Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes

ABSTRACTPurpose: The purpose of this study was to evaluate the association of VDR Apa-I, Bsm-I, Fok-I, Taq-I single nucleotide polymorphisms (SNPs) with multiple sclerosis (MS) risk in an Iranian Kurdish population.Materials and methods: A population including of 118 patients and 124 healthy matched controls were recruited to the study. Genotyping of the SNPs was accomplished using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results: The frequency of allele T of Fok-I (P = 0.003) and allele C of Taq-I (P = 0.0003) was significantly different between case and control subjects and showed significant association with risk of MS (OR = 1.84, 95% CI = 1.23–2.76; OR = 1.98, 95% CI = 1.36–2.87, respectively). CT genotype (OR = 1.7, 95% CI = 1.05–2.99) of Fok-I and CC genotype (OR = 2.18, 95% CI = 1.05–4.52) of Taq-I showed a predisposing effect. Combined TT+TC vs. CC for Fok-I (OR = 2.15, 95% = CI 1.29–3.60) and combined CC+TC vs. TT for Taq-I (OR = 2.58, 95% CI 1.51–4.40) were susceptibility genotypes for MS. Apa-I and Bsm-I were not significantly associated with risk of MS (OR < 1, P > 0.05) and any genotypes in any genetic models were not significantly different between cases and controls (P > 0.05).Conclusion: As a result, Fok-I and Taq-I showed significant association with risk of MS, while Apa-I and Bsm-I were not observed to be related to the risk of the disease in this population.

Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

MicroRNAs (miRNAs) are a group of non-coding RNAs that play a role in gene regulation. Due to their possible functional importance, genetic variants within miRNA genes have been recognized as...

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.

To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding.

Background: Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system, and genetic factors play an important role in its susceptibility. The expressions of many inflammatory genes implicated in MS are regulated by microRNA (miRNAs), whose function is to suppress the translation by pairing with miRNA Recognition Elements (MREs) present in the 3' untranslated region (3'UTR) of target mRNA. Recently, it has been shown that the Single Nucleotide Polymorphism (SNPs) present within the 3'UTR of mRNAs can affect the miRNA-mediated gene regulation and susceptibility to a variety of human diseases. Objective: The aim of this study was to analyze the SNPs within the 3'UTR of miRNA inflammatory target genes related to multiple sclerosis. Methods: By DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases, 3'UTR genetic variants were identified in all inflammatory genes associated with MS. Also, miRNA's target prediction databases were used for predicting the miRNA binding sites. Results: We identified 125 SNPs with MAF&gt;0.05 located in the binding site of the miRNA of 35 genes among 59 inflammatory genes related to MS. Bioinformatics analysis predicted 62 MRE-modulating SNPs and 59 MRE-creating SNPs in the 3'UTR of MSimplicated inflammatory genes. These candidate SNPs within miRNA binding sites of inflammatory genes can alter the miRNAs binding, and consequently lead to the mRNA gene regulation. Conclusion: Therefore, these miRNA and MRE-SNPs may play important roles in personalized medicine of MS, and hence, they would be valuable for further functional verification investigations.

Purpose: Polymorphisms in the genes encoding interleukin-23 receptor (IL23R) and the p40 subunit of IL-12/23 (IL12B) have been implicated in multiple sclerosis (MS) risk. However, results of different studies are inconsistent. Our aim was to perform a meta-analysis on this topic. Methods: We assessed two variants (rs10889677 and rs7517847) of IL23R and the A1188C polymorphism (rs3212227) of IL12B. Electronic databases (PubMed, Web of Science and Scopus) were searched for eligible studies published until September 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of association in dominant, recessive, homozygote and allelic comparison models. Results: Seven case–control studies with 2250 MS patients and 2320 controls were included in this meta-analysis. The pooled results showed no association of rs10889677 and rs7517847 with MS risk in any of the genetic models. Although the pooled analysis showed an association between rs3212227 and MS in all study subjects in dominant (OR = 0.81, 95% CI: 0.66–0.99, Ph = 0.480, Pz = 0.044) and allelic comparison (OR = 0.84, 95% CI: 0.72–0.98, Ph = 0.967, Pz = 0.030) models, subgroup analysis based on ethnicity did not suggest an association between rs3212227 and MS risk in Caucasians in any of the genetic models, and there was no association between rs3212227 and MS risk in an Asian group. Conclusions: The IL23R polymorphisms rs10889677, rs7517847, and the IL12B polymorphism rs3212227 are not associated with MS risk.

Lack of association between AQP4 polymorphisms and risk of inflammatory demyelinating disease in a Korean population

Association between IL7 Receptor Alpha (Il7ra) gene rs6897932 polymorphism and the risk of Multiple Sclerosis: A meta-regression and meta-analysis.

BackgroundPrevious studies on the influence of exposure to organic solvents on multiple sclerosis (MS) risk have yielded inconclusive results. AimTo investigate the relationship between exposure to organic solvents and MS...

Multiple sclerosis (MS) is an immune-mediated disorder of central nervous system. It most frequently occurs in young female adults, and the prevalence increases with latitude. So far, over 200 genes, loci and single nucleotide polymorphisms (SNPs) have been linked with MS, although each one contributing only slightly in the overall etiology of the disease. The HLA-DRB1*15:01 haplotype has been shown to have the strongest association with MS occurrence risk in genome-wide association studies (GWAS), while HLA-A*02 has been shown to have a protective effect. The exact etiology of MS is still unclear, but there seems to exist an interplay between genetic burden of an individual, and environmental factors which contribute to MS occurrence such as Epstein-Barr virus (EBV) infection, vitamin D levels, smoking status, and early life obesity. An interaction between HLA-DRB1*15:01 and EBV infection, the strongest environmental risk factor for MS, has been observed. It has been suggested that this interaction is a result of HLA-DRB1*15:01 acting as a coreceptor for EBV, thus providing a pathophysiological explanation connecting environmental with genetic MS risk factors. A recent study including participants from two case-control studies with over 13.000 individuals showed that an interaction exists between sun exposure, vitamin D levels, and HLA-DRB*15:01 carrier status, leading to increased risk of MS in individuals with lower sun exposure, vitamin D deficient, and HLA-DRB*15:01 positive. The interaction of HLA-DRB1*15:01 with smoking has been observed in a meta-analysis, while the same study only showed an interaction of smoking with the absence of HLA-A*02 in a subset of studies. The risk of MS has been shown to vary in obese individuals, with obese individuals with the susceptible genotype (HLA-DRB1*15:01+, HLA-A*02-) having 16x higher odds of having MS compared with non-obese persons with a non-susceptible genotype.&amp;nbsp;

It is unclear whether smoking interacts with different aspects of Epstein–Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case–control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2–0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI − 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004–0.4), but not between past smoking and IM history (AP − 0.06, 95% CI − 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.

Alzheimer's (AD) and other neurological diseases (NDs) cause substantial health-related and economic burdens, but progress toward preventative or ameliorative treatments has been limited. Genome-wide association studies (GWAS) have identified hundreds of risk loci containing single nucleotide polymorphisms (SNPs) that alter ND risk, but >90% of these SNPs are in noncoding regions, which are cell type-specific and difficult to study. To address this limitation, we have combined iPSC-based cell models and functional genomics to pinpoint the causal genes at 10 loci associated with risk for AD and multiple sclerosis (MS). We generated neural progenitors, excitatory neurons, astrocytes and microglia from iPSCs and performed RNA-seq, H3K27ac ChIP-seq and Promoter Capture Hi-C. We compared these data to those from uncultured primary (ex vivo) human brain cells to assess their physiological relevance, and determined global patterns of ND risk SNP enrichments in cell type-specific enhancers. We transduced iPSC-derived microglia-like cells (iMGLs) with a lentiviral sgRNA library targeting AD and MS risk SNPs and performed scRNA-seq to identify altered genes and cellular pathways. iPSC-derived cell types displayed gene signatures and enhancer patterns consistent with their cell identities, with iMGLs displaying the strongest similarity to primary cells. Neuronal and glial cells from both iPSC and primary brain sources show consistent enrichment of ND risk SNPs in cell type-specific enhancers, with microglia showing enrichment of AD and MS SNPs. Enhancer/promoter interactions identified in iMGLs and primary microglia nominated potential target genes of these SNPs, and these predictions were tested by CRISPRi single cell screening. We identified multiple novel AD and MS risk genes, including the transcription factor MAF, which is regulated by both AD and MS risk SNPs, and ELMO1, which we characterize as a novel MS risk gene involved in microglial homeostasis. The combination of iPSC-based cell models and functional genomics allowed for systematic perturbation of AD and MS risk SNPs, revealing previously uncharacterized risk genes linking neuroimmune pathways to disease pathophysiology. Ongoing studies are exploring the role of altered expression levels of MAF, ELMO1 and other screen hits in microglial phenotypes, including effects on neurons and astrocytes in co-culture and organoid systems.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory autoimmune diseases that affect the central nervous system. Several genome-wide and candidate gene studies have identified genetic polymorphisms associated with the risk of MS or NMO. In particular, two recently published studies of meta-analysis in European-origin populations have suggested associations of single-nucleotide polymorphisms (SNPs) in CD6, TNFRSF1A and IRF8 with MS. The aim of our study was to assess the associations between SNPs in these three genes and the risk of inflammatory demyelinating disease (IDD) including MS and NMO. To the best of our knowledge, this is the first time such a study has been performed in an Asian population. A total of 21 SNPs of CD6, TNFRSF1A and IRF8 were genotyped in 178 IDD cases (79 MS and 99 NMO patients) and 237 normal controls in a Korean population. Logistic analyses revealed that one SNP in CD6 (rs12288280, P = 0.04) and three SNPs in TNFRSF1A (rs767455, rs4149577 and rs1800693, P = 0.01-0.03) were associated with NMO. However, there was no association of IRF8 polymorphisms with IDD, including MS and NMO. Using further information from the SNP Function Prediction website, two exonic splicing enhancers (ESEs), including the polymorphic site of rs767455, were predicted to be binding sites for splicing factors (SRp55, SF2/ASF2 and SF2/ASF1). Although additional studies are needed, our findings could provide information regarding the genetic aetiology of IDD in the Korean population.

Self-reported ancestry data for the U.S. population from the 1980 decennial census and multiple sclerosis (MS) risk data derived from a large series of World War II white male veterans with MS and matched controls were aggregated on a state level and analyzed to determine the relationship between ancestry and MS risk. A significant portion of the state-by-state variation in MS risk is explainable statistically by differences in ancestry among state populations, even when geographic latitude is included in analyses. In the main, Swedish and other Scandinavian ancestry is most consistently associated with places with increased MS risk. In some analyses, Italian, French, and (to a lesser extent) Scottish ancestries are also associated with increased risk, whereas English and Dutch ancestries are each associated with decreased risk, but most of these non-Scandinavian correlations may reflect predominantly geography per se. These findings provide evidence that ancestry of the resident population, a confounded measure of genetic susceptibility and cultural environment, is part of the complicated picture of MS as a disease of place.