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Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes

Nature Genetics volume 37, pages 111–112 (2005)Cite this article

To the editor:

In the August 2004 issue, Guo et al.1 reported a highly significant association of type 1 diabetes (T1D) with a haplotype encompassing the gene encoding SUMO4, a new member of the family of small ubiquitin-like modifiers with effects on IκBα action. The G allele of the 163A→G SNP (resulting in the amino acid substitution M55V) was overtransmitted to affected children with high statistical significance when all families were examined, but in a small subset of 92 British multiplex families, the A allele was nonsignificantly overtransmitted. In a simultaneously published paper, Bohren et al.2 reported a highly significant overtransmission of the A allele in a cohort of 478 multiplex families, derived in almost equal parts from the Human Biological Data Interchange (mostly US cases) and the Warren Repository (UK). Guo et al. attribute the discrepancy between the European and UK families to genetic heterogeneity. What is notable is not the concept of locus heterogeneity in T1D but its marked subpopulation dependence and the possible genetic mechanisms and population structure that might explain these findings. Allelic heterogeneity in cis would imply that the 163A→G SNP is only a marker for some other functional variant and might have been obviously different in haplotype structure or allele frequencies in the British subset compared with the rest of the samples in the multiple SNP data that Guo et al. generated. The absence of comment to this effect may be interpreted as indication that such difference was not found. Our data (Supplementary Fig. 1 online), generated by genotyping 163A→G in the 30 families from the Centre d'Étude du Polymorphisme Humain used in the HapMap project3, confirm that 163A→G is part of a solid linkage disequilibrium block with little internal structure. Locus heterogeneity in trans, involving allele frequencies at epistatically interacting loci, would be much more interesting biologically, much more difficult to map and equally puzzling in the context of European subpopulations.

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References

  1. Guo, D. et al. Nat. Genet. 36, 837–841 (2004).

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  2. Bohren, K.M., Nadkarni, V., Song, J.H., Gabbay, K.H. & Owerbach, D. J. Biol. Chem. 279, 27233–27238 (2004).

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Authors and Affiliations

  1. The McGill University Health Center (Montreal Children's Hospital), Montréal, Quebec, Canada

    Huiqi Qu & Constantin Polychronakos

  2. Program in Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario, Canada

    Bhupinder Bharaj, Xiao-Qing Liu & Andrew D Paterson

  3. Health Care Corporation of St. John's, Outreach, St. John's, Newfoundland, Canada

    Joseph A Curtis & Leigh Anne Newhook

  4. Discipline of Pediatrics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada

    Joseph A Curtis & Leigh Anne Newhook

  5. Departments of Public Health Sciences, and Psychiatry, and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Andrew D Paterson

  6. McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada

    Thomas J Hudson

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  1. Huiqi Qu
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  2. Bhupinder Bharaj
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  3. Xiao-Qing Liu
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  4. Joseph A Curtis
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  5. Leigh Anne Newhook
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  8. Constantin Polychronakos
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Correspondence to Constantin Polychronakos.

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Qu, H., Bharaj, B., Liu, XQ. et al. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. Nat Genet 37, 111–112 (2005). https://doi.org/10.1038/ng0205-111

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