a widespread health issue linked to both modifiable and non- modifiable risk factors and has been implicated in the development of gestational hypertension (GH), responsible for about 14% of maternal deaths globally. Inheritance of defective vitamin D receptor (VDR) gene reduces the effectiveness of vitamin D signaling, thereby leading to GH. This study aimed to determine the association between vitamin D deficiency and associated risk factors, VDR gene polymorphisms, and mRNA expression profiles of selected genes in Malaysian pregnant women. The study was conducted in two phases; a cross-sectional study and a case-control study, involving 412 subjects in phase I and 180 subjects (90 GH cases and 90 controls) in phase II. Blood sample was collected using venipuncture, serum 25(OH)D3 was analysed using electrochemiluminescence immunoassay (ECLIA) while DNA and RNA were extracted from peripheral blood monocytes using standard methods for VDR gene polymorphism and gene expression studies respectively. VDR polymorphisms (FokI, BsmI, and TaqI) were determined using polymerase chain reaction-high-resolution melting (PCR-HRM) technique and Sanger sequencing. Angiotensin-converting enzyme (ACE1) and endothelial nitric oxide synthase (eNOS) gene expression was determined using quantitative polymerase chain reaction (qPCR) technique. The data were analysed using IBM SPSS v27, Chromas Technelysium pty Ltd v2.6.6 and SRplot softwares. The prevalence of vitamin D deficiency was 64.6%, with subjects' median daily vitamin D intake of 11.2 μg/day, which was significantly (p=0.017) lower than the recommended nutritional intake (RNI) value 15 μg/day. Vitamin D deficiency was significantly associated with pregnancy outcomes; gestational hypertensive disorders (ꭓ2 = 9.153; p=0.002) and preterm birth (ꭓ2 = 7.363; p=0.025). Vitamin D supplementation during pregnancy was found to be associated with a reduced risk of GH (OR = 0.279 (0.130 – 0.597) 95% CI; p=0.0001), decreased likelihood of caesarean section (OR = 0.578 (0.346 – 0.966) 95% CI; p=0.037), Subjects aged 25– 34 are 8 times more likely to experience preterm birth (OR = 8.023 (1.057 – 60.883) 95% CI; p=0.004). The Ff/TT haplotype was significantly more common among GH subjects with lower serum 25(OH)D3 levels, and there was a significant downregulation of ACE1 (p=0.0001) and eNOS (p=0.0001) gene expression was observed in GH subjects compared to non-GH subjects. This study reports a high prevalence of maternal vitamin D deficiency and highlights the significant role of VDR polymorphisms and haplotype in GH. The findings underscore the importance of integrating routine vitamin D screening and supplementation into the existing antenatal care settings for improved maternal health. Personalised vitamin D supplementation, especially for genetically susceptible women may help to reduce the risk of GH.

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