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Coronary heart disease (CHD) is the major cause of death in most industrialized and developing countries. Links between genetic and dietary factors that modify the risk of CHD should give fundamental insight into its causes and improve population-based CHD prevention strategies. We propose to identify genes that modulate the association between dietary fatty acids (FAs) and myocardial infarction (MI). We will use DNA samples obtained during a population-based, case-control study in Costa Rica of 2,150 subjects who experienced MI and 2,150 matched controls. Biochemical measurements, dietary data, and general information are available for this population. One unique aspect of the proposed study is that we will use adipose tissue biomarkers of polyunsaturated FAs to evaluate dietary exposure variables. Adipose tissue biomarkers (i.e., alpha-linolenic and linoleic acid) are very good indicators of intake in this population. Furthermore, this study showed that increase levels of these biomarkers in adipose tissue are strongly associated with decreased risk of MI, whereas increase 18:2 trans FAs increase the risk of MI. We will use gene-diet association studies and a "candidate pathway" approach to elucidate genetic mechanisms that link risk of MI with exposure to polyunsaturated FAs [including cis and trans isomers of linoleic acid (n-6), and alpha-linolenic acid (n-3)]. We will focus on peroxisome proliferator-activated receptor (PPAR) genes, and PPAR-regulated genes, that are involved in vascular inflammation. Among controls, we will examine whether genetic and dietary factors independently affect biochemical markers (phenotypes) of the proposed genes. We will also test whether these phenotypes are more clearly identified when genetic and dietary factors are examined together. Because polyunsaturated FAs are important as activators of PPARs and their capacity to regulate gene expression at the level of transcription, this metabolic system is a suitable candidate for the proposed study.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.