Potential Pathogenic and Protective Genotypes and Phenotypes of Vitamin D Binding Protein in Multiple Sclerosis

Overview

Journal Front Neurol

Specialty Neurology

Date 2025 Feb 24

PMID 39990260

Authors

Suhail Al-Shammri

Arpita Chattopadhyay

Abu Salim Mustafa

Affiliations

Soon will be listed here.

Abstract

Background: The main carrier protein of vitamin D and its metabolites in plasma is vitamin D binding protein (VDBP) or group-specific component (Gc). Two single nucleotide polymorphisms, rs7041, and rs4588 in the gene result in three major VDBP/Gc genotypes, (c.1296T, c.1307C), (c.1296G, c.1307C), (c.1296T, c.1307A), and phenotypes, Gc1F (p.432Asp, p.436Thr), Gc1S (p.432Glu, p.436Thr), and Gc2 (p.432Asp, p.436Lys). This study investigated frequencies of genotypes and phenotypes in Kuwaiti multiple sclerosis (MS) patients and healthy controls, and their associations with serum levels of 25 hydroxyvitamin D [25(OH)vitamin D] and VDBP.

Methods: The genomic DNA was isolated from blood samples of drug-naïve MS patients ( = 151) and controls ( = 127). DNA regions covering the targeted mutations were amplified by PCR, sequenced by the Sanger method, and analyzed to determine genotypes and phenotypes. Serum 25(OH)vitamin D and VDBP levels were measured by enzyme immunoassay. SPSS used for statistical analyses. Differences between independent and related groups tested by Mann-Whitney and Wilcoxon signed-rank tests respectively, Genotype and phenotype frequencies were calculated;  < 0.05 considered significant.

Results: The study detected four Gc genotypes/phenotypes, namely /Gc1F (c.1296T, c.1307C/p.432Asp, p.436Thr), /Gc1S (c.1296G, c.1307C/p.432Glu, p.436Thr), /Gc2 (c.1296T, c.1307A/p.432Asp, p.436Lys), and /Gc3 (c.1296G; c.1307A/p.432Glu, p.436Lys) in both subjects. The frequencies of genotype (control: 5.51%; patient: 28.48%) and Gc3-containing phenotypic groups (Gc1S/Gc3 + Gc2/Gc3 + Gc3/Gc3) were significantly higher in patients. Moreover, frequencies of genotype (control: 27.17%; patients: 5.30%) and Gc1F-containing phenotypic groups (Gc1F/Gc1F + Gc1S/Gc1F + Gc2/Gc1F) were higher in controls. Vitamin D levels were deficient in both groups. However, VDBP concentrations were significantly low in MS patients only.

Conclusion: The VDBP/GC genotypes and phenotypes are associated with MS. Common genotype might be protective, and , the novel variant found in MS patients appeared to be pathogenetic. Hypovitaminosis-D is prevalent in MS patients and controls.

References

Berezowska M, Coe S, Dawes H . Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review. Int J Mol Sci. 2019; 20(6). PMC: 6471017. DOI: 10.3390/ijms20061301. View

Kampman M, Wilsgaard T, Mellgren S . Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J Neurol. 2007; 254(4):471-7. DOI: 10.1007/s00415-006-0395-5. View

Alshubaili A, Alramzy K, Ayyad Y, Gerish Y . Epidemiology of multiple sclerosis in Kuwait: new trends in incidence and prevalence. Eur Neurol. 2005; 53(3):125-31. DOI: 10.1159/000085556. View

Rithidech K, Honikel L, Milazzo M, Madigan D, Troxell R, Krupp L . Protein expression profiles in pediatric multiple sclerosis: potential biomarkers. Mult Scler. 2009; 15(4):455-64. DOI: 10.1177/1352458508100047. View

Chun R, Lauridsen A, Suon L, Zella L, Pike J, Modlin R . Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010; 95(7):3368-76. PMC: 2928899. DOI: 10.1210/jc.2010-0195. View

Kurtzke J . Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11):1444-52. DOI: 10.1212/wnl.33.11.1444. View

Rinaldi A, Sanseverino I, Purificato C, Cortese A, Mechelli R, Francisci S . Increased circulating levels of vitamin D binding protein in MS patients. Toxins (Basel). 2015; 7(1):129-37. PMC: 4303818. DOI: 10.3390/toxins7010129. View

Jorde R, Schirmer H, Wilsgaard T, Mathiesen E, Njolstad I, Lochen M . The DBP Phenotype Gc-1f/Gc-1f Is Associated with Reduced Risk of Cancer. The Tromsø Study. PLoS One. 2015; 10(5):e0126359. PMC: 4436319. DOI: 10.1371/journal.pone.0126359. View

Shoemaker T, Mowry E . A review of vitamin D supplementation as disease-modifying therapy. Mult Scler. 2018; 24(1):6-11. DOI: 10.1177/1352458517738131. View

10.

Poiana C, Capatina C, Cercel A, Sandulescu O, Streinu Cercel A . HYPOVITAMINOSIS D IN HIV-INFECTED PATIENTS. Acta Endocrinol (Buchar). 2019; -5(1):102-106. PMC: 6535333. DOI: 10.4183/aeb.2019.102. View

11.

Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K . No association of vitamin D-binding protein gene polymorphisms in Japanese patients with MS. J Neuroimmunol. 2002; 127(1-2):177-9. DOI: 10.1016/s0165-5728(02)00099-1. View

12.

Kamboh M, Ferrell R . Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations. Hum Genet. 1986; 72(4):281-93. DOI: 10.1007/BF00290950. View

13.

Lucas R, Ponsonby A, Dear K, Valery P, Pender M, Taylor B . Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011; 76(6):540-8. DOI: 10.1212/WNL.0b013e31820af93d. View

14.

Al-Shammri S, Nelson R, Al-Muzairi I, Akanji A . HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population. Mult Scler. 2004; 10(4):381-6. DOI: 10.1191/1352458504ms1065oa. View

15.

Olsson T, Barcellos L, Alfredsson L . Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2016; 13(1):25-36. DOI: 10.1038/nrneurol.2016.187. View

16.

Correale J, Ysrraelit M, Gaitan M . Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009; 132(Pt 5):1146-60. DOI: 10.1093/brain/awp033. View

17.

Wacholder S, Silverman D, McLaughlin J, Mandel J . Selection of controls in case-control studies. III. Design options. Am J Epidemiol. 1992; 135(9):1042-50. DOI: 10.1093/oxfordjournals.aje.a116398. View

18.

Holick M, Binkley N, Bischoff-Ferrari H, Gordon C, Hanley D, Heaney R . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(7):1911-30. DOI: 10.1210/jc.2011-0385. View

19.

Chen H, Zhang L, He Z, Zhong X, Zhang J, Li M . Vitamin D binding protein gene polymorphisms and chronic obstructive pulmonary disease: a meta-analysis. J Thorac Dis. 2015; 7(8):1423-40. PMC: 4561265. DOI: 10.3978/j.issn.2072-1439.2015.08.16. View

20.

Chiuso-Minicucci F, Watanabe Ishikawa L, Mimura L, de Campos Fraga-Silva T, Franca T, Zorzella-Pezavento S . Treatment with Vitamin D/MOG Association Suppresses Experimental Autoimmune Encephalomyelitis. PLoS One. 2015; 10(5):e0125836. PMC: 4428830. DOI: 10.1371/journal.pone.0125836. View