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

Bonnefond, A., Yengo, L., Philippe, J., Dechaume, A., Ezzidi, I., Vaillant, E., Gjesing, A. P., Andersson, E. A., Czernichow, S., Hercberg, S., Hadjadj, S., Charpentier, G., Lantieri, O., Balkau, B., Marre, M., Pedersen, O., Hansen, T., Froguel, P. and Vaxillaire, M. (2013) Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetologia, 56 3: 492-496. doi:10.1007/s00125-012-2794-8


Author Bonnefond, A.
Yengo, L.
Philippe, J.
Dechaume, A.
Ezzidi, I.
Vaillant, E.
Gjesing, A. P.
Andersson, E. A.
Czernichow, S.
Hercberg, S.
Hadjadj, S.
Charpentier, G.
Lantieri, O.
Balkau, B.
Marre, M.
Pedersen, O.
Hansen, T.
Froguel, P.
Vaxillaire, M.
Title Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes
Formatted title
Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes
Journal name Diabetologia   Check publisher's open access policy
ISSN 0012-186X
1432-0428
Publication date 2013-03-01
Year available 2012
Sub-type Article (original research)
DOI 10.1007/s00125-012-2794-8
Open Access Status Not yet assessed
Volume 56
Issue 3
Start page 492
End page 496
Total pages 5
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted 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.
Keyword BLK
Diabesity
Genetics
Low-frequency variant
Maturity-onset diabetes of the young
MODY
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID ERANET-09 RARE-005
2003
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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