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Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes

Association Analyses in 9,518 Subjects

¹ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
² Phoenix Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
³ Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
⁴ Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
⁶ CNRS UMR 8090, Institut de Biologie de Lille, Lille, France
⁷ Faculty of Life Sciences, Imperial College, London, U.K
⁸ Department of Medicine, University of Chicago, Chicago, Illinois
⁹ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong SAR
¹⁰ Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiaotong University No. 6 People’s Hospital, Shanghai, China
¹¹ Wellcome Trust Sanger Institute, Hinxton, U.K
¹² Centre for Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K
¹³ Department of Medicine, University of Newcastle, Newcastle, U.K
¹⁴ Institute of Clinical and Biomedical Science, Peninsula Medical School, Exeter, U.K
¹⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K

Address correspondence and reprint requests to Katharine Owen, Clinical Lecturer, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: katharine.owen{at}drl.ox.ac.uk

Abbreviations: FPLD, familial partial lipodystrophy; HRC, Human Random Control; MAF, minor allele frequency; SNP, single nucleotide polymorphism

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98–1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99–1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04–1.16], P = 0.001).

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