A population-based study of single nucleotide polymorphisms as risk factors for multiple sclerosis and neuromyelitis optica spectrum disorders (Yaroslavl region)
Aug 2026· Neurology, neuropsychiatry, Psychosomatics· Vol 18, pp. 18-24· 0 citations· 33 references
TL;DR
The findings confirm the significant role of polymorphisms in the IL6, SIRT1 and MMP9 genes as potential genetic markers of an increased risk of developing MS and NMOSD in the studied population.
Abstract
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) have a complex aetiology resulting from the interaction of genetic predisposition and environmental factors. Analysis of single nucleotide polymorphisms (SNPs) in genes associated with the immune response and neurodegenerative diseases plays a key role in elucidating the mechanisms underlying the development of these conditions, identifying population-level predispositions and discovering new targets for therapeutic intervention.
Objective:
to determine the frequency of SNPs in genes involved in immune responses and neurodegenerative processes among patients with MS and NMOSD, using the Yaroslavl Region as a case study.
Material and methods.
This cross-sectional, single-centre observational study included 10 patients with NMOSD (AQP4-IgG+), 63 patients with MS and 47 clinically healthy volunteers, who formed the control group. Genotypes for nine SNPs (IL6, IL6ST, CNTF, SOD2, SIRT1, TP53, PER2, MMP9) were determined using the FastPCR method. Statistical analysis of the data included descriptive statistics, as well as the c2 test and calculation of the odds ratio (OR) with a 95% confidence interval.
Results.
Significant associations (p<0.05) were identified between carriage of certain alleles/genotypes and the presence of MS and/or NMOSD in the study population. The homozygous G/G genotype of the IL6 C174G polymorphism (rs1800795) was associated with an increased risk of disease (OR=4.00). An association was demonstrated between the minor allele A of the CNTF gene (rs1800169) and NMOSD. Carriage of the alternative allele T of the SOD2 C47T gene (rs4880) was less common in patient groups (OR=0.24). A strong association was identified between the minor allele G of the SIRT1 C(-1411)G gene (rs7069102) and the risk of both diseases (OR=16.45). Heterozygous A/G status of the PER2 A1984G (rs6343159) gene and the homozygous G/G genotype of the MMP9 A249G (rs17576) gene were also significantly more common in MS and NMOSD.
Conclusion.
The findings confirm the significant role of polymorphisms in the IL6, SIRT1 and MMP9 genes as potential genetic markers of an increased risk of developing MS and NMOSD in the studied population. The findings regarding the associations between SNPs in the SOD2, CNTF and PER2 genes and these diseases are new for this population and require further investigation in a larger sample, particularly for the NMOSD group.
Multiple sclerosis (MS) is a chronic T-cell-mediated neurological disease, where the immune system mistakenly attacks the protective myelin sheath around axons in the central nervous system, which leads to progressive neurological impairment. It is a multifactorial disease combining genetic, environmental and immunological factors. The aim of the present study is to explore the association between the single nucleotide polymorphisms (SNPs) rs1544410 (BsmI) of the vitamin D receptor (VDR) gene and rs1520333 of the Interleukin-7 (IL7) gene and genetic susceptibility to MS in the Tunisian population. In a case-control study involving 90 MS patients and 80 healthy controls (HC), genotyping of these polymorphisms was performed using Polymerase Chain Reaction (PCR) followed by automatic sequencing. Allelic and genotype frequencies of rs1544410 and rs1520333 were compared between MS patients and HC, and the differences were not significant (p > 0.05). Also, the calculated odds ratios (OR) did not demonstrate any risk or protective genotype or allele (p(OR) > 0.05) for the studied SNPs. Our findings indicate that rs1544410 of VDR and rs1520333 of IL7 show no significant association with MS susceptibility, suggesting that these variants are unlikely to serve as useful diagnostic markers in the Tunisian population, although this does not exclude a potential involvement of the VDR and IL7 pathways through other mechanisms.
Faten Alaya, Afef Achouri, Hela Jamoussi et al.· The Egyptian Journal of Neur...· 0 citations
Vitamin D has significant effects on neurofibroma development in patients with neurofibromatosis type 1 (NF1). Additionally,
vitamin D receptor
(
VDR
) gene polymorphisms are associated with various cancers.
This study aimed to determine the correlation between NF1 and the serum vitamin D level, along with the
VDR
single nucleotide polymorphisms (SNPs)
Fok1, Bsm1, Taq1, Apa1
, and
Cd × 2
.
This observational study included 64 patients with NF-1 and 64 age- and gender-matched controls. The serum 25(OH) D3 level was measured, and 5
VDR
SNPs were analysed.
The median serum 25(OH) D3 level was lower in the NF1 patients than in the controls (
P
< 0.001). Heterozygous and mutant type
FokI
and
TaqI
polymorphisms decrease the risk of NF1, whereas mutant and heterozygous
ApaI
polymorphisms increase the risk of NF1. The primary limitation of this study is its small population. Extrapolation of the present findings to the general Turkish population may not be valid. Causality was not assessed due to case-control design of the study.
The findings indicate that some alleles of
FokI, ApaI
, and
TaqI
nucleotides are strongly associated with NF1. Additionally, there is a possible role for vitamin D and
VDR
gene SNP pathways in the pathogenesis of NF1.
Neslihan Akdoğan, T. Çandar, E. Karabulut et al.· Indian Journal of Dermatolog...· 0 citations
Abstract Objectives Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a significant genetic component, often linked to disruptions in the serotonergic system. The HTR2A gene, specifically the rs6313 (102T>C) polymorphism, is a primary candidate for investigating ASD susceptibility. The aim of this study is to investigate the association of rs6313 polymorphism with susceptibility to ASD in the Jordanian population. Methods In this case-control study, 99 Jordanian children with ASD and 109 neurotypical controls were genotyped using PCR-RFLP. Genotype and allele frequencies were analyzed under multiple genetic models. Results No statistically significant differences were found between cases and controls regarding genotype (p=0.54) or allele frequencies (p=0.3284). The distribution adhered to Hardy-Weinberg equilibrium in both groups. Conclusions Our findings suggest no significant association between the HTR2A rs6313 and ASD susceptibility in the Jordanian population. These results emphasize the need for larger, multi-marker studies to account for regional genetic diversity.
Wiam Khalil, Elaf Adel Al-Dalabeeh, M. Zihlif· Drug Metabolism and Personal...· 0 citations
Background: Granulomatosis with polyangiitis (GPA) is an autoimmune disorder that results from an interplay of genetic factors and environmental influences. We investigated the association between two polymorphisms in the VEGF gene, specifically rs2010963 and rs833061, and the likelihood of developing GPA. Methods: A case-control study involving 224 participants was conducted, comprising 104 individuals diagnosed with GPA and 120 control subjects. The high-resolution melting (HRM) technique was employed for genotyping these polymorphisms. Results: The findings revealed a significant difference in the distribution of the CC genotype and C allele for rs2010963 between the control and case groups (CC vs GG; OR: 2.687; 95% CI [1.185-6.264], P: 0.014; C vs G; OR: 1.628; 95% CI [1.097-2.421], P: 0.012). Moreover, patients with the GC + CC genotype exhibited elevated mean levels of creatinine, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), as well as a higher incidence of alveolar hemorrhage compared to those with the GG genotype. Concerning rs833061, no association with GPA risk was identified; however, correlations were noted with certain laboratory and clinical parameters, including PR3-ANCA levels, septal perforation, alveolar hemorrhage, renal involvement, and rapidly progressive glomerulonephritis (RPGN). Conclusion: The C allele of rs2010963 is linked to an increased risk of developing GPA and certain laboratory and clinical parameters, while the rs833061 polymorphism does not appear to be associated with GPA risk but is correlated with various laboratory and clinical indices.
Amirali Pourebrahimi, Mozhdeh Saghaei, Naeim Ehtesham et al.· Caspian Journal of Internal...· 0 citations
INTRODUCTION
To evaluate the causal effects of circulating inflammatory proteins on the development of Multiple Sclerosis (MS) and to discover potential therapeutic targets for the disease.
METHODS
Two-sample Mendelian randomization analysis was used to evaluate causal relationships between levels of 91 inflammatory proteins in serum and the risk of MS. For each circulating protein, genetic variation data were from a genome-wide association study of 14,736 individuals of European ancestry. The MS dataset included 47,429 cases and 68,374 controls. Additional sensitivity, colocalization, functional enrichment, and protein-protein interaction analyses were performed to assess the robustness and biological relevance of the findings. Soluble proteins causally associated with MS were assessed for their therapeutic target potentials using the Drug-Gene Interaction Database.
RESULTS
The analysis identified 9 circulating inflammatory proteins with nominal evidence of association with MS risk. Among them, CD40 (Odds Ratio [OR]: 0.907) and VEGFA (OR: 0.971) appear protective, while IL1A (OR: 1.139), CD6 (OR: 1.047), TNF (OR: 1.058), LIF-R (OR: 1.052), CCL25 (OR: 1.032), CD244 (OR: 1.057) and CXCL10 (OR: 1.061) were associated with higher risks of MS. After correcting for multiple testing, associations with MS risks remained significant only for CD40. Supportive analyses highlighted immune- and inflammationrelated pathways, particularly cytokine signaling, as mediators of the risks of MS. Six circulating proteins were identified as candidates in an exploratory assessment of druggability.
DISCUSSION
These results offered new insight into the inflammatory landscape of MS, reinforcing the pathogenic relevance of immune signaling pathways. The robust statistical significance of CD40 highlighted it as a primary candidate for further investigation, while the additional eight proteins provided a foundation for future hypothesis-generating studies. While the findings strengthened the biological plausibility of inflammation-driven disease mechanisms, the presence of nominal significance and potential pleiotropy for certain markers necessitated a cautious interpretation.
CONCLUSION
Genetic evidence linking inflammatory proteins to MS pathogenesis was uncovered, offering clues for novel therapeutic targets for this condition.
Runyang Xu, Ancha Baranova, H. Cao et al.· Current Neurovascular Resear...· 0 citations
Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), encoded by TNFRSF13B, plays a central role in B cell maturation and antibody responses through its interactions with BAFF and APRIL, with variants being linked to common variable immunodeficiency (CVID) and selective IgA deficiency. To characterise the clinical, immunological and genetic spectrum of these individuals, we recruited 30 participants (21 patients and nine family members) and classified patients into Group 1 (n = 16), carrying only TACI variants and Group 2 (n = 5), carrying both an IEI-related variant and an additional TACI variant. With a male/female ratio of 12/9, the median age was 2 years at symptom onset and 14 years at genetic diagnosis. Common clinical manifestations included recurrent infections (90%), autoimmune/inflammatory features (62%) and lymphoproliferation (57%). Twelve distinct TNFRSF13B mutations were identified, predominantly clustering in the cysteine-rich domain 2 (CRD2), with Cys104Arg being the most frequent (57%) variant. Immunophenotyping revealed decreased switched-memory and marginal zone B cells, reduced naïve CD4+ T cells and increased effector memory subsets. Notably, clinical and laboratory features overlapped between Groups 1 and 2, as well as between monoallelic and biallelic TNFRSF13B variant carriers. Patients with TNFRSF13B variants display broad phenotypic heterogeneity ranging from asymptomatic carriage to CVID and combined immunodeficiency phenotypes. Given the high polymorphism ratio and incomplete penetrance observed, TACI acts as both a genetic modifier and a monogenic disease-causing gene in this cohort, suggesting that coexisting genetic variants and exposomal factors likely determine the clinical expression and disease severity.
Begum Cicek, Deniz Ilgun Gurel, Ismail Yaz et al.· Immunology· 0 citations