Common variation in the LMNA gene (Encoding Lamin A/C) and type 2 diabetes : Association analyses in 9,518 subjects

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 3; pp. 879 - 883
• Main Authors: OWEN, Katharine R, GROVES, Christopher J, WEIPING JIA, DELOUKAS, Panos, HITMAN, Graham A, WALKER, Mark, FRAYLING, Timothy M, HATTERSLEY, Andrew T, ZEGGINI, Eleftheria, MCCARTHY, Mark I, HANSON, Robert L, KNOWLER, William C, SHULDINER, Alan R, ELBEIN, Steven C, MITCHELL, Braxton D, FROGUEL, Philippe, NG, Maggie C. Y, CHAN, Juliana C
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2007
• Subjects: Adipocytes; Adult; Aged; Biological and medical sciences; Case-Control Studies; Consortia; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genes; Genetic aspects; Genetic code; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; Genetic Variation - genetics; Genetics; Haplotypes; Human genetics; Humans; Insulin resistance; Lamin Type A; Lamin Type A - genetics; Life Sciences; Male; Medical sciences; Metabolic syndrome; Middle Aged; Mutation; Mutation - genetics; Odds Ratio; Polymorphism, Single Nucleotide; Polymorphism, Single Nucleotide - genetics; Type 2 diabetes; Variation (Genetics); United States; United Kingdom; United Kingdom > UK; Endocrinopathy; Type 2 diabetes; Human; Metabolic diseases; Association; Gene
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0930

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).