Low-Frequency Variants in HMGA1 Are Not Associated With Type 2 Diabetes Risk
- Marcel Marquez1,
- Marlène Huyvaert1,
- John R.B. Perry2,3,
- Richard D. Pearson2,
- Mario Falchi4,
- Andrew P. Morris2,
- Sidonie Vivequin1,
- Stéphane Lobbens1,
- Loïc Yengo1,
- Stefan Gaget1,
- Francois Pattou5,
- Odile Poulain-Godefroy1,
- Guillaume Charpentier6,
- Lena M.S. Carlsson7,
- Peter Jacobson7,
- Lars Sjöström7,
- Olivier Lantieri8,
- Barbara Heude9,
- Andrew Walley4,
- Beverley Balkau9,
- Michel Marre10,
- the DIAGRAM Consortium*,
- Philippe Froguel1,4⇓ and
- Stéphane Cauchi1
- 1UMR CNRS 8199, Genomic and Metabolic Disease, Lille, France
- 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
- 3Genetics of Complex Traits, Peninsula Medical School, University of Exeter, Exeter, U.K.
- 4Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K.
- 5Cell Therapy of Diabetes, INSERM 859, Lille, France
- 6Corbeil-Essonnes Hospital, Department of Endocrinology-Diabetology, Corbeil-Essonnes, France
- 7Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, The Sahlgrenska Academy, Gothenburg, Sweden
- 8Institut inter Régional pour la SAnté, La Riche, France
- 9INSERM Centre de recherche en Epidémiologie et Santé des Populations U1018, Villejuif, France
- 10Endocrinology-Diabetology-Nutrition, Bichat-Claude Bernard Hospital, Paris, France, and the University Denis Diderot Paris 7, Paris, France
- Corresponding author: Philippe Froguel, .
It has recently been suggested that the low-frequency c.136–14_136–13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136–14_136–13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136–14_136–13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0728/-/DC1.
*A complete list of the DIAGRAM Consortium members can be found in the Supplementary Data.
- Received May 26, 2011.
- Accepted October 4, 2011.
- © 2012 by the American Diabetes Association.
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