A novel sequence polymorphism in exon 1 of the human vitamin D-binding protein (GC) gene

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.

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Polymorphisms in the GC Gene for Vitamin D Binding Protein and Their Association with Vitamin D and Bone Mass in Young Adults

Journal of College of Physicians And Surgeons Pakistan ◽

10.29271/jcpsp.2019.08.715 ◽

2019 ◽

Vol 29 (08) ◽

pp. 715-719 ◽

Cited By ~ 2

Author(s):

Aysha Khan ◽

Lena Jafri ◽

Areeba Siddiqui ◽

Ghazala Naureen ◽

Howard Morris ◽

...

Keyword(s):

Vitamin D ◽

Young Adults ◽

Bone Mass ◽

Binding Protein ◽

Vitamin D Binding Protein ◽

Gc Gene

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Vitamin D-binding protein deficiency and homozygous deletion of the GC gene

Yearbook of Paediatric Endocrinology ◽

10.1530/ey.16.5.4 ◽

2019 ◽

Author(s):

Henderson CM ◽

Fink SL ◽

Bassyouni H ◽

Argiropoulos B ◽

Brown L ◽

...

Keyword(s):

Vitamin D ◽

Binding Protein ◽

Homozygous Deletion ◽

Protein Deficiency ◽

Vitamin D Binding Protein ◽

Gc Gene

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Methylation in 3′ near region of GC gene and its association with the level of vitamin D binding protein and type 2 diabetes mellitus

Nutrition Research ◽

10.1016/j.nutres.2018.03.016 ◽

2018 ◽

Vol 54 ◽

pp. 52-59 ◽

Cited By ~ 2

Author(s):

Songcheng Yu ◽

Yan Wang ◽

Xing Li ◽

Zhenxing Mao ◽

Fei Yu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Vitamin D ◽

Type 2 Diabetes Mellitus ◽

Binding Protein ◽

Vitamin D Binding Protein ◽

Gc Gene

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

Journal of the Endocrine Society ◽

10.1210/jendso/bvab104 ◽

2021 ◽

Author(s):

Ronadip R Banerjee ◽

Tara Spence ◽

Stuart J Frank ◽

Raj Pandian ◽

Andrew N Hoofnagle ◽

...

Keyword(s):

Vitamin D ◽

Gene Deletion ◽

Binding Protein ◽

Pathogenic Variant ◽

Plasma Vitamin ◽

Vitamin D Metabolites ◽

Vitamin D Binding Protein ◽

Hydroxyvitamin D ◽

Vitamin D Levels ◽

Gc Gene

Abstract 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>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.

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Vitamin D–Binding Protein Deficiency and Homozygous Deletion of the GC Gene

New England Journal of Medicine ◽

10.1056/nejmc1905282 ◽

2019 ◽

Vol 380 (26) ◽

pp. 2582-2587

Keyword(s):

Vitamin D ◽

Binding Protein ◽

Homozygous Deletion ◽

Protein Deficiency ◽

Vitamin D Binding Protein ◽

Gc Gene

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Independent associations of polymorphisms in vitamin D binding protein (GC) and vitamin D receptor (VDR) genes with obesity and plasma 25OHD3 levels demonstrate sex dimorphism

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2015-0284 ◽

2016 ◽

Vol 41 (4) ◽

pp. 345-353 ◽

Cited By ~ 16

Author(s):

Norah Almesri ◽

Nagalla S. Das ◽

Muhallab E. Ali ◽

Khalid Gumaa ◽

Hayder Ahmed Giha

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Plasma Levels ◽

Binding Protein ◽

Nucleotide Polymorphisms ◽

Sex Dimorphism ◽

Vitamin D Binding Protein ◽

Vdr Gene ◽

Gc Gene ◽

High Bmi

We investigated a possible association between polymorphisms in vitamin D binding protein (GC) and vitamin D receptor (VDR) genes and obesity in Bahraini adults. For this purpose, 406 subjects with varying body mass indexes (BMIs) were selected. Plasma levels of 25-hydroxyvitamin D3 (25OHD3) were measured by chemiluminescence immunoassay. Six single nucleotide polymorphisms, 2 in the VDR gene (rs731236 TC and rs12721377 AG) and 4 in the GC gene (rs2282679 AC, rs4588 CA, rs7041 GT, and rs2298849 TC), were genotyped by real-time polymerase chain reaction. We found that the rs7041 minor allele (G) and rare genotype (GG) were associated with higher BMI (p = 0.007 and p = 0.012, respectively), but they did not influence 25OHD3 levels. However, the minor alleles of rs2282679 (A) and rs4588 (C) were associated with low 25OHD3 plasma levels (p = 0.039 and p = 0.021, respectively), but not with BMI. Having categorized the subjects based on their sex, we found that (i) rs7041 GG associated with high BMI in females (p = 0.003), (ii) rs4588 CC associated with high BMI in females (p = 0.034) and low 25OHD3 levels in males (p = 0.009), and (iii) rs12721377 AA associated with low 25OHD3 levels in females (p = 0.039). Notably, none of the common haplotypes (6 in the GC gene and 3 in the VDR gene) were associated with BMI. Therefore, polymorphisms in the GC (rs2282679, rs4588, rs7041) and VDR (rs12721377) genes were independently associated with obesity and 25OHD3 levels with a clear sex dimorphism.

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