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Cat:
Genetic determinants of coronary heart disease/cardiomyopathies
A MICRO-RNA-410 REGULATED LIPOPROTEIN LIPASE POLYMORPHISM
IS ASSOCIATED WITH TRIGLYCERIDES AND STROKE INCIDENCE
D. Corella1,2, O. Coltell1,3, J.V. Sorli1,2, R. Estruch1,4, M. Fito1,5, F. Aros1,6, E. Ros1,7,
J. Lapetra1,8, G.T. Saez1,9, J.M. Ordovas1,10
1. CIBER Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain
2. Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia,
Valencia, Spain
3. Department of Computer Languages and Systems, University Jaume I, Castellon, Spain
4. Department of Internal Medicine, Hospital Clinic, IDIBAPS, Barcelona, Spain
5. Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research (IMIM), Barcelona, Spain
6. Department of Cardiology, Hospital Txagorritxu, Vitoria, Spain
7. Lipid Clinic, Endocrinology and Nutrition Service, Institut d’Investigacions Biomediques August Pi
Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain,
8. Department of Family Medicine, Primary Care Division of Sevilla, Sevilla, Spain
9. Department of Biochemistry and Molecular Biology, Clinical Analysis Service-CDB, HGUV, University
of Valencia, Valencia, Spain
10. Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts
University, Boston, MA, USA
Objectives and Background: microRNAs (miRNAs), small noncoding RNAs, have
emerged as important epigenetic regulators of many processes related to cardiovascular
diseases (CVD). miRNAs act as inhibitors of gene expression by binding to miRNA
recognition elements within the 3' UTR of their target mRNAs. Single nucleotide
polymorphisms (SNPs) can alter miRNA binding by either creating a new or destroying
an existing target site. In a previous work we demonstrated that the minor allele of the
rs13702 SNP (T>C) in the 3' UTR of the lipoprotein lipase (LPL) gene disrupts a miRNA
recognition element seed site for the miRNA-410, resulting in a gain-of-function. Our
objective was to analyze the association of this SNP with triglycerides, HDL-C, oxidative
stress parameters and incidence of CVD in a Mediterranean population.
Methods: We studied 7,187 participants in the PREDIMED with a median follow-up of
4.8 years. Triglycerides, HDL-C and oxidative stress parameters were determined at
baseline. Incidence of major CVD was assessed. We estimated hazard ratios (HR) by Cox
regression.
Results: We observed a strong inverse association between this miRNA target site SNP
and triglycerides [B: -0.13 mmol/l (-11 mg/dl) per C-allele, 95%CI: -0.20, -0.05;
P=3.4x10-13] and a direct association with higher HDL-C [B: 0.029 mmol/l per C-allele,
95%CI: 0.02, 0.04; P=1.1x10-5] in the whole population at baseline. We also detected an
inverse association with the oxidative stress markers malondialdehyde and 8-oxo-7'8'dihydro-2'-deoxyguanosine in nuclear DNA (in a sub-sample). Moreover, this miRNA410 target site SNPs was associated with lower stroke incidence in the whole population,
that remained significant after multivariable adjustment (HR: 0.74; 95%CI: 0.57,
0.97;P=0.029 per C-allele).