Vitamin-D Binding Protein Gene Polymorphisms and Serum 25-Hydroxyvitamin-D in a Turkish Population

The rs7041 and rs4588 polymorphisms found in the GC gene, encoding vitamin D-binding protein (DBP), have distinct biochemical phenotypes. The aim of this study was to investigate vitamin D parameters with these polymorphisms, in individuals with possible vitamin D deficiency. The most common (49% of the cohort) genotype in rs7041 was GT, especially among individuals with high levels of free 25(OH)D calculated but with low levels of bioavailable 25(OH)D, and in rs4588 it was AC in particular among the individuals with low levels of bioavailable 25(OH)D. The most common phenotypes were Gc1s/2 (35.3%) and Gc1s/1s (31.4%), and Gc1f/1f was rare (5.9%). The variations in free and bioavailable 25(OH)D levels among healthy Turkish individuals may be attributed to the variations in total 25(OH)D as well as GC gene polymorphisms. The Turkish population shares a similarity for allele frequencies of rs7041 with the European population and similarity for allele frequencies of rs4588 with Gujarati Indians, and this may also be important in relation to certain ethnic populations showing associations between vitamin D and COVID-19.

Total, Bioavailable, and Free 25-Hydroxyvitamin D Equally Associate with Adiposity Markers and Metabolic Traits in Mexican Adults

Epidemiological studies suggest a relationship between total 25-hydroxyvitamin D [25(OH)D], adiposity, and metabolic traits. The bioavailability of 25(OH)D is regulated by the albumin, vitamin D binding protein (VDBP), and variants of the GC gene. Therefore, it is not clear if bioavailable or free 25(OH)D offer additional benefits compared to total 25(OH)D when estimating the magnitude of these associations. Our aim was to evaluate the association between 25(OH)D (total, free and bioavailable) with adiposity and metabolic traits. This was a cross-sectional study of 1904 subjects from the Health Workers Cohort Study from Mexico. Free and bioavailable 25(OH)D were calculated based on VDBP and albumin determinations, using a formula adjusted for the GC gene diplotypes. Adiposity and metabolic traits were measured with standardized procedures. Free and bioavailable 25(OH)D levels correlated with total 25(OH)D, r = 0.71 and 0.70, respectively (p < 0.001). Total, bioavailable and free 25(OH)D levels were negatively associated with the adiposity marker (visceral adiposity index) and metabolic traits (metabolic syndrome, type 2 diabetes, triglycerides, triglycerides/HDL-c ratio, and triglycerides/glucose index) in multivariate regression models (ORs = 0.73 to 0.96). Our findings suggest that free and bioavailable 25(OH)D do not offer additional advantages over total 25(OH)D regarding its association with adiposity and several metabolic traits in Mexican adults.

Association of GC Variants with Bone Mineral Density and Serum VDBP Concentrations in Mexican Population

Vitamin D-binding protein (VDBP) is encoded by the GC gene and is an active participant in the control of bone metabolism. However, the effect of its major variants on VDBP concentration and bone mineral density (BMD) remains unclear. Our aim was to analyze the effect of major GC variants on serum VDBP concentration and BMD. We recruited individuals from the Health Workers Cohort Study, which includes employees of the Mexican Institute of Social Security (IMSS). A total of 1853 adults were included. The single nucleotide polymorphisms (SNPs) rs7041 and rs4588 were genotyped to identify the three best characterized haplotypes of GC. Serum VBDP, 25(OH)D and BMD were also measured. Among women, the G allele of rs7041 was associated with higher VDBP and BMD compared to homozygous TT. The A allele of rs4588 was associated with lower VDBP and BMD compared to CC homozygous. In men, GC variants were only associated with VDBP levels. We did not observe an association between free/bioavailable 25(OH)D and BMD in men and women. Our results support an association of VDBP in bone health. The G and C alleles, from rs7041 and rs4588, respectively, are associated with high concentrations of VDBP and BMD in this sample of Mexican postmenopausal women.

Very Low Vitamin D in a Patient with a Novel Pathogenic Variant in the GC Gene that encodes Vitamin D-Binding Protein

Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin. DBP, encoded by the GC gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous GC gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of GC revealed a homozygous pathogenic variant affecting a canonical splice site (c.702-1G&gt;A). These findings indicate that loss of function variants in GC that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.

Tumors Widely Express Hundreds of Embryonic Germline Genes

We have recently described a class of 756 genes that are widely expressed in cancers, but are normally restricted to adult germ cells, referred to as germ cell cancer genes (GC genes). We hypothesized that carcinogenesis involves the reactivation of biomolecular processes and regulatory mechanisms that, under normal circumstances, are restricted to germline development. This would imply that cancer cells share gene expression profiles with primordial germ cells (PGCs). We therefore compared the transcriptomes of human PGCs (hPGCs) and PGC-like cells (PGCLCs) with 17,382 samples from 54 healthy somatic tissues (GTEx) and 11,003 samples from 33 tumor types (TCGA), and identified 672 GC genes, expanding the known GC gene pool by 387 genes (51%). We found that GC genes are expressed in clusters that are often expressed in multiple tumor types. Moreover, the amount of GC gene expression correlates with poor survival in patients with lung adenocarcinoma. As GC genes specific to the embryonic germline are not expressed in any adult tissue, targeting these in cancer treatment may result in fewer side effects than targeting conventional cancer/testis (CT) or GC genes and may preserve fertility. We anticipate that our extended GC dataset enables improved understanding of tumor development and may provide multiple novel targets for cancer treatment development.

Polymorphism of gene GC, encoding vitamin D binding protein, in aboriginal populations of Siberia

The analysis of the nucleotide sequences of exons and adjacent non-coding regions of the GC gene in 108 representatives of various ethnic groups of aboriginal population of Siberia was carried out. Polymorphism was found in four nucleotide positions: non-synonymous substitutions at the rs4588 and rs7041 loci, a synonymous substitution at the rs4752 locus, and a replacement in the non-coding region at the rs3733359 locus. Seven haplotypes of the GC gene were identified. Of these, 4 haplotypes encode the Gc1F isoform, 2 haplotypes encode the Gc1S isoform, and 1 haplotype encodes the Gc2 isoform. Between-regional differences were found in the distribution of variants of the GC gene: in the northeast and in the central part of Siberia, the highest prevalence of the Gc1F and Gc1F / Gc1F variants is observed, and in the south and west of Siberia, the Gc2, Gc1S / Gc2 and Gc2 / Gc2 variants are most common. In the case of the GC gene, gene-environment interactions are apparently aimed at creating a balance between the activity of vitamin D-binding protein and the level of 25-hydroxyvitamin D in the blood serum.

Evaluation of the Associations of GC and CYP2R1 Genes and Gene-Obesity Interactions with Type 2 Diabetes Risk in a Chinese Rural Population

Introduction: Group-specific component (GC) and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) gene polymorphisms and obesity have been associated with an increased risk for development of type 2 diabetes mellitus (T2DM) in Asian populations. Objective: This study assessed the associations of interactions between GC gene variants and CYP2R1 gene variants and between genes and obesity with T2DM risk. Methods: A study that included 2,271 subjects was performed. Eight single nucleotide polymorphisms in the GC and CYP2R1 genes were genotyped. Interaction analysis was performed using rs7041 in the GC gene and rs1993116 in the CYP2R1 gene. The effects of multiplicative and additive gene-gene and gene-environment interactions on T2DM risk were assessed. Results: The T2DM risk was significantly associated with being overweight/obese, abdominal obesity, rs7041, and rs1993116. A significant additive interaction between rs1993116 and rs7041 was associated with T2DM. In addition, there was a significant multiplicative interaction between rs7041 and body mass index (BMI) associated with elevated blood glucose levels, and at a higher BMI (>28.47), the G allele carrier showed a stronger effect than the TT genotype. Conclusions: The interactions between GC rs7041-CYP2R1 rs1993116 and GC rs7041-BMI may explain the mechanisms by which these factors increase the risk of T2DM development.