Vitamin D and VDR FokI Polymorphisms in Thyroid Cancer: A Comprehensive Review

Abstract

Thyroid cancer is one of the fastest-rising endocrine malignancies worldwide, with a particularly notable surge across Asian populations, including India. In North India, this escalating burden reflects a multifactorial interplay between environmental exposures, nutritional deficiencies, hormonal influences, and genetic predispositions. Among nutritional determinants, Vitamin D deficiency stands out as a critical and widespread problem despite ample sunlight. Vitamin D, beyond its classical role in calcium and bone homeostasis, exerts significant antiproliferative, pro-differentiation, immunomodulatory, and anti-inflammatory functions, largely mediated through the Vitamin D receptor (VDR). Genetic variations within the VDR gene—especially the FokI (rs2228570) polymorphism—modify receptor efficiency and alter downstream transcriptional responses, potentially influencing individual susceptibility to malignant transformation in tissues such as the thyroid, which expresses VDR abundantly. Emerging literature indicates that the FokI polymorphism generates two receptor isoforms with differing biological activity, with the shorter F-allele–encoded VDR demonstrating stronger transcriptional signaling. Populations carrying the less active f-allele may have impaired vitamin D–mediated tumor suppression, particularly under conditions of chronic vitamin D insufficiency. This is highly relevant for North Indians, who exhibit among the world’s highest rates of hypovitaminosis D due to cultural clothing, indoor lifestyles, air pollution, skin pigmentation, and limited dietary Vitamin D intake. Parallel epidemiological evidence links low Vitamin D levels with aggressive clinicopathological features of thyroid cancer, including larger tumor size, lymph node metastasis, and extrathyroidal extension. Additionally, long-standing iodine deficiency persists in pockets of North India despite national fortification programs, contributing to chronic TSH stimulation, oxidative stress, nodular hyperplasia, and potential genomic instability within the thyroid gland. Environmental radiation exposure—both medical and atmospheric—further heightens carcinogenic risk, with childhood exposure being particularly detrimental. Ionizing radiation is known to induce DNA double-strand breaks, chromosomal rearrangements, and oncogenic events such as RET/PTC fusions, which drive pathways central to thyroid tumorigenesis. The convergence of nutritional insufficiencies (Vitamin D and iodine), VDR FokI polymorphisms, radiation exposure, and other region-specific determinants creates a unique biological milieu that may predispose North Indians to higher thyroid cancer susceptibility and potentially more aggressive disease. This review synthesizes epidemiological trends, molecular mechanisms, and gene–environment interactions underpinning this relationship. Understanding the synergistic effects of vitamin D status, VDR functionality, and environmental factors is essential for developing predictive models tailored to Indian populations. Such models hold promise for improving early detection, refining risk stratification, and guiding targeted prevention strategies for high-risk groups in North India.