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New gene implicated in type 2 diabetes

Analysis of a study published in a science journal   |   By Dr Gurdeep Sagoo   |   Published 11 March 2011
Study: Functional variants of the HMGA1 gene and type 2 diabetes mellitus
By: Chiefari E. et al. (18 authors total)
In: Journal of the American Medical Association
Link: http://dx.doi.org/10.1001/jama.2011.207
What this study set out to do:

To examine the association between variants in the HMGA1 gene and type 2 diabetes mellitus (T2DM). 

How they went about it:

The researchers sequenced the HMGA1 gene in almost 6000 Italian T2DM patients and healthy controls. Genotyping was conducted in a further 784 Italian healthy controls, and in nearly 2500 individuals of European descent from two additional case-control populations.

Outcome:

The initial sequencing of the HMGA1 gene revealed 25 variants of which 4 were associated with T2DM in the Italian population. The IVS5-13insC variant was then chosen (by virtue of being more common) for genotyping in the additional study populations and again showed association. This variant was present in 7-8% of T2DM patients in all three populations, but varied amongst the three control populations.

Conclusion:

The authors conclude that their results indicate that variants in this gene are associated with T2DM in patients of European ancestry. Carriers of the IVS5-13insC variant showed altered levels of HGMA1 messenger RNA and HMGA1 protein expression with T2DM patients associated with significantly reduced levels. The authors believe that these observations could have important clinical implications such as on the clinical course of the disease as well as response to drug treatments.

Our view:

The accompanying editorial in JAMA highlights three main concerns. First, although the IVS5-13insC variant is present in around 7% of patients, it varies in the control populations (0.4% to 5%). Different populations, recruitment procedures and sample sizes may partly explain these differences. Second, the cohorts used to replicate these findings in the Italian cohort were not large enough, which is evinced by only 50 controls in the French cohort. Third, despite the increased number of T2DM patients carrying these variants, none were reported as homozygotes or compound heterozygotes and the effect of carrying either one or two copies of these variants cannot be compared. The authors themselves acknowledge that “further studies of the HMGA1 gene and its variants, including studies in other racial types, are needed to understand the role of HMGA1 in insulin resistance and type 2 DM”.

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