Alzheimer's Disease Risk Variant rs3865444 in the CD33 Gene: A Possible Role in Susceptibility to Multiple Sclerosis.

Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer's disease-linked variant rs3865444:C>A in the CD33 gene and MS risk, (2) assess the effect of the strongest MS risk allele HLA-DRB1*15:01 on this association, and (3) analyze the correlation of rs3865444 with selected clinical phenotypes, i.e., age of onset and disease severity. CD33 rs3865444 was genotyped in a cohort of 579 patients and 1145 controls and its association with MS risk and clinical phenotypes was analyzed by logistic and linear regression analysis, respectively. Statistical evaluation revealed that rs3865444 reduces the risk of MS in the HLA-DRB1*15:01-positive subpopulation but not in the cohort negative for HLA-DRB1*15:01. A significant antagonistic epistasis between rs3865444 A and HLA-DRB1*15:01 alleles in the context of MS risk was detected by the interaction synergy factor analysis. Comparison of allele and genotype distribution between relapsing-remitting MS, secondary progressive MS, and control groups revealed that rs3865444 C to A substitution may also be associated with a decreased risk of transition of MS to its secondary progressive form, irrespective of the HLA-DRB1*15:01 carrier status. On the other hand, no correlation could be found between rs3865444 and the age of disease onset or MS severity score. Future studies are required to shed more light on the role of CD33 in MS pathogenesis.

Neurofilament light chain and MRI volume parameters as markers of neurodegeneration in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is considered a major marker of neurodegeneration and disease activity. Higher levels of NfL are associated with worse clinical outcomes and increased brain atrophy. In treated patients with Relapsing-Remitting Multiple Sclerosis (RRMS), we aimed to determine the level of NfL, an association between NfL and demographic, clinical and magnetic resonance imaging (MRI) characteristics as well as brain volume parameters. We wanted to confirm that level of NfL is clinically useful as biomarker of neurodegeneration and disease activity. METHODS: 56 treated RRMS patients were enrolled. Plasmatic levels of NfL (pNfL) were measured by SIMOA® technique. Clinical severity of MS was expressed by Expanded Disability Status Scale (EDSS), and volumetric analysis of MRI data was performed using Icobrain software. RESULTS: The mean pNfL level was significantly higher in MS patients than in healthy controls (14.73 ± 6.38 versus 6.67 ± 3.9, p<0.001). In patients, we did not find association between pNfL and MRI activity, number of new T2 lesions, and number of enhancing lesions. Levels of pNfL correlated significantly with atrophy of whole brain volume (Wbv), atrophy of grey matter volume (Gmv), and negatively with Wbv. We found significantly positive correlation between pNfL levels and EDSS. CONCLUSION: Study shows association of pNfL with Wbv, presence of brain atrophy and EDSS, and strong correlation of EDSS with multiple MRI volume parameters. We did not confirm association pNfL with disease activity. Our data suggest that pNfL and MRI volume parameters could be considered as biomarkers of neurodegeneration in MS.

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population.

Tumour necrosis factor (TNF)-mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction-restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23-2.12), irrespective of sex and carriage of the major MS risk allele HLA-DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71-2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex- and HLA-DRB1*15:01-independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation.

Analysis of ICAM1 gene polymorphism in Slovak multiple sclerosis patients.

Infiltration of immune cells into CNS is one of the essential events in multiple sclerosis (MS) development. Adhesion molecules like the intercellular adhesion molecule 1 (ICAM-1) play critical role in this process. Therefore, the ICAM1 gene containing two important single-nucleotide polymorphisms (SNPs) belongs to candidate loci with possible involvement in MS susceptibility and/or severity. The objective of our case-control study was to analyze the association of two functional ICAM1 polymorphisms rs1799969 (or G241R) and rs5498 (or K469E) with susceptibility to MS and evaluate their influence on the age at disease onset, severity, neurological disability and progression rate. Two hundred forty-eight MS subjects (mean 39.2 years) and 208 age-matched controls (mean 35.6 years) were involved in the study. Genotyping of ICAM1 rs1799969 and rs5498 SNPs was performed by PCR-RFLP. Presence of the rs3135388 polymorphism tagging the major MS risk allele HLA-DRB1*15:01 allele was determined as well. Our analysis revealed no statistically significant association of ICAM1 polymorphisms with risk of MS development in the Slovak population. Stratification of study cohorts by gender, age at onset and presence of the HLA-DRB1*15:01 risk allele showed only moderate changes. Correlation of clinical findings as age at onset, Kurtzke Expanded Disability Status Scale, Multiple Sclerosis Severity Score and progression index with ICAM1 genotypes in MS patients revealed no significant association; however, patients with earlier onset of MS showed slightly higher frequencies of the homozygous G allele at rs5498 in comparison to other genotypes (P = 0.04), suggesting that GG carriers tend to induce MS at an earlier age.

The +190 G/A (rs1799864) polymorphism in the C-C chemokine receptor 2 (CCR2) gene is associated with susceptibility to multiple sclerosis in HLA-DRB1*15:01-negative individuals.

C-C chemokine receptor 2 (CCR2) is one of the key players involved in the transmigration of mononuclear cells into the central nervous system (CNS) and subsequent development of multiple sclerosis (MS). The aim of the current study was to analyse the association of CCR2 +190 G/A (rs1799864) polymorphism with susceptibility to MS and its influence on the age at onset, severity and neurological disability in MS. CCR2 genotyping was carried out by a polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) in 301 MS patients and 342 healthy controls. Logistic regression analysis suggested a marginally significant association between MS and rs1799864 A allele (AA+GA vs. GG, P=0.047, OR=1.50, 95% CI=1.00-2.25), however, after stratification of study groups for the presence of HLA-DRB1*15:01 risk allele, this association could be found in HLA-DRB1*15:01-negative individuals only (AA+GA vs. GG, P=0.014, OR=1.84, 95% CI=1.13-2.98). Furthermore, there was no association between CCR2 polymorphism and clinical features of MS. In conclusion, our results suggest that CCR2 +190 G/A polymorphism may increase the susceptibility to MS, but its action seems to be restricted to individuals who do not possess the major risk allele HLA-DRB1*15:01.