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Abstract
Background Knowledge of genetic susceptibility to autoimmune disorders is growing exponentially. One of the messages emerging from these data is the growing overlap in genetic susceptibility to different autoimmune disorders. KIF21B is a member of the kinesin superfamily and was recently established as a susceptibility locus for inflammatory bowel disease and for multiple sclerosis.
Results We here replicate the association with multiple sclerosis in a Belgian study population of 791 patients and 1098 controls.
Conclusion As SNPs in KIF21B increase risk for both inflammatory bowel disease and multiple sclerosis, this suggests a common pathway in the pathogenesis of these diseases.
- Multiple sclerosis
- association
- genetics
- autoimmune disease
- kinesin
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Multiple sclerosis (MS) is a common neurological disorder characterised by inflammation, demyelination and axonal loss. It is thought to be an autoimmune disorder directed against components of the myelin sheath. Our knowledge of susceptibility genes for MS, as for other autoimmune diseases, is growing exponentially.1–9 One important conclusion emerging from these studies is the overlap in genetic susceptibility loci between different autoimmune disorders.10 We and others previously demonstrated for example variation in the known type 1 diabetes risk loci CLEC16A and CD226 to also influence MS susceptibility.2 6 11 12 Hence, following up susceptibility genes for one autoimmune disorder as candidate genes for another proves to be an efficient strategy.
We here started from current progress in unravelling susceptibility to Crohn's disease. In a meta-analysis of genome-wide association screens on this disease, Barrett et al reported 21 novel loci as being associated with Crohn's disease.13 One single nucleotide polymorphism (SNP), rs11584383, was located downstream of KIF21B, a member of the kinesin superfamily (KIF). In a recent study, following up on a genome-wide association screen for MS,2 a correlated SNP, rs12122721, located in an intron of KIF21B was found to be associated with MS.14 We here investigate both KIF21B SNPs in an independent Belgian study population of 791 MS patients and 1098 controls.
Methods
Participants
A total of 791 patients and 1098 unrelated controls were included in this study. All individuals gave informed consent. Among the patients and the unrelated controls, 64% and 52% were women, respectively. Among the patients, 664 (84%) had bout-onset MS and 108 (14%) primary progressive MS. Average age at onset was 34 (±11 years).
Genotyping
SNPs rs11584383 and rs12122721 were genotyped with Taqman Assays-on-Demand C___3030223_10 and C__30856017_20 (Applied Bioystems) according to the manufacturer's instructions and run on a 7300 SDS real-time PCR system.
Statistical analysis
Analysis was done with the Plink V.1.06 software package.15
Results and discussion
Genotyping success rate was ≥96%. No deviation from Hardy–Weinberg equilibrium was observed (p>0.57). The two SNPs, rs11584383 and rs12122721, are correlated with an r2 of 0.83.
In particular, the T allele of SNP rs11584383 and the G allele of SNP rs12122721 are overrepresented among MS cases compared to controls (table 1), an effect that is in the same direction as that reported for Crohn's disease,13 ulcerative colitis16 17 and for multiple sclerosis,14 respectively. The association with SNP rs12122721 reaches nominal significance with a p value of 0.01. The corresponding OR is 1.21 (95% CI 1.04 to 1.41). No association was observed with age at onset (p>0.35).
Association of SNPs in KIF21B with MS
The SNPs investigated here are located in a 170-kb region of high linkage disequilibrium containing three genes: C1orf106, KIF21B and CACNA1S. KIFs are molecular motors and are involved in intracellular organelle transport. For another member of the KIF family, KIF1B, association with MS was recently reported.18 However, this association could not be replicated in other studies (International MS Genetics Consortium, unpublished data).9 In contrast, the association with KIF21B is consistent in a study reported elsewhere14 as well as in our independent study population. The modest effect size is comparable to that of the susceptibility genes outside of the HLA region that have been identified so far.1–9
KIF21B expression is detected in the lungs, brain, testes and thymus.19 20 In neurons, KIF21B is localised in the dendrites19 and in the oligodendrocyte lineage KIF21B is specifically expressed in the precursor cells.21 In the immune system, expression is highest in CD4+ and CD8+ T cells, CD56bright NK cells and B cells (T1Dbase, http://www.t1dbase.org/). The function of KIF21B is still unknown. The fact that this gene is associated with at least two autoimmune disorders with the same direction of effect suggests that the mechanism of action may be related to an as yet unravelled function of KIF21B in the immune system. Notably, the mouse homologue, Kif21b, is located in a region linked to susceptibility (Idd5.4a) for a mouse model for diabetes.22
In conclusion, we here report additional evidence for KIF21B being a susceptibility locus shared between inflammatory bowel disease and multiple sclerosis, suggesting a common pathway involved in the pathogenesis of both diseases.
Acknowledgments
We thank all individuals for participating in this study and are grateful to Cindy Thys, Katleen Clijsters and Ann Van Remoortel for their crucial role in patient recruitment and sampling.
References
Footnotes
Funding This work has been supported by Wetenschappelijk Onderzoek Multiple Sclerose (WOMS). BD is a Clinical Investigator of the Research Foundation Flanders (FWO-Vlaanderen) and holds the Bayer Chair on fundamental genetic research regarding the neuroimmunological aspects of multiple sclerosis at the KU Leuven, Leuven, Belgium.
Competing interests None.
Ethics approval This study was conducted with the approval of the local hospital ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.