Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study

Reduced FOXP3+ regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms

BackgroundMultiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown.ResultsConsistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele.ConclusionsOur data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0367-4) contains supplementary material, which is available to authorized users.

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...

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios ( affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.

Cytokine and cytokine receptor genes, including IL2RA, IL7R and IL12A, are known risk factors for multiple sclerosis (MS). Excitotoxic oligodendroglial death mediated by glutamate receptors contributes to demyelinating reactions. In the present study, we screened 368 single-nucleotide polymorphisms (SNPs) in 55 genes or gene clusters coding for cytokines, cytokine receptors, suppressors of cytokine signaling (SOCS), complement factors and glutamate receptors for association with MS in a Spanish-Basque resident population. Top-scoring SNPs were found within or nearby the genes coding for SOCS-1 (P=0.0005), interleukin-28 receptor, alpha chain (P=0.0008), oncostatin M receptor (P=0.002) and interleukin-22 receptor, alpha 2 (IL22RA2; P=0.003). The SOCS1 rs243324 variant was validated as risk factor for MS in a separate cohort of 3919 MS patients and 4003 controls (combined Cochran-Mantel-Haenszel P=0.00006; odds ratio (OR)=1.13; 95% confidence interval (CI)=1.07-1.20). In addition, the T allele of rs243324 was consistently increased in relapsing-remitting/secondary progressive versus primary-progressive MS patients, in each of the six data sets used in this study (P(CMH)=0.0096; OR=1.24; 95% CI 1.05-1.46). The association with SOCS1 appears independent from the chr16MS risk locus CLEC16A.

We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress.

The subunit of IL-23 (IL12B) and its receptor (IL23R) gene single-nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases such as inflammatory bowel disease, psoriasis and ankylosing spondylitis. However, the association studies between multiple sclerosis (MS) and SNPs of IL12B or IL23R gene have been reported with inconsistent results in Caucasian population. These discrepancies prompted us to investigate whether IL12B and IL23R variants are associated with susceptibility to MS in Chinese southern population. In this study, we investigated four SNPs (rs2201841, rs10889677, rs7517847 in IL23R and rs3212227 in IL12B) in 178 MS patients and 221 health controls in southern China using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. There was no difference of genotype or allele distribution of these SNPs between MS patients and controls. No association was found between gene polymorphisms and clinical characteristics in MS patients. Furthermore, haplotypes analysis showed similar distribution of haplotype frequencies in MS patients and controls. Our study showed that the IL12B and IL23R gene SNPs does not seem to be associated with MS susceptibility in Chinese southern population.

Smoking and Risk of Multiple Sclerosis

Multiple sclerosis, also known as sclerosis multiplex, is a chronic autoimmune disease of the central nervous system that occurs in over 2.9 millions individuals worldwide, most commonly in young to middle-aged adults, with a greater prevalence in females than males and in higher latitudes. There are different types of multiple sclerosis, varying in the presence and frequency of relapses and remissions. Various risk factors for the disorder have been identified as well – both modifiable and unmodifiable. Although many remain elusive, there are multiple theories regarding them. The causes of multiple sclerosis are yet to be established but a family history of the disease may increase the risk, and also environmental factors are believed to play a role. This paper focuses on the potentially modifiable factors. The most common theory seems to postulate an association between the disorder and viral infections, especially in individuals with Epstein–Barr virus infection, but also human herpesvirus 6, varicella-zoster virus, cytomegalovirus, or John Cunningham virus. Other risk factors include vitamin D insufficiency, or even its low levels, as multiple sclerosis is more frequent in higher latitudes. Obesity, especially during childhood and adolescence, can also be a risk factor of so-called paediatric-onset multiple sclerosis. Obesity is also linked to a higher severity of multiple sclerosis in adults. Risk factors associated with a potentially lower risk, or even some positive effects, include alcohol and caffeine consumption, as well as smoking and oral tobacco use.

The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

COMORBID PRIMARY HEADACHE: OCCURANCE AND PREVALENCE IN PATIENTS WITH RELAPSING REMITTING MULTIPLE SCLEROSIS

Background: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). Objective: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA-DR15 are associated with NMO or TM. Methods: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. Results: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. Conclusions: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently.

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

Susceptibility to the development of atopic diseases is known to involve genetic factors. Several investigators have reported the interleukin-4 (IL-4) receptor alpha gene to be involved in the development of atopy. Recent study has shown that the R allele of a polymorphism in the IL-4 receptor alpha chain gene (Q576R) to be associated with atopy. The objective of this study was to evaluate the possible role of the IL-4 receptor alpha gene in modulating allergic response and asthma in the Japanese population. We conducted linkage analysis using microsatellite markers flanking the IL-4 alpha receptor gene in 82 families ascertained through asthmatic children. The IL-4 receptor Q576R polymorphism was also genotyped by PCR-restriction fragment length polymorphism analysis. We did not find evidence for linkage of the asthma and atopy phenotypes with the markers D16S298 and D16S403 (P = 0.10 and P = 0.56, respectively, for the atopy phenotype and P = 0.17 and P = 0.60, respectively, for the asthma phenotype). The IL-4 receptor R576 allele was not preferentially transmitted to atopy- or asthma-affected children (chi2 = 1.67, P = 0.24 for atopy and chi2 = 0.91, P = 0.40 for asthma). In addition, the prevalence of the R576 allele among parents with and without atopy was similar, 20 of 81 (24.7%) parents with atopy and 22 of 77 (28.6%) parents without atopy. Our findings indicate that the IL-4 receptor alpha gene does not exert a substantial influence on the inheritance of atopy or asthma in this Japanese population.

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Earlier family linkage studies have identified high-penetrance breast cancer genes, such as BRCA1, BRCA2, and TP53. Moreover, genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, have been associated with moderate breast cancer risk. Recent Genome-wide Association Studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with breast cancer risk. We evaluated whether breast cancer risk is associated with multiple SNPs in DNA damage signaling and repair and immune and inflammatory responses in addition to SNPs identified from GWAS. We hypothesize that targeting critical candidate pathways may yield important information regarding SNP-SNP interactions in breast cancer risk. We selected SNPs from DNA damage signaling and cell cycle control, base excision repair, nucleotide excision repair, double-strand break repair, mismatch repair, and immune and inflammatory responses. We have genotype results of 3,754 SNPs in 910 controls (763 Whites and 147 African Americans) and 793 breast cancer cases (667 Whites and 116 African Americans). 16.2% and 20.6% of controls and cases (respectively) had a first degree relative with breast cancer. 48% and 55.7% of the controls and cases (respectively) had their first child before or at the age of 24. 40.5% and 42.2% of the controls and cases (respectively) had a history of smoking. Our study results suggest that 6 SNPs were associated with breast cancer risk in Whites: (1) 2 SNPs from GWAS - rs3817198 in LSP1 (p<0.001) and rs3803662 in TNRC9 (p<0.001); (2) 2 SNPs from inflammation - rs1801157 in SDF-1 (p<0.001) and rs12720356 in Tyk2 (p<0.001) and (3) 2 SNPs from DNA repair and apoptosis - rs2992 in CHAF1A (p<0.0001) and rs2231301 in BCL2l2 (p<0.001). Only 1 SNP, rs1990760 in IFIH1 (p<0.01) was associated with breast cancer risk in African Americans. The IFIH1 gene was previously linked to Type 1 diabetes but not in cancer risk. There was significant trend in breast cancer risk with increasing numbers of risk genotypes for rs3817198, rs3803662, rs1801157, rs12720356, rs2992, and rs2231301 (p test for trend <0.0001) in Whites after adjustment for potential confounders. Our results suggest that multiple SNPs contribute to breast cancer risk in a racial/ethnic specific manner and larger studies are warranted to further evaluate our findings. More importantly, functional analysis is under way to corroborate the association of multiple SNPs with breast cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2613. doi:1538-7445.AM2012-2613