title: Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects.
abstract: 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).
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. katharine.owen@drl.ox.ac.uk
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Chan
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A