Cytogenetic location:1p36 Genomic coordinates(GRCh38) :1:1-27,600,000
| Location | Phenotype | Inheritance | Phenotype mapping key | Phenotype MIM number | Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36 | {Multiple sclerosis, susceptibility to, 4} | 2 | 612596 | MS4 | 612596 | |
| 5p13.2 | {Multiple sclerosis, susceptibility to, 3} | 2 | 612595 | MS3 | 612595 | |
| 6p21.32 | {Multiple sclerosis, susceptibility to, 1} | Mu | 3 | 126200 | HLA-DRB1 | 142857 |
| 6p21.32 | {Multiple sclerosis, susceptibility to, 1} | Mu | 3 | 126200 | HLA-DQB1 | 604305 |
| 10p15.1 | {Multiple sclerosis, susceptibility to, 2} | 2 | 612594 | MS2 | 612594 | |
| 12p13.31 | {Multiple sclerosis, susceptibility to, 5} | 3 | 614810 | TNFRSF1A | 191190 |
For a discussion of genetic heterogeneity of multiple sclerosis (MS), see MS1 (126200).
In a genomewide association study of 45 patients with multiple sclerosis and 195 controls in a genetically isolated Dutch population,Aulchenko et al. (2008) found an association between MS and the C allele ofrs10492972 in intron 5 of the KIF1B gene (605995) on chromosome 1p36. The findings were replicated in 3 larger cohorts from the Netherlands, Sweden, and Canada. Pooled data comprising 2,679 patients and 3,125 controls from all 4 groups yielded a p value of 2.5 x 10(-10) (odds ratio of 1.35).
TheInternational Multiple Sclerosis Genetics Consortium (2010) (IMSGC) was unable to replicate the association between MS and the C allele ofrs10492972 reported byAulchenko et al. (2008). Genotyping of the variant in 8 case-control and 3 trio-family collections, including a total of 8,391 cases, 8,052 controls, and 2,137 trio families, found that none of them had a statistically significant association with the variant. In fact, more than half of the studies showed a trend in the opposite direction. In addition,International Multiple Sclerosis Genetics Consortium (2010) found that the frequency of the C allele was 0.33 in their pooled control group, which included samples from Australia, Belgium, Finland, Norway, Italy, Sweden, the U.K., and U.S., which was significantly different from the frequency of 0.27 found in Dutch controls byAulchenko et al. (2008). These results suggested population differences in allele frequencies which may have influenced the original findings.Hintzen et al. (2010) replied that they were surprised that the findings could not be replicated and defended their original findings (Aulchenko et al., 2008).Hintzen et al. (2010) noted that the U.K. and Italian control groups ofInternational Multiple Sclerosis Genetics Consortium (2010) did not find the allele in Hardy-Weinberg equilibrium, which may have led to incorrect conclusions. Furthermore, the disparate results between the 2 studies may reflect a prevalence/incidence bias of MS in the Dutch population.
Sombekke et al. (2011) found no association betweenrs10492972 and clinical or MRI findings of neurodegeneration among 214 patients with MS. They also found no association between this SNP and disease susceptibility.
Alcina et al. (2010) attempted to replicate the risk contribution of 19 SNPs associated with MS identified by theWellcome Trust Case Control Consortium (2007). Only 1 SNP,rs17368528 in exon 5 of the H6PD gene (138090) on chromosome 1p36.22, showed a significant disease association among 732 Spanish patients and 974 controls, with replication in 1,318 Canadian patients and 1,507 controls (odds ratio (OR) of 0.83, p = 0.04). This marker is 1 Mb away from KIF1B, and the association was independent of KIF1B.Alcina et al. (2010) noted that the H6PD gene is involved in the pentose phosphate pathway, which provides reducing equivalents for regeneration of the antioxidant glutathione.
Alcina, A., Ramagopalan, S. V., Fernandez, O., Catala-Rabasa, A., Fedetz, M., Ndagire, D., Leyva, L., Arnal, C., Delgado, C., Lucas, M., Izquierdo, G., Ebers, G. C., Matesanz, F.Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. Europ. J. Hum. Genet. 18: 618-620, 2010. [PubMed:19935835,related citations] [Full Text]
Aulchenko, Y. S., Hoppenbrouwers, I. A., Ramagopalan, S. V., Broer, L., Jafari, N., Hillert, J., Link, J., Lundstrom, W., Greiner, E., Sadovnick, A. D., Goossens, D., Van Broeckhoven, C., Del-Favero, J., Ebers, G. C., Oostra, B. A., van Duijn, C. M., Hintzen, R. Q.Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis. Nature Genet. 40: 1402-1403, 2008. [PubMed:18997785,related citations] [Full Text]
Hintzen, R. Q., Aulchenko, Y. S., Ramagopalan, S., Ebers, G., van Duijn, C. M.Reply to International Multiple Sclerosis Genetics Consortium (IMSGC). (Letter) Nature Genet. 42: 470-471, 2010.
International Multiple Sclerosis Genetics Consortium.Lack of support for association between the KIF1B rs10492972C variant and multiple sclerosis. Nature Genet. 42: 469-470, 2010. [PubMed:20502484,related citations] [Full Text]
Sombekke, M. H., Jafari, N., Bendfeldt, K., Mueller-Lenke, N., Radue, E. W., Naegelin, Y., Kappos, L., Matthews, P. M., Polman, C. H., Barkhof, F., Hintzen, R., Geurts, J. J. G.No influence of KIF1B on neurodegenerative markers in multiple sclerosis. Neurology 76: 1843-1845, 2011. [PubMed:21606458,related citations] [Full Text]
Wellcome Trust Case Control Consortium.Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39: 1329-1337, 2007. [PubMed:17952073,related citations] [Full Text]
DO: 2377;
Cytogenetic location: 1p36 Genomic coordinates(GRCh38) : 1:1-27,600,000
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 1p36 | {Multiple sclerosis, susceptibility to, 4} | 612596 | 2 |
For a discussion of genetic heterogeneity of multiple sclerosis (MS), see MS1 (126200).
In a genomewide association study of 45 patients with multiple sclerosis and 195 controls in a genetically isolated Dutch population, Aulchenko et al. (2008) found an association between MS and the C allele of rs10492972 in intron 5 of the KIF1B gene (605995) on chromosome 1p36. The findings were replicated in 3 larger cohorts from the Netherlands, Sweden, and Canada. Pooled data comprising 2,679 patients and 3,125 controls from all 4 groups yielded a p value of 2.5 x 10(-10) (odds ratio of 1.35).
The International Multiple Sclerosis Genetics Consortium (2010) (IMSGC) was unable to replicate the association between MS and the C allele of rs10492972 reported by Aulchenko et al. (2008). Genotyping of the variant in 8 case-control and 3 trio-family collections, including a total of 8,391 cases, 8,052 controls, and 2,137 trio families, found that none of them had a statistically significant association with the variant. In fact, more than half of the studies showed a trend in the opposite direction. In addition, International Multiple Sclerosis Genetics Consortium (2010) found that the frequency of the C allele was 0.33 in their pooled control group, which included samples from Australia, Belgium, Finland, Norway, Italy, Sweden, the U.K., and U.S., which was significantly different from the frequency of 0.27 found in Dutch controls by Aulchenko et al. (2008). These results suggested population differences in allele frequencies which may have influenced the original findings. Hintzen et al. (2010) replied that they were surprised that the findings could not be replicated and defended their original findings (Aulchenko et al., 2008). Hintzen et al. (2010) noted that the U.K. and Italian control groups of International Multiple Sclerosis Genetics Consortium (2010) did not find the allele in Hardy-Weinberg equilibrium, which may have led to incorrect conclusions. Furthermore, the disparate results between the 2 studies may reflect a prevalence/incidence bias of MS in the Dutch population.
Sombekke et al. (2011) found no association between rs10492972 and clinical or MRI findings of neurodegeneration among 214 patients with MS. They also found no association between this SNP and disease susceptibility.
Alcina et al. (2010) attempted to replicate the risk contribution of 19 SNPs associated with MS identified by the Wellcome Trust Case Control Consortium (2007). Only 1 SNP, rs17368528 in exon 5 of the H6PD gene (138090) on chromosome 1p36.22, showed a significant disease association among 732 Spanish patients and 974 controls, with replication in 1,318 Canadian patients and 1,507 controls (odds ratio (OR) of 0.83, p = 0.04). This marker is 1 Mb away from KIF1B, and the association was independent of KIF1B. Alcina et al. (2010) noted that the H6PD gene is involved in the pentose phosphate pathway, which provides reducing equivalents for regeneration of the antioxidant glutathione.
Alcina, A., Ramagopalan, S. V., Fernandez, O., Catala-Rabasa, A., Fedetz, M., Ndagire, D., Leyva, L., Arnal, C., Delgado, C., Lucas, M., Izquierdo, G., Ebers, G. C., Matesanz, F.Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. Europ. J. Hum. Genet. 18: 618-620, 2010. [PubMed: 19935835] [Full Text: https://doi.org/10.1038/ejhg.2009.213]
Aulchenko, Y. S., Hoppenbrouwers, I. A., Ramagopalan, S. V., Broer, L., Jafari, N., Hillert, J., Link, J., Lundstrom, W., Greiner, E., Sadovnick, A. D., Goossens, D., Van Broeckhoven, C., Del-Favero, J., Ebers, G. C., Oostra, B. A., van Duijn, C. M., Hintzen, R. Q.Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis. Nature Genet. 40: 1402-1403, 2008. [PubMed: 18997785] [Full Text: https://doi.org/10.1038/ng.251]
Hintzen, R. Q., Aulchenko, Y. S., Ramagopalan, S., Ebers, G., van Duijn, C. M.Reply to International Multiple Sclerosis Genetics Consortium (IMSGC). (Letter) Nature Genet. 42: 470-471, 2010.
International Multiple Sclerosis Genetics Consortium.Lack of support for association between the KIF1B rs10492972C variant and multiple sclerosis. Nature Genet. 42: 469-470, 2010. [PubMed: 20502484] [Full Text: https://doi.org/10.1038/ng0610-469]
Sombekke, M. H., Jafari, N., Bendfeldt, K., Mueller-Lenke, N., Radue, E. W., Naegelin, Y., Kappos, L., Matthews, P. M., Polman, C. H., Barkhof, F., Hintzen, R., Geurts, J. J. G.No influence of KIF1B on neurodegenerative markers in multiple sclerosis. Neurology 76: 1843-1845, 2011. [PubMed: 21606458] [Full Text: https://doi.org/10.1212/WNL.0b013e31821cccd4]
Wellcome Trust Case Control Consortium.Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39: 1329-1337, 2007. [PubMed: 17952073] [Full Text: https://doi.org/10.1038/ng.2007.17]
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