|Year : 2016 | Volume
| Issue : 2 | Page : 77-83
Remarkable achievements in multiple sclerosis
Selvarasu Vaitheeshvaran, Manickam Agaath Hedina
Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
|Date of Web Publication||7-Jul-2016|
Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Multiple sclerosis as a demyelinating disease is characterized by divergent clinical symptoms in the central nervous system. To date, its etiology is still indefinite. Out of the human leukocyte antigen (HLA) region, there are different aspects contributing to multiple sclerosis. Some genome-wide association studies have shown several non-HLA genes play a major role in multiple sclerosis. Additionally, a few single nucleotide polymorphisms in non-HLA genes are likely to be predisposing markers for multiple sclerosis, including rs6897932 in IL7RA, and rs2104286, rs12044852 in IL2RA and CD58 genes, respectively. However, the exact region in the mitochondria is still now indefinite. Given that relevant studies are mostly from Europe, further investigation in different cohorts throughout the world is warranted.
Keywords: multiple sclerosis; SNP; IL2RA gene; IL7RA gene; CD58 gene
|How to cite this article:|
Vaitheeshvaran S, Hedina MA. Remarkable achievements in multiple sclerosis. Clin Trials Degener Dis 2016;1:77-83
| Introduction|| |
Multiple sclerosis (MS) is a demyelinating disease in the central nervous system, as accompanied by various clinical symptoms in different stages, including balance problems, weakness, blurred vision, muscle weakness, fatigue, and dizziness. Initial symptoms are commonly one or more as follows: diminished dexterity, monocular visual loss, double vision (diplopia), ataxia, gait instability. With the disease progression, bladder dysfunctions, fatigue, heat sensitivity will happen in common. Impaired attention, memory loss, problem solving difficulties will occur at the advanced stage, and especially, 60% patients can experience depression (Hauser and Oksenberg, 2006). Nowadays, it brings about heavy social and economic burdens (Farjam et al., 2015).
MS is a noteworthy physical and cognitive disability that usually affects young adults (Goris et al., 2012). MS belongs to a multifactorial disorder, due to the interaction of environmental and genetic factors (Hoffjan and Akkad, 2010). The shared genetic factors mainly include increased familial risk, half and step siblings, rather than lifestyle factors (Ebers et al., 1995, 2004; Dyment et al., 2006).
Environmental factors associated with MS incidence include childhood obesity, low vitamin D level, Epstein Barr Virus infection, smoking (Housley et al., 2015). MS exhibits a relatively high incidence in high latitude regions and northern European populations (1/400), which affects over 2.5 million people (2 to 160/100,000) worldwide and approximately 4,00,000 people from USA (Compston and Coles, 2008). Genome-wide association studies have identified over 100 variant genes associated with this disease (Ingram et al., 2009). therefore, MS is classified into the four subtypes: (1) primary progressive MS (PPMS); (2) relapsing-remitting MS (RRMS); (3) secondary-progressive MS (SPMS); and (4) progressive-relapsing MS (PRMS).
PPMS is characterized by steady, constantly developing symptoms with minor attacks, and RRMS defined by clear attacks of new or increasing neurologic dysfunctions. With the progression of RRMS, SPMS is likely to occur with continuous symptoms. PRMS refers to a pattern of relapses within PPMS, defined as steadily worsening neurologic function. Almost 85% of MS patients have the relapsing-remitting form of MS, and approximately half of them will progress to SPMS (Raphael et al., 2015). In addition, 20% of MS patients are diagnosed with PPMS (Witte et al., 2014).
Numerous studies have been done on interleukin 7 receptor alpha chain (IL7RA), interleukin 2 receptor alpha chain (IL2RA), CD58 genes and mitochondrial DNA in MS. Here, we review the results of significant single nucleotide polymorphisms (SNPs) in those genes in different cohorts. Because SNP is a genetic marker in divergent population studies, as well as a successful marker tool for different diseases, such as type 1 diabetes mellitus, Crohn's disease and systemic lupus erythematosus (Ogura et al., 2001; Prokunina et al., 2002; Florez et al., 2003).
| IL7RA|| |
Interleukin 7 (IL-7) is a tissue-derived cytokine, monomer in structure, which has a 25 kDa molecular weight, total weight of 152 amino acids. It is produced by stromal tissues, epithelial cells in the thymus and bone marrow, including B cells, monocytes, keratinocytes. IL-7 contributes to the proliferation and development of B cells and T cells. Target cells of IL-7 are developing B and T lymphocytes, mature T cells, and NK cells (Fry and Mackall, 2002). IL-7 is expressed in lymphoid cells during cell development and maturation. IL-7 has two receptors, respectively, IL7R and soluble IL7R. IL7R consists of two receptor chains, the IL7RA (also known as CD127) and the common gamma chain (CD132) (Hofmeister et al., 1999). IL7RA belongs to type I cytokine receptor family that is encoded by the IL7RA gene (Akdis et al., 2011). IL7R gene is a SNP on chromosome 5p13 that exerts some vital roles in development, maturation, and homeostasis of T and B cells in the immune system (Fry and Mackall, 2002). Approximately 30 years later, IL7RA was identified as the initial non-major histocompatibility complex (non MHC) in MS susceptibility loci in different populations (Zuvich et al., 2010). Studies have shown IL7RA as a susceptible gene for MS (Weber et al., 2008; Baranzini et al., 2009; Kallio et al., 2009; Sombekke et al., 2011).
IL7RA gene has been shown to be associated with MS in different cohort studies reported from 1999 till today. Booth et al. (2005) showed that rs6897932 leads to the exon 6 skipping in IL7RA, finally resulting in the augment in the production of soluble form of IL7Rα for the persons who having the risk allele. But rs11567686 might manipulate the expression of IL7Rα (Haj et al., 2015). SNP rs11567686 and SNP rs11567685 located in 449 bp and 504 bp from start codon on the promoter of IL7RA gene illustrated optimistic association with MS, which has been already reported. The studies clarified that three SNPs in IL7RA gene can influence the expression of this disease (Booth et al., 2005).
Teutsch et al. (2003) was found DRB1*1501-positive in MS patients, and identified 11 novel SNPs, however, with no statistical significance. A study by Zhang et al. (2005) recruited 672 MS patients and 672 controls, in which, 66 genes identified for 123 SNPs. On the basis of regions related to other autoimmune diseases, chromosomes 5, 7, 12, 17, 19 were selected (Becker et al., 1998; Oksenberg et al., 2001). rs987107, rs987106, rs3194051 from IL7R showed a moderate risk in the immune system in MS patients (Zhang et al., 2005). Gregory et al. (2007) confirmed rs987106 in intron 6 was a bit significant for the initiation of previous study from IL7R, and they found rs6897932 was significant in the IL7RA gene. However, they proved rs6897932 determined by the functional effect in MS patients. Zuvich et al. (2010) studied 2,961 samples (1,479 cases and 1,482 controls), even though one SNP in IL7 (rs2587156) came close (P value = 2.46 × 10-5 ). Interestingly, the reported rs6897932 in IL7RA, having the risk allele C, is actually less common in Australian MS patients (0.751) than controls (0.758) (Rubio et al., 2008).
But association with rs6897932 in the IL7RA gene is likely to induce the susceptibility of the disease (Zuvich et al., 2010). However, rs6897932 indicates the strongest association among different SNPs in IL7RA through divergent cohorts (Teutsch et al., 2003; Zhang et al., 2005; Gregory et al., 2007; Lundmark et al., 2007; Ramagopalan et al., 2007; Alcina et al., 2008; Akkad et al., 2009).
| IL2RA|| |
Gillis and Smith (1977) and Morgan et al. (1976) showed the proliferation of antigen-activated T cells was induced by the activated T cells, which contain mediators in culture media. Kasakura and Lowenstein (1965) and Gordon and MacLean (1965) found a soluble mitogenic factor in the culture media. In the following years, it had become clear, that a single protein was accountable for this cause, and that factor was called as interleukin-2 (IL-2). IL-2 is a monomer that contains 133 amino acids with a weight of 15.5 kDa (Wang et al., 2009). It can bind to the IL-2R, whose function in autoimmunity control is consistent (Cavanillas et al., 2010).
The IL2R contains three subunits: IL-2Ralpha, IL-2Rbeta, and the common gamma-chain. Il-2Ralpha contains two sushi domains (Malek, 2008). Studies from Rubio et al. (2008) showed rs2104286 in IL2RA gene in chromosome 10p15, in the first intron, was associated with MS. In the Australian population, three genes were selected for the study, KIAA0350, IL2RA and CD58. Among 42 SNPs passing in the IL2RA gene, rs12722605 and rs791589 were nominally associated with the MS (Perera et al., 2009). Cavanillas et al. (2010) genotyped some SNPs, but the signal of association was found for rs6822844. Therefore, a similar scenario involving IL-2 in MS risk seems to emerge.
A recent study from Ainiding et al. (2014) analyzed rs2104286, rs12722489, rs7090512 in IL2RA gene, in Japanese patients with MS, although IL2RA modified the disease activity of the female MS patients instead of being a genetic risk factor in MS patients. Only few studies concluded the SNP rs2104286, rs12722489 might be MS markers.
| Both il2ra and il7ra gene|| |
Weber et al. (2008) showed in the German and French cohorts, MS is associated with SNPs rs12722489, rs2104286 in IL2RA, and rs6897932 in an IL7RA gene in different odds ratios from 1.1 to 1.5. Based on the odds ratio they concluded SNPs in IL2RA and IL7RA, are modest in huge number of divergent studies, and also further perspective studies about these will make a clear path in MS susceptibility locus. In 2007, Genome-Wide Association Studies proved SNP rs12722489 from IL2RA, SNP rs6897932 from IL7RA as susceptible genes in MS (Ramagopalan et al., 2007). In the meantime, another independent replication in a Canadian population exhibited an association of IL2RA with MS susceptibility.
Akkad et al. (2009) studied five nucleotide polymorphisms in IL7RA and four in IL2RA gene. But PPMS and SPMS patients only indicate the IL7RA gene polymorphisms. The two SNPs rs12722489 and rs2104286 in intron 1 of IL2RA gene were not clearly associated with MS in this cohort. rs1570538, rs2104286, rs12722489, rs1570538 of IL2RA was previously confirmed to be weakly associated with MS, but with an increased statistical significance in an actual extended cohort study. Additionally, no MS-related significant data were found in rs41295061 and rs12722489 (Alcina et al., 2009).
| CD58|| |
CD58 gene encodes a receptor called CD2 that is present in chromosome 1p13, to modify immune recognition and be involved in contacts between cytolytic effectors to target cells, antigen presenting cells to T helper cells (Wang et al., 1999), for signal transduction as well s differentiation and proliferation of T cell. Given these, CD58 shares a critical role (Deckert et al., 1992). Past studies showed a role for CD58 susceptibility shared by some other autoimmune diseases, such as chronic inflammatory polyneuropathies (Van Rhijn et al., 2000). Risk allele from CD58 leads to less CD58 expression, causing dysfunction of regulatory T cells in MS patients through down-regulation of FoxP3 (Bahreini et al., 2010).
The first report from Hafler et al. (2007) by International Multiple Sclerosis Genetics Consortium (IMSGC) showed the association of 14 loci with MS including CD58 gene. Again it is repeated by an Australian cohort study (Rubio et al., 2008). However, the genome wide significance cannot show that relationship (Hoppenbrouwers et al., 2009). SNPs within the first intron of CD58 showing strong linkage disequilibrium are frequently confirmed as genetic markers in MS (De Jager et al., 2009). And rs2300747 is also a best susceptibility allele in the MS patients from the United Kingdom and the United States. In 2007, a study enrolling MS patients from 931 families showed an odd ratio of 1.48 for rs12044852, which is again conformed at replication phase (Hafler et al., 2007). Rubio et al. (2008) found intron 1 of CD58 gene, providing evidence of a predisposing effect for rs12044852.
Another genome-wide association study in 2011 reported an odd ratio of 1.37 in SNP rs2300747. Large-scale IMSGC studies in 2011 and 2013 showed the odd ratios for rs1335532 was 1.22 and 1.29, respectively (International Multiple Sclerosis Genetics Consortium et al., 2011; Kemppinen et al., 2011; Patsopoulos et al., 2011). But the rs2300747 polymorphism was found within the first intron of CD58 and did not have a identified efficient consequence (De Jager et al., 2009).
The strongest genetic association was seen in rs12044852 (odds ratio = 2.13) with DRB1*15 allele more discriminative patients (Hecker et al., 2014) and interferon-β therapy treatment patients in RRMS stage cases (Torbati et al., 2015). rs12044852 was confirmed in enlarged risk allele frequency, with an odd ratio of 2.63 (D'Netto et al., 2009). Hecker et al. (2014) also studied mRNA levels in vivo, but there were no proper method for prognosis of the MS progression. They also concluded the alternative splicing of CD58, revealing the pathophysiology of MS. These achievements indicated rs12044852 from CD58 locus will be a genetic marker of MS.
| Mitochondrial DNA (MTDNA)|| |
Most of eukaryotic cells, as well as human body cells contain mitochondria, an intracellular organelle. Their primary function is to perform oxidative phosphorylation to produce adenosine triphosphate (ATP) in cell for energy (Ruiz-Pesini et al., 2007). mtDNA is a double-stranded DNA, circular in shape, maternally inherited, and different from nuclear DNA. mtDNA, in humans, has 16,569 base pairs in length (Andrews et al., 1999).
The cell contains 100 to 10,000 mitochondria, and each contains 2-10 copies of mtDNA. The two strands of mitochondrial DNA are termed respectively, the heavy (H-strand) guanine rich and light (L-strand), cytosine rich strand (Wiesner et al., 1992). mtDNA contains 37 genes, 28 as H-strand and 9 as L-strand. The mitochondrial tRNA is encoded by 22 genes, including 13 genes encoding polypeptide components of the mitochondrial respiratory chain, 2 genes encoding a 16s rRNA (large ribosomal subunit), and 1 gene encoding a 12s rRNA (small ribosomal subunit) (Keogh and Chinnery, 2015). High-level mtDNA mutation is one of the most important reasons for MS (Witte et al., 2014). Specific mtDNA background might be a factor for optic nerve damage in MS patients (Penisson-Besnier et al., 2001).
The previously identified mtDNA K* haplotype, defined by variants at mtDNA 9055, 10,398 and 14,798, have showed a strong association with MS (Torroni et al., 1996; Kalman et al., 1999). Ban et al. (2008) stated that haplogroup U may be a risk for MS. Haplogroups J, T and X were not particularly associated with MS (Penisson-Besnier et al., 2001). Fourteen mtDNA polymorphisms were studied through the restriction enzyme analysis in the Bulgarian patients who diagnosed with RRMS (Mihailova et al., 2007). The T4216C mutation was positive in 21 out of 58 patients. Given this, base substitution might be a risk factor (Mao and Reddy, 2010). Andalib et al. (2015b) showed no significant statistical difference in the frequency of mtDNAA4917G, mtDNA T4216C variation between the cases and the controls in ND2 gene in the Iranian population. Frequency of G14179A variation in ND6 gene was considerably elevated in the control group compared with the patients, while prevalence of ND1, ND2, ND3, ND4 and ND5 gene variations was considerably elevated in patients than the healthy controls (Poursadegh Zonouzi et al., 2014) (some mtDNA variations shown in [Table 1]). There was no association in G13708A, T14798C mutations and MS (Mihailova et al., 2007). Vogler et al. (2005) found that G866A mtDNA variation in the promoter region, which results in a change in uncoupling protein 2, was related with vulnerability to MS in a German population.
|Table 1: Some previous results in mtDNA variations in multiple sclerosis|
Click here to view
During neuronal death and injury as well as ATP synthesis, the UCP2 prevents the proton passing in to the mitochondria. In this study, different two cohorts were analyzed, including 1,097 MS patients. It indicated the G866A variation in mtDNA was related with MS (P = 0.0015). Also, G4298A mutation was shown as a susceptibility gene in MS (Taylor et al., 1998; Andalib et al., 2013).
Andalib et al. (2015) showed mtDNA G15257A was found in 1 of 100 patients, but mtDNA G15812A was not found in 1 of 100. Their findings were inconsistent with the hypothesis that tRNA(Thr) gene is associated with MS (Mayr-Wohlfart et al., 1996).
| Conclusion|| |
Further investigations on rs12044852 from CD58 gene, rs6897932 from IL7RA gene and rs2104286 from IL2RA gene in MS are warranted, as the pathogenesis of MS is unknown until now. The T4216, G11778A and A4917G variation in mitochondrial genes have been repeatedly in different cohorts, without any specific results. Further exploration in different cohorts throughout the world will provide a new insight into the MS treatment.
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