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).