LncRNA <Emphasis Type="Italic">ANRIL</Emphasis> Expression and <Emphasis Type="Italic">ANRIL</Emphasis> Gene Polymorphisms Contribute to the Risk of Ischemic Stroke in the Chinese Han Population

The aim of the present study was to explore the role of lncRNA ANRIL in the pathogenesis of ischemic stroke (IS) and coronary artery disease (CAD) and to determine the association between ANRIL variants and the genetic susceptibility of IS and CAD in the Chinese Han population. A genetic association study including 550 IS patients, 550 CAD patients, and 550 healthy controls was conducted. The expression levels of lncRNA ANRIL, CDKN2A, and CDKN2B were detected using qRT-PCR. Genotyping was performed by Sequenom MassARRAY on an Agena platform. Our study showed that IS patients had an increased lncRNA ANRIL expression (P?=?0.002) and a decreased CDKN2A expression (P?<?0.001) compared with normal controls. A significant difference with regard to the genotype distribution of rs2383207 was found between male IS patients and controls (P?=?0.011). The minor allele of rs2383207 significantly increased the IS risk under a recessive model (OR?=?1.52, 95% CI?=?1.05–2.21, P?=?0.027). The minor allele of rs1333049 was significantly associated with the risk of IS among the male patients under a recessive model (OR?=?1.56, 95% CI?=?1.04–2.35, P?=?0.031). However, no significant association was found between the ANRIL variants and the risk of CAD (all P?>?0.050). In addition, we found a decreased lncRNA ANRIL expression in IS patients who carried the GG genotype of rs1333049 compared with IS patients who carried the CC or CG genotype (P?=?0.041). In summary, we found that IS patients had an increased lncRNA ANRIL expression and a decreased CDKN2A expression compared with the controls, which might play an impellent role in pathological processes of IS. The ANRIL variants rs2383207 and rs1333049 were significantly associated with the risk of IS among males but not females in the Chinese Han population.     

Associations of rs3740677 within <Emphasis Type="Italic">GAB2</Emphasis> Gene with LOAD in Chinese Han Population

GRB2-associated binding protein 2 (GAB2) has been identified as a crucial factor in Alzheimer’s disease (AD), and ten common variants within GAB2 have been detected to be associated with AD onset risk in genome-wide association studies (GWAS). Here, we first screened a common locus (rs3740677) in 3′ UTR of GAB2 sequence which is targeted by the miRNA-185 and initiatively explored the probable associations of rs3740677 with risk for late-onset AD (LOAD) in a large scale case–control study from Chinese Han populations (992 LOAD patients and 1358 healthy subjects). Eventually, the genotype (P?=?0.024) and allele (P?=?0.008) distribution of rs3740677 showed significant difference between LOAD and control group, and we observed a significant association of T allele in rs3740677 with LOAD risk in multivariate analysis and it decreased the risk for LOAD (dominant: OR?=?0.831, 95 % CI?=?0.702–0.983, P?=?0.031; additive: OR?=?0.855, 95 % CI?=?0.745–0.983, P?=?0.027) adjusted for age, gender, and APOE ε4 status. Our study further confirmed the association of GAB2 and AD. However, the absolute and correct association of rs3740677 with AD still required more investigations in diverse regions and ethnics.     

Genome-wide association study of <Emphasis Type="Italic">Mycobacterium avium</Emphasis> subspecies <Emphasis Type="Italic">Paratuberculosis</Emphasis> infection in Chinese Holstein

Background

Paratuberculosis is a contagious, chronic and enteric disease in ruminants, which is caused by Mycobacterium avium subspecies paratuberculosis (MAP) infection, resulting in enormous economic losses worldwide. There is currently no effective cure for MAP infection or a vaccine, it is thus important to explore the genetic variants that contribute to host susceptibility to infection by MAP, which may provide a better understanding of the mechanisms of paratuberculosis and benefit animal genetic improvement. Herein we performed a genome-wide association study (GWAS) to identify genomic regions and candidate genes associated with susceptibility to MAP infection in dairy cattle.

Results

Using Illumina Bovine 50?K (54,609 SNPs) and GeneSeek HD (138,893 SNPs) chips, two analytical approaches were performed, GRAMMAR-GC and ROADTRIPS in 937 Chinese Holstein cows, among which individuals genotyped by the 50?K chip were imputed to HD SNPs with Beagle software. Consequently, 15 and 11 significant SNPs (P?<?5?×?10^??5) were identified with GRAMMAR-GC and ROADTDRIPS, respectively. A total of 10 functional genes were in proximity to (i.e., within 1?Mb) these SNPs, including IL4, IL5, IL13, IRF1, MyD88, PACSIN1, DEF6, TDP2, ZAP70 and CSF2. Functional enrichment analysis showed that these genes were involved in immune related pathways, such as interleukin, T cell receptor signaling pathways and inflammatory bowel disease (IBD), implying their potential associations with susceptibility to MAP infection. In addition, by examining the publicly available cattle QTLdb, a previous QTL for MAP was found to be overlapped with one of regions detected currently at 32.5?Mb on BTA23, where the TDP2 gene was anchored.

Conclusions

In conclusion, we identified 26 SNPs located on 15 chromosomes in the Chinese Holstein population using two GWAS strategies with high density SNPs. Integrated analysis of GWAS, biological functions and the reported QTL information helps to detect positional candidate genes and the identification of regions associated with susceptibility to MAP traits in dairy cattle.

     

<Emphasis Type="Italic">EPSTI1</Emphasis> polymorphisms are associated with systemic lupus erythematosus

Epithelial stromal interaction 1 (EPSTI1) is an interferon (IFN) response gene, which was originally identified as a stromal fibroblast-induced gene in breast cancer. Our previous study using a customized SNP chip found evidence of an association between EPSTI1 and susceptibility to the chronic inflammatory disease, systematic lupus erythematosus (SLE). This study aimed to validate whether polymorphisms in EPSTI1 are associated with susceptibility to SLE. We analyzed genotype and allele frequencies of SNPs at EPSTI1 using genomic DNA from 119 patients with SLE and 512 healthy controls. We found that the genotype frequencies of rs1044856 and rs1359184 in patients with SLE were significantly different from those found in the control group (P?=?0.03 and P?=?0.01, respectively). In addition, we found that genotype and allele frequencies of rs1359184 in female patients with SLE were significantly different from those found in female controls (P?=?0.02 and P?=?0.04, respectively). We identified two major haplotypes in EPSTI1 that were significantly different between patients with SLE and healthy controls (P?=?0.01 and P?=?0.05, respectively). Furthermore, we found that rs1359184 and rs1044856 in EPSTI1 were associated with antinuclear antibody (ANA) and erythrocyte sedimentation rate (ESR) levels in patients with SLE (P?=?0.0035 and P?=?0.021, respectively). Our findings indicate that polymorphisms in EPSTI1 are associated with susceptibility to SLE and that haplotypes at EPSTI1 may be useful genetic markers for SLE.     

Haplotype-specific <Emphasis Type="Italic">MAPT</Emphasis> exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders

Background

Genome wide association studies have identified microtubule associated protein tau (MAPT) H1 haplotype single nucleotide polymorphisms (SNPs) as leading common risk variants for Parkinson’s disease, progressive supranuclear palsy and corticobasal degeneration. The MAPT risk variants fall within a large 1.8 Mb region of high linkage disequilibrium, making it difficult to discern the functionally important risk variants. Here, we leverage the strong haplotype-specific expression of MAPT exon 3 to investigate the functionality of SNPs that fall within this H1 haplotype region of linkage disequilibrium.

Methods

In this study, we dissect the molecular mechanisms by which haplotype-specific SNPs confer allele-specific effects on the alternative splicing of MAPT exon 3. Firstly, we use haplotype-hybrid whole-locus genomic MAPT vectors studies to identify functional SNPs. Next, we characterise the RNA-protein interactions at two loci by mass spectrometry. Lastly, we knockdown candidate splice factors to determine their effect on MAPT exon 3 using a novel allele-specific qPCR assay.

Results

Using whole-locus genomic DNA expression vectors to express MAPT haplotype variants, we demonstrate that rs17651213 regulates exon 3 inclusion in a haplotype-specific manner. We further investigated the functionality of this region using RNA-electrophoretic mobility shift assays to show differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213 and rs1800547 and subsequently identified candidate trans-acting splicing factors interacting with these functional SNPs sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrate a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.

Conclusions

We identified common splice factors hnRNP F and hnRNP Q regulating the haplotype-specific splicing of MAPT exon 3 through intronic variants rs1800547 and rs17651213. This work demonstrates an integrated approach to characterise the functionality of risk variants in large regions of linkage disequilibrium.

     

Association of <Emphasis Type="Italic">Toll like receptor 2</Emphasis> and <Emphasis Type="Italic">9</Emphasis> gene variants with pulmonary tuberculosis: exploration in a northern Indian population

Tuberculosis (TB) is a disease of global importance. There is an increasing recognition of the role of Toll like receptors, important pattern recognition receptors of host immune system, in determining the susceptibility or resistance to TB in various populations. In an attempt to examine the importance of Toll like receptors in immune response to Mycobacterium tuberculosis infection, we explored two variants each of TLR2 and TLR9 in a population residing in Uttar Pradesh, India. Genotyping was performed to detect -196 to -174 del polymorphism and G2258A SNP (Arg753Gln, rs5743708) in TLR2 gene and -T1237C (rs5743836) and G2848A (rs352140) SNP in TLR9 gene in patients with pulmonary TB and healthy controls. The A allele of G2848A SNP in TLR9 gene was found with a marginally higher frequency among TB patients as compared to healthy controls, suggesting that A allele at position 2848 of TLR9 gene may be associated with susceptibility to TB in North Indian population [p?=?0.05, Mantel–Haenszel OR?=?1.34, 95% CI (1.0–1.82)].     

GWAS-Linked Loci and Neuroimaging Measures in Alzheimer’s Disease

Recently, 19 susceptibility loci for Alzheimer’s disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and β-amyloid (Aβ) deposition on neuroimaging in a large cohort from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aβ deposition. APOE ε4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE ε4) have been detected to be associated with one or a few established AD-related neuroimaging measures.     

Significant association of the <Emphasis Type="Italic">GABRP</Emphasis> polymorphisms with ulcerative colitis patients

The γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the central nervous system. The π subunit receptor of GABA (GABRP) is a transmembrane multi-subunit chloride channel that is expressed in the CNS and several other non-neuronal tissues. The exact function of this gene in non-neuronal tissues is not clearly identified. Our previous customized pilot SNPs chip screens analysis indicated that this gene had strong susceptibility to ulcerative colitis (UC). This study was aimed to validate whether the polymorphisms in the GABRP gene are associated with the susceptibility to UC. The genotype and allele frequencies of the rs929763 rs1063310, rs3805455, rs382819 and rs732157 of the GABRP gene were significantly associated with UC patients. Two haplotype frequencies including a major haplotype of GABRP SNPs were more significantly different between the UC patients and the healthy controls. These results suggest that the polymorphisms in the GABRP gene might be associated with the susceptibility to UC, and the haplotype of GABRP SNPs are useful genetic marker for UC.     

Polymorphisms in <Emphasis Type="Italic">VEGF-A</Emphasis> are associated with COPD risk in the Chinese population from Hainan province

In this study, we examined and validated how common variants contribute to susceptibility to chronic obstructive pulmonary disease (COPD) in the Han Chinese population. Here, we genotyped 18 nucleotide polymorphisms and evaluated their association with COPD using chi-square test and genetic model analysis (246 COPD patients and 350 controls), and found three SNPs that might cause a predisposition to COPD. Both rs3025030 and rs3025033 are located on chromosome 6 in VEGF-A. We found one risk allele ‘C’ from rs3025030 and another ‘G’ from rs3025033 using the log-additive model (OR 1.40; 95% CI 1.05–5.96; P = 0.022), (OR 1.38; 95% CI 1.03–1.84; P = 0.03). We also found another risk allele ‘A’ of rs9296092 in gene region ZBTB9-BAK1 by the allele model (OR 2.63; 95% CI 1.27–5.45; P = 0.0078), (adjusted OR 3.53; 95% CI 1.12–11.11; P = 0.031). We found a risk haplotype ‘CG’ associated with the risk of COPD (OR 1.39; 95% CI 1.04–1.86; P=0.028). Our results when compared with previous studies showed significant association between VEGF-A polymorphism and COPD. We also identified rs9296092 as a risk factor for COPD.     

Association of rs1057035polymorphism in microRNA biogenesis pathway gene (<Emphasis Type="Italic">DICER1</Emphasis>) with azoospermia among Iranian population

Since genes involved in microRNA biogenesis pathways have a main role in impaired spermatogenesis, in this research, we evaluated different genotypes frequency of seven single-nucleotide polymorphisms in DICER1 and DROSHA genes. Different genotypes frequency of DICER1 (rs12323635, rs1057035, rs13078 and rs3742330) and DROSHA (rs10719, rs642321 and rs2291102) were determined by sequencing method in 385 infertile men and 120 fertile controls. It was found that CC genotype (P?=?0.000) and C allele (P?=?0.0) of rs1057035 T?>?C polymorphism were associated with idiopathic male infertility (azoospermia). Gene expression study in blood and testis samples was done by real time PCR technique. Our results showed significant under expression of DICER1 gene in blood and testis tissues of azoospermic samples (P?<?0.05), but we did not observed significant difference in expression ratio between infertile men with and without C allele of rs1057035 SNP (P?>?0.05). The results of this study showed that among the studied variants, only one of them in DICER1 might be associated with azoospermia, but additional studies needs in different populations and ethnics.     

Genome-wide association study of body weight in Wenshang Barred chicken based on the SLAF-seq technology

Chicken body weight (BW) is an economically important trait, and many studies have been conducted on genetic selection for BW. However, previous studies have detected functional chromosome mutations or regions using gene chips. The present study used the specific-locus amplified fragment sequencing (SLAF-seq) technology to perform a genome-wide association study (GWAS) on purebred Wengshang Barred chicken. A total of 1,286,715 single-nucleotide polymorphisms (SNPs) were detected, and 175,211 SNPs were selected as candidate SNPs for genome-wide association analysis using TASSEL general linear models. Six SNP markers reached genome-wide significance. Of these, rs732048524, rs735522839, rs738991545, and rs15837818 were significantly associated with body weight at 28 days (BW28), while rs314086457 and rs315694878 were significantly associated with BW120. These SNPs are close to seven genes (PRSS23, ME3, FAM181B, NABP1, SDPR, TSSK6L2, and RBBP8). Moreover, 24 BW-associated SNPs reached “suggestive” genome-wide significance. Of these, 6, 13, 1, and 4 SNPs were associated with BW28, BW56, BW80, and BW120, respectively. These results would enrich the studies on BW and promote the use of Chinese chicken, especially the Wenshang Barred chicken.     

A functional polymorphism,rs28493229, in <Emphasis Type="Italic">ITPKC</Emphasis> and risk of Kawasaki disease: an integrated meta-analysis

Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case–control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case–control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34?1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P _{heterogeneity} = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.     

Association of the <Emphasis Type="Italic">rs1870634</Emphasis> Variant in Long Intergenic Non-protein Coding RNA 841 with Coronary Artery Disease: A GWAS-Replication Study in an Iranian Population

Recent genome-wide association studies (GWAS) identified a list of single-nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). Replication of GWAS findings in different population corroborated the observed association in the parent GWAS. In this study, we aimed to replicate the association of rs1870634, a GWAS identified SNP, to CAD in an Iranian population. The study population consisted of 267 subjects undergoing coronary angiography coronary angiography including 155 CAD patients and 112 non-CAD age- and gender-matched controls. The genotype determination of rs1870634 SNP performed using high-resolution melting analysis (HRM) technique. Our results revealed that the GG genotype frequency was significantly higher in CAD patients compared with controls (P?=?0.03). The results of binary logistic regression suggested that this genotype was significantly associated with CAD risk adjustment for age, BMI, sex, TC, and LDL-C lipid levels (OR of 2.78, 95% CI (1.10–7.01), P?=?0.03). Moreover, our results showed that the GG+TG genotypes were 2.52 times more likely to develop CAD (95% CI 1.05–6.03) than TT genotype carriers after adjusting for age, sex, and lipid profiles (P?=?0.037). These data showed that the GG genotype could be associated with increased risk of CAD in a sample of Iranian population.     

Impact of variants on type-2 diabetes risk genes identified through genomewide association studies in polycystic ovary syndrome: a case–control study

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, and is associated with altered metabolic processes in particular insulin resistance and diabetes mellitus. PCOS shares with type-2 diabetes (T2D) a number of features, including beta cell dysfunction, impaired glucose tolerance and dyslipidaemia. Recently, genomewide association studies (GWAS) have reported a number of genes with reproducible associations and susceptibilities to T2D. To address this, we examined the association between the T2D GWAS candidate genes (CDKAL1, CDKN2B, COL8A1, HHEX, IGF2BP2, KCNJ1, KCNQ1 and SLC30A8) and PCOS in Saudi women. A case–control study, includes 162 cases and 162 controls was enrolled. Genotyping was carried out by the allelic discrimination method. Our results showed that the variants including rs792837 of COL8A1, rs61873498 of KCNQ1 and rs13266634 of SLC30A8 genes to be significantly more frequent in PCOS patients than in controls. Our results suggest that COL8A1, KCNQ1 and SLC30A8, which are previously identified through GWAS as T2D-associated genes, are associated with PCOS.     

Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma

Background

We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype.

Methods

We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped.

Results

In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P?=?0.001–0.004, OR?=?0.59–0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P?=?0.033), but the other four SNPs in hapblock2 were not.

Conclusion

To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition.

     

<Emphasis Type="Italic">PPARGC1B</Emphasis> gene is associated with Kashin-Beck disease in Han Chinese

Kashin-Beck disease (KBD) is a chronic osteochondropathy. The genetic basis of KBD remains elusive now. To investigate the relationship between PPARGC1B gene polymorphism and KBD, we conducted a two-stage association study using 2743 unrelated Han Chinese subjects. In the first stage, three SNPs rs1078324, rs4705372, and rs11743128 of PPARGC1B gene were genotyped in 559 KBD patients and 467 health controls using Sequenom MassARRAY platform. In the second stage, the association analysis results of PPARGC1B with KBD were replicated using an independent sample of 1717 subjects. SNP association analysis was conducted by PLINK software. Genotype imputation was conducted by IMPUTE 2.0 against the reference panel of the 1000 genome project. Bonferroni multiple testing correction was performed. We observed a significant association signal at rs4705372 (P?=?0.0160) and a suggestive association signal at rs11743128 (P?=?0.0290). Further replication study confirmed the association signals of rs4705372 (P?=?0.0026) and rs11743128 (P?=?0.0387) in the independent validation sample. Our study results suggest that PPARGC1B is a novel susceptibility gene of KBD.     

Genetic variants influencing lipid levels and risk of dyslipidemia in Chinese population

Recently, several human genetic and genomewide association studies (GWAS) have discovered many genetic loci that are associated with the concentration of the blood lipids. To confirm the reported loci in Chinese population, we conducted a cross-section study to analyse the association of 25 reported SNPs, genotyped by the ABI SNaPshot method, with the blood levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in 1900 individuals by multivariate analysis. Logistic regression was applied to assess the association of the genetic loci with the risk of different types of dyslipidemia. Our study has convincingly identified that 12 of 25 studied SNPs were strongly associated with one or more blood lipid parameters (TC, LDL, HDL and TG). Among the 12 associated SNPs, 10 significantly influence the risk of one or more types of dyslipidemia. We firstly found four SNPs (rs12654264 in HMGCR; rs2479409 in PCSK9; rs16996148 in CILP2, PBX4; rs4420638 in APOE-C1-C4-C2) robustly and independently associate with four types of dyslipidemia (MHL, mixed hyperlipidemia; IHTC, isolated hypercholesterolemia; ILH, isolated low HDL-C; IHTG, isolated hypertriglyceridemia). Our results suggest that genetic susceptibility is different on the same candidate locus for the different populations. Meanwhile, most of the reported genetic variants strongly influence one or more plasma lipid levels and the risk of dyslipidemia in Chinese population.     

Analysis of <Emphasis Type="Italic">ICAM1</Emphasis> 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.