Vitamin K: Genetics of Vascular Calcification

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Vascular calcification of the coronary arteries and aorta is a risk factor for coronary heart disease (CHD) and other cardiovascular diseases (CVD). In addition, vascular calcification has also been associated with osteoporosis. Both CVD and osteoporosis represent major age-associated health problems and their impact will increase in importance as the global aging of the population continues. A substantial proportion of CHD risk results from modifiable coronary risk factors, such as hypertension, hyperlipidemia, and cigarette smoking. This knowledge has been used to implement successful prevention and therapeutic strategies to stop the increase in CHD mortality that took place during the latter part of the 20th Century. Likewise, identification of those modifiable factors that contribute to an increase in vascular calcification and a reduction in bone mass in older populations could lead to additional effective interventions to reduce the burden not only for CHD but also for fractures in the general population. From the standpoint of prevention, the identification of dietary risk factors common to both diseases is particularly important, because the relatively low cost and safety of dietary therapy. The primary objectives of this study are to identify genetic components underlying vitamin K metabolism, osteoporosis, and vascular calcification and the variability in response to dietary supplementation in elderly men and women. For this purpose, we will evaluate associations between single nucleotide polymorphisms (SNPs) and haplotypes at certain candidate genes [apolipoprotein E (APOE), lipoprotein lipase (LPL), Matrix Gla Protein (MGP), Vitamin D Receptor (VDR)] and baseline levels of vitamin K metabolism related measures, osteoporosis, and vascular calcification in 450 elderly subjects participating in a NIH funded phase III clinical study. Moreover, we will analyze gene by treatment interactions in order to determine the contribution of the genes examined to the variability in response to vitamin supplementation. To the best of our knowledge, this is the first proposal of its kind to study the influence of genetic variation in response to vitamin K supplementation, progression of age-related bone loss and vascular calcification. This research should provide the basis for more comprehensive genetic studies aimed to provide better identification of risk and more precise therapeutic approaches for these age-related disorders.