Variation in the lamin A/C gene: associations with metabolic syndrome.
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.


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.


CONCLUSIONS
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.
Steinle
Nanette I
NI
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA. nsteinle@medicine.umaryland.edu
Kazlauskaite
Rasa
R
Imumorin
Ikhide G
IG
Hsueh
Wen-Chi
WC
Pollin
Toni I
TI
O'Connell
Jeffrey R
JR
Mitchell
Braxton D
BD
Shuldiner
Alan R
AR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D015331:Cohort Studies; D003241:Consanguinity; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D006946:Hyperinsulinism / Q000235:genetics; D015228:Hypertriglyceridemia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D034904:Lamin Type A / Q000235:genetics* / Q000502:physiology; D015810:Linkage Disequilibrium; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D010414:Pennsylvania; D020641:Polymorphism, Single Nucleotide
D034904:Lamin Type A; D008075:Lipoproteins, HDL; C440308:lamin C