Elsevier

Human Immunology

Volume 68, Issue 11, November 2007, Pages 934-937
Human Immunology

The autoimmune disease–associated IL12B and IL23R polymorphisms in multiple sclerosis

https://doi.org/10.1016/j.humimm.2007.09.005Get rights and content

Summary

Recently published genetic studies in psoriasis, inflammatory bowel disease, and ankylosing spondylitis identified significant associations with IL12B and IL23R polymorphisms. An important role for the IL-12/IL-23 pathway in multiple sclerosis (MS) is supported by immunologic studies in patients and animal models. To determine whether IL12B/IL23R disease-associated polymorphisms play a role in susceptibility to MS, we genotyped 910 MS-nuclear families, totaling 3132 individuals. Family-based association analysis was performed. There was no evidence of transmission distortion of any of the tested alleles in this data set.

Introduction

A recently reported, large-scale genetic association study in three independent psoriasis sample sets (1446 case and 1432 control subjects) using >25,000 genecentric single nucleotide polymorphisms (SNPs) identified a highly significant association with a common IL12B (5q31.1–q33.1) haplotype, including a 3′-untranslated-region SNP (rs3212227) and a SNP located ∼60kb upstream of the coding region (rs6887695) (Global Pcomb = 5.94 × 10−10) [1]. These data confirmed and extended the results of Tsunemi et al., who reported association of rs3212227 with risk of psoriasis in a Japanese study of 143 patients and 100 control subjects [2]. IL12B encodes the common IL-12p40 subunit of the cytokines IL-12 and IL-23. Interestingly, follow-up analysis of other genes in the IL-12/IL-23 axis identified two IL23R (1p31.3) missense SNPs (rs7530511 and rs11209026) that, together, also confer susceptibility to psoriasis (Global Pcomb = 4.14 × 10−6) [1]. The association of IL12B and IL23R with psoriasis was recently confirmed in an independent study from the United Kingdom [3].

Duerr et al.[4] and Libioulle et al.[5] independently reported that one of the IL23R missense SNPs, rs11209026, was also associated with Crohn’s disease (CD) and ulcerative colitis. The association of IL23R with CD has recently been replicated in a subsequent genome-wide association study [6]; this study also reported a modest association of the IL12B SNP rs6887695 with CD [6], [7]. Finally, Revielle et al. have recently reported an association among the IL23R missense SNP, rs11209026, and ankylosing spondylitis risk [8].

Although awaiting replication, IL-12B alleles have been also reported to be associated with asthma [9], atopic dermatitis [2], and chronic hepatitis C virus infection [10]. Furthermore therapeutic intervention by blocking IL-12/IL-23, which appears to be highly effective for psoriasis [11] and promising for CD [12], is currently being explored in multiple sclerosis (MS) [13]. Altogether these results are consistent with the hypothesis that there are common genetic variants that contribute to general susceptibility to autoimmunity [14], [15], and the findings support an important role for the IL-12/IL-23 pathway in the homeostatic regulation of the immune response, most likely by driving the differentiation of Th1 and Th17 cells. Consequently the analysis of these SNPs in other autoimmune disorders is warranted.

MS is a severe autoimmune disorder of the central nervous system characterized by chronic inflammation, myelin loss, gliosis, axonal pathology, and progressive neurologic dysfunction [16]. A large body of research supports a multifactorial etiology for MS, with an underlying complex genetic component likely acting in concert with undefined environmental exposures. The HLA-DRB1*1501, DQB1*0602 haplotype within the major histocompatibility complex on chromosome 6p21 is the only locus that has consistently demonstrated both linkage and association in MS family and case-control studies [17], [18]. Depending on the model, it has been estimated to account for 17–62% of the genetic etiology as calculated from sibling relative risk [19]; hence much of the genetic effect in MS remains to be explained. The co-occurrence of psoriasis and inflammatory bowel disease in MS families is higher than expected [15], and previous work with murine models of MS highlights the key role of IL-12 [20] and/or IL-23 [21], [22], [23] in the induction and/or effector phases of experimental autoimmune demyelination, all supporting the rationale for studying the IL12B and IL23R autoimmune disease-associated polymorphisms in MS.

Section snippets

Subjects and methods

To determine whether the four IL12B/IL23R psoriasis-associated polymorphisms play a role in susceptibility to MS, we genotyped these SNPs in 910 MS-nuclear families, totaling 3132 individuals. The trio families used in this study were recruited from across the United States in collaboration with a network of specialized clinical sites. All individuals and their known ancestors were Caucasian and of European descent, and the female-to-male ratio for the affected persons was 3.2:1. All subjects

Results and discussion

We calculated the power for analysis in the available MS families, assuming a minor allele frequency of 10% (derived from control subjects used in this study) and a type 1 error rate of 5%. Based on these assumptions, we estimate that we have close to 80% power to detect a moderate genotype relative risk of 1.5 (Aa) and 2.0 (AA) for disease susceptibility. All family genotypes were examined for Mendelian inconsistencies using PEDCHECK [26], and any discrepancies were addressed. No deviations

Acknowledgments

We are grateful to the MS patients and their families for participating in this study. This work was funded in part by grant RG2901 from the National Multiple Sclerosis Society.

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