Vitamin D is a pro-hormone characterized by an intricate metabolism and regulation. It is well known for its role in calcium and phosphate metabolism, and in bone health. However, several studies have assessed a huge number of extra-skeletal functions, ranging from cell proliferation in some oncogenic pathways to antioxidant and immunomodulatory functions. Vitamin D exerts its role by binding to VDRs (vitamin D receptors), which are located in many different tissues. Moreover, VDRs are able to bind hundreds of genomic loci, modulating the expression of various primary target genes. Interestingly, plenty of gene polymorphisms regarding VDRs are described, each one carrying a potential influence against gene expression, with relapses in several chronic diseases and metabolic complications. In this review, we provide an overview of the genetic aspects of vitamin D and VDR, emphasizing the gene regulation of vitamin D, and the genetic modulation of VDR target genes. In addition, we briefly summarize the rare genetic disease linked to vitamin D metabolism.

Context: Patients with endogenous Cushing syndrome (CS), in addition to significant cardiovascular morbidity, are burdened by a high prevalence of fragility fractures. Bone mineral density (BMD) alone poorly predicts the risk of fracture, and the implementation of trabecular bone score (TBS) is supported only by scant evidence. Indeed, reliable predictors of fractures in endogenous CS are still lacking. Objective: This work aimed to analyze the prevalence and the potential predictors of fragility fractures in our patients with CS. Methods: A monocentric, retrospective, cross-sectional study. A total of 51 patients with overt CS were enrolled. Main outcome measures included biochemical evaluation, BMD measurement, TBS evaluation, fracture presence, body composition evaluation, and arterial intima-media thickness (IMT) assessment. Results: Fragility fractures were found in 62.7% of patients at diagnosis. Fractured patients exhibited lower spine T-score (P = .03), longer disease duration (P = .025), higher waist circumference (P = .006), and predominantly male sex (P = .008). Increased serum uric acid levels (P = .001), greater IMT (P = .017), and higher prevalence of venous thromboembolism events (31.3% vs 5.3%, P = .037) and atherosclerotic plaques (47% vs 5.3%, P = .002) were described in the fracture group. Multivariable logistic regression identified the presence of atherosclerosis (OR 13.35; 95% CI 1.154-154.34, P = .038) and osteoporosis (OR 11.30; 95% CI 1.55-82.56, P = .017) as independent predictors. TBS values were inversely correlated with body mass index, fat and lean mass, and serum uric acid, and positively correlated with high-density lipoprotein cholesterol. Conclusion: CS patients with higher overall burden of cardiovascular morbidity are more prone to experience fragility fractures.

Purpose: This study investigates the role of CASR gene polymorphisms (A986S, R990G, Q1011E) in PHPT genetic susceptibility and its clinical variability. The aim is to evaluate the prevalence of these polymorphisms in patients with sporadic PHPT and their impact on clinical course, biochemistry, and histological features. Methods: 106 patients underwent clinical and anamnestic evaluations, focusing on major PHPT complications, as well as biochemical analyses of blood and urine. Genetic testing was conducted for CASR gene polymorphisms. Histological data were available for 68 patients who underwent parathyroidectomy. Results: The sample included 83 women and 23 men; mean age at diagnosis was 54.5 years. 55 patients carried CASR gene polymorphisms, while 51 were wild-type. Prevalence rates of polymorphisms were consistent with data for the Caucasian population, with A986S being the most common (31%). No significant associations were found between polymorphisms and increased levels of ionized calcium or other blood phospho-calcium metabolism parameters. However, 24-h urinary calcium levels were higher in patients with polymorphisms (p = 0.0185), particularly in those older than 50 years (p = 0.030) and with the A986S variant. Hypercalciuria was predictive of CASR polymorphism presence (OR = 2.76, p = 0.003). No significant association with PHPT complications, such as renal calculi or bone involvement, was confirmed. Histological data revealed no clear links between polymorphisms and more aggressive variants. Conclusions: CASR gene polymorphisms are associated with hypercalciuria but do not significantly influence age of onset or clinical phenotype in PHPT. Genetic analysis may be useful in selected cases to better understand individual clinical profiles.