Aging syndrome genes and premature coronary artery disease.
BACKGROUND
Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD.


METHODS
We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon.


RESULTS
Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus.


CONCLUSIONS
Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.
Low
Adrian F
AF
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA. mdclowa@nus.edu.sg;
O'Donnell
Christopher J
CJ
Kathiresan
Sekar
S
Everett
Brendan
B
Chae
Claudia U
CU
Shaw
Stanley Y
SY
Ellinor
Patrick T
PT
MacRae
Calum A
CA
D019588:Aging, Premature / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005966:Glucuronidase; D006801:Humans; D000090265:Klotho Proteins; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome
D034904:Lamin Type A; D008565:Membrane Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins