Gene polymorphisms involved in the etiopathogenesis of MS [3, 44–48].
Abstract
Sclerosis multiplex (multiple sclerosis, MS) is a chronic autoimmune inflammatory disease of the central nervous system. The immune regulatory defects lead to the process of inflammation and neurodegenerationthat results in the deterioration of neurological functions. It is still unclear as to why MS is so devastating and rapidly progressive in one patient and less so in another. It is known that the etiopathogenesis of MS is very complex, and many factors can be involved in the risk and character of the disease and its progression. In this chapter, we discuss the general molecular and cellular mechanisms of action of genetic and biochemical factors that are related to immune system regulation and thus can be connected to the individually varying risk and disability progression of MS. We found that gene variants of the gene polymorphism rs6897932 in interleukin 7 receptor α chain gene rs10735810 in vitamin D receptor gene and HLA-DR and HLA-DQ genes as well as the serum level of vitamin D are associated with MS risk or disability progression in Central European Slovak population.
Keywords
- multiple sclerosis
- risk
- disability progression
- gene polymorphism
- biochemical marker
1. Introduction
In triggering an autoimmune response in multiple sclerosis (MS), environmental factors have a strong effect and interact with complex risk-conferring genetic variants [1–3]. In this process, the myelin reactive Tcells with altered functional characteristics are formed and activated [4]. The immune regulatory defects and increased migration of autoreactive lymphocytes within the brain, that are the typical traits in MS, lead to the process of inflammation, myelin sheath breakdown, demyelination, remyelination, neuronal and axonal degeneration, and subsequent deterioration of neurological functions [5]. Neurodegeneration, neuronal and axonal damage that correlate with the progression of the disease can be a process partly independent from inflammation and demyelination or even can be the cause of demyelination occurring from the disease onset. Axonal damage in MS is a result of many pathological processes [6, 7].
It is still unclear as to why MS is so devastating and rapidly progressive in one patient and less so in another. Because the etiopathogenesis of MS is very complex, disease development as well as the characteristics of disease progression is probably the consequence of multifactorial interaction. Our work is dedicated to genetic and biochemical markers that were chosen according to their possible role in the modulation of the immune response in MS patients and thus could be associated with MS risk and disability progression. In our work, we discuss the immune response-related genetic factors associated with MS that can be generally classified into
2. Immune response-related genetic factors in the risk and progression of multiple sclerosis
MS is a typical gender-dependent disease; a higher risk of MS is observed in women than in men in all populations and races. A study conducted in Canada found female to male ratio in individuals affected by MS to be 3:1 [11]. The risk of MS development in siblings of an affected individual is estimated to be 5%, in children 2%, in monozygotic twins 25% [5]. However, it has been shown that genetic predisposition is not strong enough to induce disease development, and appropriate environmental triggers are necessary to start the disease process [1, 12]. In general, the MS-associated genes can be classified into genes of the HLA-complex and
3. Gene polymorphisms and haplotypes in the aetiology of multiple sclerosis
The single-nucleotide polymorphism (SNP) is a variation of a single nucleotide, which is present in the population in a frequency higher than 0.01. SNPs are the most common type of genetic variation and are usually caused by somatic or gametic mutations. Nucleotide change can cause the formation or loss of restriction sites for bacterial endonucleases that are able to cleave the specific DNA sequence. The identification of gene polymorphisms that are in correlation with other risk factors, including biochemical markers, can be useful in establishing the risk of MS development, prognosis, clinical course of the disease and response to therapy. Haplotype (haploid genotype) is a certain combination of alleles or SNPs in the sequence of the DNA, whichis localized on one chromosome and is inherited together. When two alleles are in linkage disequilibrium, they are inherited together in a higher frequency than expected randomly [13]. The combination of more alleles, known as tagging SNPs, enables us to identify the other associated alleles. For example, the allele A of gene polymorphism rs3135388 corresponds to the incidence of allele HLA-DRB1*1501, which is the most common genetic risk factor for MS development [14–16].
4. HLA genes and MS
Antigen expression that is inducible by cytokines is different on the various immune cells. Major histocompatibility complex II (MHCII) antigens are transmembrane proteins localized on the immune cells, thus having an important role in the process of exogenous antigen presentation to Tcells. MHCII molecules are coded by the gene of human leucocyte antigens D (
The DQB1*06:02 allele was found to be linked to the increased risk of MS with a proved tight linkage disequilibrium between DRB1*15 and DQB1*06 in Caucasians [35]. As the risk factor of MS, DQB1*06:02 allele has also been identified in a cohort of Afro-Brazilians [36] and Spaniards [33]. Kaushansky et al. [37] suggested that the role of the DRB1*15:01 and DQB1*06:02 alleles in MS depends on the heterogeneous interaction of target antigen, genotype, and phenotype. On the contrary, Isobe et al. [38] found none of the HLA-DQB1 alleles to be associated with MS in African Americans. According to the combinations of HLA-alleles, the association of HLA-DRB1*15/*15 genotype with MS was identified by several studies [32, 34, 39]. In multi-case MS families, Barcellos et al. [39] identified a high risk DRB1*15/*08 genotype and protective DRB1*15/*14 genotype. The study of Sawcer et al. [23] indicates that in all populations of North-European ancestry, a predisposition to MS is linked with the DRB1*15:01-DQB1*06:02 haplotype. Furthermore, Link et al. [34] in a Scandinavian cohort showed that risk haplotypes for MS are almost all DRB1*15 bearing haplotypes, while protective effect against MS development are HLA class I A*02 allele-bearing haplotypes. In Sardinian MS patients, Cocco et al. [40] confirmed a positive association of the haplotype HLA DRB1*03:01-DQB1*02:01 with MS.
In the study from our laboratory, we analysed the association of the
5. Non-HLA genes and MS
Gene products of
Antigen presentation | 6p21 | rs3135388 | C/T | |
rs3135005 | C/T | |||
Proliferation of memory Tcells, T- and B-cell development | 5p13 | rs6897932 | C/T | |
Sensitization of Tcells to IL-2, proliferation of Tcells | 10p15 | rs2104286 | A/G | |
rs12722489 | A/G | |||
rs11256369 | C/G | |||
rs7076103 | C/T | |||
Function of regulatory Tcells | 1p13 | rs2300747 | A/G | |
rs6677309 | A/C | |||
rs12044852 | A/C | |||
Regulation, adhesion of TH17 and other Tcells | 11q13 | rs17824933 | C/G | |
rs12288280 | G/T | |||
Cell receptor, induction of immune response | 16p13 | rs6498169 | A/G | |
rs12708716 | A/G | |||
Lymphocyte survival, differentiation and proliferation | 19p13 | rs2546133 | C/T | |
rs2617822 | A/G | |||
Regulation of IL-2 expression, receptor | 17q22-q23 | Allele variants in introns 3, 8 | ||
Nuclear protein, cell cycle regulation | 1p22 | rs6680578 | A/T | |
rs11808092 | A/C | |||
rs11804321 | C/T | |||
Regulation of cytokine activation | 7q32 | rs4728142 | A/G | |
rs3807306 | A/C | |||
Expression of interferon response genes, development of Bcells | 16q24 | rs17445836 | A/G | |
Gene expression | 19p13 | rs34536443 | C/G | |
rs55762744 | C/T | |||
Receptor for tumour necrosis factor | 12p13 | rs1800693 | A/G | |
rs4149584 | A/C/G | |||
rs767455 | C/T | |||
rs4149577 | C/T | |||
Receptor for tumour necrosis factor | 20q12-q13 | rs1883832 | C/T | |
Activator of NKcells, lymphocyte adhesion, co-stimulator of Tcells | 18q22 | rs763361 | C/T | |
Neuronal regeneration | 1p36 | rs10492972 | C/T | |
Neuronal growth and reparation | 13q32 | rs9523762 | A/G |
6. Genetic variants in interleukin 7 receptor α chain (IL-7Ra) gene
IL7 is a type 1 short-chain cytokine of the haematopoietin family involved in the modulation of T- and B-cell development and T-cell homeostasis. To perform the immune system functions, IL7 binds to the transmembrane receptor that is formed by heterodimerisingthe common cytokine gamma chain and IL7 receptor alpha chain (IL7Ra or CD127). IL7Ra is a membrane glycoprotein folded to bind and mediate the action of IL7 and other alpha helical cytokines. IL7Ra consists of an extracellular domain, transmembrane region and cytoplasmic tail, which uses kinases for signal transduction [49]. The localization of the
Single-nucleotide polymorphisms in
It has been found that allele C of SNP rs6897932 in
Only a few studies addressed the question whether the rs6897932 in
Results of our own work suggest the relevance of rs6897932 allele and gene variants in MS pathogenesis in Slovaks [10]. Our results have revealed that allele C is present in a higher frequency in MS patients (77.4%) as compared to the control group (72.3%), which indicates an increased risk of MS development (OR=1.314, 95% CI=1.004–1.720,
After stratification of MS patients according to the disease disability progression rate, we found a significantly lower frequency of allele T in the subgroup of rapidly progressing MS patients (18.1%) as compared to 27.7% in controls. These results suggest that allele T is associated with protection against rapid disability progression of MS (OR = 0.576, 95% CI = 0.348–0.955,
We have shown for the first time in a Central European Slovak population that allele C of rs6897932 is associated with the risk of MS, and allele T has a protective additive effect against MS susceptibility. Moreover,we revealed that minor allele T and genotype TT of rs6897932 in the
7. Vitamin D and its role in risk and progression of multiple sclerosis
In the past decades, much attention has been given to vitamin D and its role in MS and other autoimmune diseases. The following sectionsare dedicated to the metabolism and structure of vitamin D, its immunological effects, serum level and mechanisms of action of vitamin D in the prevention and treatment of MS. We also describe the genetic factors that can modulate the biological effects of vitamin D.
7.1. The structure and metabolism of vitamin D
Vitamin D in the human body undergoes a complex metabolism. Cholecalciferol (vitamin D3), as a precursor of a hormonally active form, is produced in the skin from 7-dehydrocholesterol after sunlight exposure and can also be absorbed from the diet. Subsequently, cholecalciferol is hydroxylated in the liver forming 25-hydroxycholecalciferol, calcidiol. The hormonally active form of vitamin D, 1,25- dihydroxycholecalciferol, calcitriol, is produced by further hydroxylation especially in the kidneys and also in other tissues. The enzyme catalysing this hydroxylation is 25-hydroxyvitamin D-1α-hydroxylase, coded by
7.2. The effect of vitamin D on the functions of immune cells
There is growing evidence that vitamin D not only regulates bone metabolism but also has large-scale immunomodulatory and anti-inflammatory effects. A linkage has been found between vitamin D deficiency and increased risk of autoimmune diseases [70]. The immunocompetent cells—macrophages, dendritic cells, Tcells and Bcells are able to produce calcitriol and express the VDR at the high rate. Through this, vitamin D modulates the synthesis of various cytokines and immunoglobulins and is involved in the regulation of innate and adaptive immune response. Autocrine and paracrine effects of vitamin D depend also on its serum level, and individuals with hypovitaminosis D are in a state of immune system dysfunction and are predisposed to the development of autoimmune diseases [71].
In Tcells, calcitriol inhibits the production of IL-12 and IFN-γ and subsequent differentiation of TH1 lymphocytes that are the key cells involved in the MS development. Calcitriol improves the immunosuppressive functions of TREGcells and ameliorates the TH2-cell development by the activation of the promotor region of
Calcitriol formed in macrophages inhibits the immune response by suppressing proliferation of TH1- and TH17cells and promoting the functions of TH2- and TREGcells [71]. Calcitriol inhibits the secretion of IL-12 by antigen-presenting cells and monocytes [77]. Vitamin D blocks the differentiation of immature dendritic cells and the expression of co-stimulatory molecules CD40, CD80, CD86 and MHC II, thus decreasing the capacity of dendritic cells to activate autoreactive Tcells. Vitamin D also ameliorates the spontaneous apoptosis of mature dendritic cells [73]. In macrophages, calcitriolsuppresses intracellular oxidative burst and listericidal activity. It also suppresses the expression of Fc and TLR receptors induced by IFN-γ that are important for antigen recognition [78]. Vitamin D suppresses the proliferation of antigen-specific Tcells and chemotaxisof dendritic cells by decreasing the expression of differentiation antigens CD80, CD86 and HLA-DR molecules [79].
7.3. The murine model of MS and vitamin D
In mice that lack the
7.4. Serum level of vitamin D and dose management
To reflect vitamin D status in the human body, calcidiol plasma level measurement is usually used. Calcidiol is the main circulating form of vitamin D in plasma, and its biological half-time is 19 days [85]. The recommended daily dose of vitamin D is approximately 10times higher than in the past. The optimal serum level of vitamin D is 75–250 nmol/l (30–100 ng/ml). In countries with less sunny climate, the necessary daily dose of vitamin D is 1000–4000 IU/day (1 μg = 40 IU) [86].
The risk of vitamin D overdosing is hypercalcaemia and subsequent organ and tissue damage. Whole body exposure to sunlight results in the production of around 10,000 IU of vitamin D, so it is not simple to cause vitamin D intoxication by its short-term peroral supplementation. The results of several studies suggest that even high-dose vitamin D3 supplementation in MS patients is safe and clinically useful. Burton et al. [87] administered high peroral doses of vitamin D to healthy individuals and MS patients. The initial dose was 40,000 IU/dayduring 28 weeks, followed by 10,000 IU/day during 12 weeks; later it was gradually decreased to 0 IU/day, combined with 1.2 grams of calcium per day. During the period of 40,000 IU of vitamin D per day, the serum levels reached 413 nmol/l, which was higher than the conventional limit established for vitamin D toxicity (250 nmol/l). Calcidiol serum levels remained around this limit for 18 weeks without any observed negative effects. The serum level of calcium was in the physiological reference range during the whole study duration. Moreover, no cardiac rhythm abnormalities or impairment of hepatic or renal functions was observed. Kimball et al. [88] administered 4000–40,000 IU/day to patients in the active phase of MS together with 1.2 grams of calcium. Medium serum level of calcidiol was 78 ± 35 nmol/l and rose to 386 ± 157 nmol/l. Serum calcium level and urinary calcium to creatinine ratio did not exceed the physiological reference values. Vitamin D supplementation in this study did not cause any change in the serum level of hepatic enzymes, creatinine, electrolytes, proteins and parathormone. Although the serum level of calcidiol doubled the physiological upper range value, hypercalcaemia or hypercalciuria was not observed.
Although the significant toxicity of vitamin D3 was not observed even in doses of 40,000 IU/day, its daily dose in healthy individuals should not exceed 2000 IU. The optimal daily dose of vitamin D3 that should be routinely recommended to women during pregnancy and lactation is 1000 IU. Children born in families with MS history should be administered daily 200–400 IU of vitamin D3 [66].
7.5. Vitamin D and the course, prevention and treatment of MS
The role of vitamin D in the prevention of MS development has been confirmed by many experimental, epidemiological, genetic and immunological studies. Vitamin D insufficiency during the whitematter development can alter the pathways of axonal differentiation and adhesion and increase the apoptosis of oligodendrocytes that express VDR. This results in local microenvironmental changes and altered regeneratory and remyelinating capacity [66]. In individuals with an increased genetic risk of MS, it is possible to prevent the demyelination process by preventive vitamin D administration. This preventive strategy would be better than reparation of already developed myelin and axonal damage [12, 66].
High-dose peroral vitamin D intake has been found to be inversely associated with the risk of MS in a cohort of more than 90,000 women. Peroral vitamin D supplementation in a dose higher than 400 IU/day leads to the reduction of MS risk when compared to the individuals with no vitamin D intake (RR = 0.59, 95% CI = 0.38–0.91,
Vitamin D is not only a factor modifying MS risk, but it can also have a role in the modulation of disease course. It has been observed that in relapsing remitting MS, calcidiol plasma levels are lower during relapses compared to the periods of remission [91]. In addition, there is evidence that lower calcidiol levels are associated with higher relapse rates and higher risk of exacerbation, as well as higher expanded disability status scale (EDSS) scores and progressive forms of MS [92–94]. Vitamin D can improve memory and cognitive impairments in patients with MS, Alzheimer disease and in patients after chemotherapeutical treatment [95]. High-dose peroral vitamin D supplementation has immunomodulatory effects and leads to reduction in the number of relapses and suppression of the inflammatory activity and proliferation of Tcells [87], as well as the decrease in the number of gadolinium-enhancing lesions in brain [88].
In our study, we examined the serum levels of calcidiol in a group of MS patients from the Central-Northern part of Slovakia. We found that hypovitaminosis D is more frequent in MS patients, when compared to healthy individuals. Serum levels of calcidiol were significantly lower in MS patients when compared to controls (15.0 ± 6.1 ng/ml vs. 18.2 ± 8.3 ng/ml,
7.6. Genetic factors related to vitamin D effects in MS
Nucleotide exchange in DNA sequence can cause the production of protein products with different activities. Polymorphisms of the genes involved in the activation, transport, signalling and degradation of vitamin D can, together with other factors, modify the individual immune response and thus can be related to MS. Because of the beneficial effects of vitamin D, in individuals with genes predisposing to its higher serum levels, the risk of MS should be reduced [96]. The serum level of vitamin D can be modified by
Hydroxylation | 12q13 | rs703842 | C/T | |
rs10877012 | G/C | |||
rs4646536 | C/T | |||
rs10877015 | A/G | |||
rs118204009 | A/G | |||
rs118204012 | A/G | |||
rs118204011 | C/T | |||
Hydroxylation | 11p15 | rs10741657 | A/G | |
rs10500804 | G/T | |||
rs12794714 | A/G | |||
Transport in plasma | 4q12 | rs7041 | G/T | |
rs4588 | A/C | |||
Receptor | 12q13 | rs1544410 (BsmI) | A/G (B/b) | |
rs7975232 (ApaI) | T/C (A/a) | |||
rs731236 (TaqI) | T/C (T/t) | |||
rs10735810 (FokI) | C/T (F/f) | |||
rs11568820 (Cdx2) | G/A | |||
rs2254210 | A/G | |||
rs98784 | C/T | |||
Deactivation | 20q13 | rs2296241 | A/G |
7.6.1. Genetic variants in vitamin D receptor gene in MS
According to the effects of vitamin D in MS, the molecular mechanisms of vitamin D function should be considered. As mentioned earlier, vitamin D executes its physiological effect via binding and activation of VDR. Interestingly, the activation of VDR by calcitriol can suppress the induction of EAE, while animals that lack VDR are not protected against EAE [102]. The gene for VDR is located on the 12q13 chromosomal region and consists of 11 exons. Non-coding exons 1A, 1B and 1C are located in the 5′ end of the VDR gene, and exons 2–9 encode the structural portion of the VDR protein [103]. VDR sequence is similar to that of the receptors for steroid hormones and hormones of the thyroid gland. VDR is a regulatory transcription factor and consists of highly conservative DNA-binding and ligand-binding domains. The signal pathways associated with the VDR regulate the transcription of genes involved in the regulation of bone metabolism, immune response and cancer [83]. The polymorphisms in the initiation codon of the
Interestingly, several studies have found an association between
The role of VDR gene polymorphisms is still not completely understood, and it seems to vary among different populations. For proper cell signalling to decrease the risk of MS, it is probably necessary to reach a certain level of the transcriptional activity of VDR that is also modified genetically. For proper immunoregulation, the individuals that have the genotype causing the decreased VDR protein activity can need a higher peroral vitamin D intake or higher level of sun exposure. Contrarily, in individuals with higher transcriptional activity of VDR, a lower sun exposure or vitamin D intake can be sufficient for proper immune system regulation.
The findings of our previous study in MS patients from the Central-Northern region of Slovakia have confirmed the association of FokI heterozygous genotype Ff with an increased risk of MS in women [10]. Although we found no statistically significant differences in the proportions of FokI genotypes or allele frequencies between total MS patient and the control group, we have observed significant differences in the FokI genotype distribution between women with MS and the female control group (
8. Conclusions
In summary, we can conclude that many genetic and biochemical factors can be involved in the etiopathogenesis of MS. These markers could be used to evaluate the risk of MS development and the risk of rapid disease disability progression.
The proposed markers that have been found to be associated with MS risk or disability progression in Central European Slovak population are summarized in Table 3. In our studies, we identified decreased serum level of vitamin D, allele C and genotype CC of polymorphism rs6897932 in the
Decreased serum vitamin D | Decreased serum vitamin D | |
rs6897932 in genotype CC |
rs6897932 in gene—genotype CC |
|
HLA-alleles DRB1*15, DRB1*03, DQB1*06; HLA-genotypes DRB1*15/*15, DQB1*06/*06; HLA-haplotype DRB1*15-DQB1*06 |
||
rs10735810 in Ff (only women) |
||
rs6897932 in genotype CT and TT |
rs6897932 in genotype TT |
|
HLA-alleles DRB1*07, DRB1*13, DQB1*03; HLA-genotypes DRB1*13/*11, DQB1*05/*03; HLA-haplotypes DRB1*13-DQB1*06, DRB1*11- DQB1*03 |
From the results of our study, we conclude that rs6897932 of the
Acknowledgments
The work was supported by the projects '“Centre for Translational Medicine' code: 6220220021, 'Identification of Novel Markers in Diagnostic Panel of Neurological Diseases' code: 26220220114, 'Martin Biomedical Center (BioMed Martin)' ITMS code: 26220220187 co-financed from EU sources and European Regional Development Fund and the grant of Ministry of Health, 2012/30-UKMA-7 and APVV No. 15/0107.
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