IL10 Polymorphisms and MS

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Multiple sclerosis (MS) is an autoimmune/inflammatory disease of the central nervous system (CNS) of unknown aetiology resulting in polymorphic and unpredictable clinical manifestations. Current views attribute environmental factors to the triggering of the onset of MS in genetically susceptible individuals. Evidence for the role of genetic factors is shown by studies on twins and by the development of the disease in family members. The autoimmune nature of MS suggests that cytokine genes may be potent candidates, with different loci contributing to disease susceptibility and/or to disease progression.

Data concerning the relationship between IL-10 polymorphism and susceptibility to MS is summarized in Table 2. In studies on the relationship between MS and IL-10 promoter polymorphisms (-1082, -819, -592, and microsatellites), no association between the three SNPs and susceptibility to, or severity of MS could be established.51-53 However, the study of recently described IL-10 SNPs,32 by De Jong et al, indicated that the frequency of IL-10 -2849G polymorphism is lower in patients with primary progressive forms than in patients having relapse-onset MS and control subjects.36

In a Spanish population, both IL-10.G and IL-10.R microsatellites, as well as the three promoter SNPs, failed to exhibit any association between IL-10 haplotypes and susceptibility to MS.54 Nevertheless, in this population, the IL-10.G12 allele showed a significant difference between MS patients and controls. In contrast, this association was not detected in three other

Table 2. Characteristics of tested markers and their reported associations with autoimmune disease

Associated Alleles, Location of Haplotypes

Disease Polymorphism or Genotypes Population Clinical Criteria Refs.

-1082/-819 /-S92 -1082/-819 /-S92 -1082 -3S7S/-2849/ -2763/-1082/-819 -1082/-819 /-S92 and IL-10.R/G IL-10.G IL-10.G IL-10.G IL-10.R/G -1082/-819 /-S92

none none none -2849 G

IL-10.G12

none none none

Caucasian (UK) Caucasian Caucasian (Germany) Caucasian

Spanish

Swedish Northern Irish French

IL-10.G genotypese ACC GCC ATA none none

French Northwest England

Southern Chinese Caucasian Anglo-Saxon Caucasian African-American Caucasian (UK)

EDSSa MS forms

PIb MS forms

MS forms

Ro+C

renal disease dsDNA-Abs renal disease

52 36

32 38

IL-10.G

IL-10.G10

Mexican-American

74

IL-10.R/G

IL-10.G11

Italian

7S

IL-10.R/G

none

Taiwan

77

IL-10.G

none

Mexican

78

IL-10.G

none

Mexican Swedish

76

RA

-1082/-819 /-S92

none

UK

80

-1082

none

French

82

-1082/-819 /-S92

-1082 A

Dutch

Joint destruction

17

-1082/-819 /-S92

IL-10.G12

Spanish

and IL-10.R/G

81

-1082/-819 /-S92

ACC

Caucasian

IgA RF+/IgG RF-

83

IL-10.R/G

IL-10.R2 IL-10.R3

Caucasian

Different origins

39

IL-10.R/G

none

South African Caucasian (UK)

44

Primary

-1082/-819 /-S92

GCC

Finnish

86

Sjogren's -

1082/-819 /-S92

GCC

Caucasian

87

Syndrome

IL-10.G

IL-10.G9

IgA RF/anti-Ro/anti-La

88

Psoriasis

-1082

none

Caucasian

age-at-onset

84

IL-10.R/G

none

Caucasian (German)

age-at-onset

8S

Type 1

-1082/-819 /-S92

ATA

Japanese

age-at-onset

90

Diabetes

-S92

C

Japanese

GADab+d

89

a EDSS: Expanded Disability Status Scale;98 b PI: Progression Index (PI=EDSS/duration [years]); c Ro+: patients with SLE positive for anti-Ro antibodies; d GADab+: patients with type 1 Diabetes positive for antibodies to glutamic acid decarboxylase; e IL-10.G9/9, G10/13, G11/13 and G13/14 genotypes were associated with MS patients with mild disease progression; IL-10.G9/10, G9/11, G9/13 and G12/13 were associated with MS patients with severe disease progression.

a EDSS: Expanded Disability Status Scale;98 b PI: Progression Index (PI=EDSS/duration [years]); c Ro+: patients with SLE positive for anti-Ro antibodies; d GADab+: patients with type 1 Diabetes positive for antibodies to glutamic acid decarboxylase; e IL-10.G9/9, G10/13, G11/13 and G13/14 genotypes were associated with MS patients with mild disease progression; IL-10.G9/10, G9/11, G9/13 and G12/13 were associated with MS patients with severe disease progression.

studies conducted on northern Irish, Swedish or French populations.55-57 We also analyzed the distribution of both the IL-10.R and the IL-10.G alleles in a French Caucasian population58 with a predisposition to MS. Our study corroborates previous reports that have demonstrated the absence of an association between any of the IL-10 microsatellite polymorphisms and susceptibility to MS. On the other hand, some IL-10.G genotypes were distributed differently in MS patients that were stratified according to the rate of progression of their disease (i.e., progression index).58

Although the genetic factor in MS is substantial—30% concordance in identical twins59— attempts to find associations between these IL-10 promoter polymorphisms and MS have failed. All of the data indicates that IL-10 does not seem to be a major susceptibility locus in MS. Such data is consistent with full genome analysis results, which have demonstrated that there is no single master gene for MS. 2

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