Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-03

AUTHORS

A. Bonnefond, L. Yengo, J. Philippe, A. Dechaume, I. Ezzidi, E. Vaillant, A. P. Gjesing, E. A. Andersson, S. Czernichow, S. Hercberg, S. Hadjadj, G. Charpentier, O. Lantieri, B. Balkau, M. Marre, O. Pedersen, T. Hansen, P. Froguel, M. Vaxillaire

ABSTRACT

AIMS/HYPOTHESIS: MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. METHODS: BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. RESULTS: No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. CONCLUSIONS/INTERPRETATION: No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation. More... »

PAGES

492-496

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00125-012-2794-8

DOI

http://dx.doi.org/10.1007/s00125-012-2794-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1034783008

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23224494


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