Association of two variants in IL-1β and IL-1 receptor antagonist genes with multiple sclerosis
Introduction
The IL-1 family of cytokines consists of IL-1α, IL-1β and IL-1 receptor antagonist (IL-1ra). IL-1ra is a pure antagonist of the other two (Arend, 1991). IL-1α and IL-1β are pro-inflammatory cytokines with pleiotropic activities including growth and differentiation of T- and B-cells, and induction of other interleukins, adhesion molecules, histamine and thromboxane (Dinarello, 1994). Their functions overlap with those of TNFα and IL-6. IL-1 is expressed by many cell types including macrophages and microglia within MS lesions (Canella and Raine, 1995). Naturally occurring IL-1ra inhibits clinical signs of EAE (Martin and Near, 1995). Altintas et al. (1997) found that the CSF and serum IL-1β levels rise during relapses of multiple sclerosis (MS) and are suppressed by corticosteroid treatment. These data suggest a role for glycoproteins of the IL-1 family in the immuno-pathogenesis of MS.
The genes encoding for the three members of the IL-1 family are located close to one another on chromosome 2q14-q21 (Steinkasserer et al., 1992). This study focuses on two previously described genetic polymorphisms: a variable number tandem repeat (VNTR) polymorphism of 86 base pairs within the fourth intron of the human IL-1ra gene (Tarlow et al., 1993), and a polymorphism in the fifth exon of the human IL-1β gene that abolishes a TaqI restriction site (Pociot et al., 1992).
Allele-2 (two repeats) of the IL-1ra polymorphism is associated with increased IL-1ra levels and decreased IL-1α production in human monocyte cultures (Danis et al., 1995). This allele has been associated positively with susceptibility to ulcerative colitis (Bioque et al., 1995, Bioque et al., 1996, Heresbach et al., 1997) and alopecia areata (Tarlow et al., 1994). Crusius et al. (1995) reported an association with MS in the Netherlands, but could not confirm the association in a larger number of patients (Schrijver et al., 1999). Association studies in Sweden (Huang et al., 1996), Finland (Wansen et al., 1997) and France (Semana et al., 1997) were also negative. However, De la Concha et al. (1997) reported that HLA-DRB1*1501 and IL-1ra allele-2 interact to increase susceptibility to relapsing–remitting MS and recently Sciacca et al. (1999) reported that allele-1 increases susceptibility to MS.
IL-1 α and β variants have been associated with other autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease and insulin dependent diabetes mellitus (Dinarello and Wolff, 1993). The less frequent allele (allele-2) of the TaqI polymorphism in the human IL-1β gene is associated with a high-secretor phenotype (Pociot et al., 1992). Studies in the Netherlands (Schrijver et al., 1999) and Finland (Wansen et al., 1997) did not demonstrate an association between this polymorphism and susceptibility to MS.
Schrijver et al. (1999) have shown that the combination of IL-1ra allele-2 (+)/IL-1β allele-2(−) is associated with greater disability indexed to time in patients from the Netherlands. However, allele-1 of IL-1ra is associated with more severe and allele-2 with more benign disease in patients from Italy and Spain (De la Concha et al., 1997, Sciacca et al., 1999).
To address these findings, we studied the association of these polymorphisms with disease susceptibility and disease severity in a well-characterized population-based sample of patients with MS in Olmsted County, MN (Rodriguez et al., 1994), and controls who were strictly matched for ethnicity.
Section snippets
Patient selection
We analyzed DNA from 122 patients with MS. The sample constitutes 73% of a prevalence cohort of MS patients in Olmsted County (Rodriguez et al., 1994). Relapsing remitting and secondary progressive cases were classified together as bout-onset. Patients with disease duration of 5 years or longer were previously ranked for disease severity by stratifying for progression index (EDSS/duration) within 5 year cohorts according to disease duration (Weinshenker et al., 1997). A score of 1 was
Demographics and overall allele distribution
The male to female ratio in cases was 1:3. The course was bout-onset in 83% of the patients. The mean age at onset was 29.6±8.9 years and the mean disease duration was 18.7±11.7 years. One hundred and twenty of 122 patients and 237 of 244 controls were successfully typed for both polymorphisms.
We did not detect any allele-5 (6 repeats) of IL-1ra and homozygotes of the rare alleles 3 and 4 in either cases or controls. Both of the variants were in Hardy–Weinberg equilibrium in cases and controls (
Discussion
The contribution of a common genetic polymorphism to disease severity may be independent of its effect on susceptibility. In MS the polymorphisms of the genes of the IL-1 family (De la Concha et al., 1997, Schrijver et al., 1999, Sciacca et al., 1999) and IgG Fc receptor (Myhr et al., 1999) were previously suggested to affect disease severity. There are also examples of association between outcome genes and disease severity in autoimmune disorders other then MS. For example, a TNF-α-238 G→A
Acknowledgements
This study has been supported by the National MS Society, grant no.: RG-2870-A-2. Dr.McMurray is supported by the Mayo Foundation, grant no.:DK 43694-01A2 and National Institutes of Health grant no.:MH-56207. Dr.Kantarci has been supported by a NATO Science Fellowship Program granted by the Scientific and Technical Research Council of Turkey and is currently supported by an advanced fellowship award granted by the National MS Society.
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