Analysis of Cdx2 VDR gene polymorphism rs11568820 in association with multiple sclerosis in Slovaks

ABSTRACT

Vitamin D deficiency is involved in the pathogenesis of multiple sclerosis (MS), a severe autoimmune demyelinating disease of the central nervous system. The gene polymorphism Cdx-2 (rs11568820, G/A) seriously influences the trancriptional activity of the vitamin D receptor (VDR) that binds the vitamin D responsive elements of target genes including HLA-DRB1*15. The aim of the present study in Slovaks was to analyse the association of Cdx-2 variants with the risk of MS and disability progression, and to assess the DRB1*15:01 allele as a possible confounding factor. In total, 493 MS patients and 417 healthy controls were involved in this study. The genotyping of Cdx-2 was performed using restriction analysis; DRB1*15:01 positivity was determined by a high-resolution melting analysis of its surrogate marker rs3135388 (G/A). Our results did not prove any allelic association between Cdx-2 and a risk of MS (minor allele A − 0.181 in patients vs. 0.161 in controls, OR = 1.15, .95 CI = 0.90–1.47, p = 0.289). The logistic regression analysis, adjusted for sex and age, showed no differences in Cdx-2 genotype counts when using an additive, dominant or recessive genetic model (p = 0.351, 0.150, 0.240 respectively). The Cdx-2 variants were also not associated with disease disability progression, evaluated using the Multiple Sclerosis Severity Score. The HLA-DRB1*15:01 allele was found to strongly increase the risk of MS in our study (0.300 in patients vs. 0.101 in controls, OR = 3.83, .95 CI = 2.94–4.99, p = 1.016 × 10⁻²⁶, dominant genetic model OR = 4.62, .95 CI = 3.40–6.26, p = 9.1 × 10⁻²³). In summary, we found the Cdx-2 as a single genetic marker not to be associated with MS development or progression in Slovaks, independently of HLA-DRB1*15:01 status.

KEYWORDS:

• Multiple sclerosis
• susceptibility
• disability progression
• vitamin D receptor
• Cdx-2 (rs11568820)
• gene polymorphism
• HLA-DRB1*15:01

Acknowledgments

The authors would like to thank the patients with multiple sclerosis and healthy control individuals for their generous agreement to participate in this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Abbreviations

CNS, central nervous system; EDSS, Expanded Disability Status Scale score; HRMA, high resolution melting analysis; GWAS, Genome-Wide Association Studies; MS, Multiple sclerosis; MSSS, Multiple Sclerosis Severity Score; OR, odds ratios; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism; VDR, vitamin D receptor

CRediT authorship contribution statement

Daniel Čierny: Conceptualization, Data curation, Investigation, Formal analysis, Writing – original draft. Dušan Dobrota: Supervision. Ema Kantorová: Data curation. Bibiana Malicherová: Methodology. Mária Škereňová: Methodology, Formal analysis. Juraj Javor: Data curation. Egon Kurča: Conceptualisation. Ján Lehotský: Funding acquisition, Writing – review & editing.

Additional information

Funding

The work was supported by the Slovak Research and Development Agency [grant number APVV 15/0107] andScientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences [grant numbers VEGA 230/20, 274/23].