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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1708.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Variation in the Lamin A/C Gene

Associations With Metabolic Syndrome

Nanette I. Steinle; Rasa Kazlauskaite; Ikhide G. Imumorin; Wen-Chi Hsueh; Toni I. Pollin; Jeffrey R. O’Connell; Braxton D. Mitchell; Alan R. Shuldiner

From the Department of Medicine (N.I.S., T.I.P., J.R.O., B.D.M., A.R.S.), University of Maryland School of Medicine, Baltimore, Md; the Department of Medicine (R.K.), Rush Medical College, Chicago, Ill; the Department of Biology (I.G.I.), Valdosta State University, Georgia; the Department of Medicine (W.-C.H.), University of California, San Francisco; and the Geriatric Research and Education Clinical Center (A.R.S.), Veterans Administration Medical Center, Baltimore, Md.

Correspondence to Nanette Steinle, MD, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 W Redwood St, Room 467, Baltimore, MD 21201. E-mail nsteinle{at}medicine.umaryland.edu

Objective— Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM). The lamin A/C (LMNA) gene, mutations of which cause rare syndromes of severe insulin resistance and dyslipidemia, is located on chromosome 1q21-q24, a region linked to T2DM in several genome wide scans, including in the Old Order Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components.

Methods and Results— We performed DNA sequence analysis of LMNA. Six single-nucleotide polymorphisms (SNPs) were identified: c.141889C>T (intron 3), c.141906G>T (intron 3), A287A (c.141253T>C; exon 5), c.140353G>A (intron 6), c.139418C>T (intron 8), and H566H (c. 138747C>T; exon 10). In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations. However, no differences in allele frequencies were observed for any SNP among participants with T2DM or impaired glucose homeostasis (IGH) and normoglycemic controls. Haplotype analysis showed that >87% of individuals carried 1 of 2 common LMNA haplotypes. There were no significant differences in haplotype frequencies among subjects with metabolic syndrome T2DM, IGH, and controls.

Conclusion— Sequence variation in LMNA may confer modest susceptibility for development of metabolic syndrome and dyslipidemia in the Amish.

To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components, we performed DNA analysis of polymorphisms in LMNA. The H566H polymorphism was associated with metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations in the Old Order Amish.

Key Words: lamin A/C • lipids • triglyceride • metabolic syndrome • insulin resistance • positional cloning • chromosome 1q21-q24

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