Focus on atherosclerosis and the pig as a model to identify genes affecting cholesterol and other plasma lipid levels

Cholesterol is a ubiquitous steroid and a vital component of cellular membranes in vertebrates. At the same time, subendothelial deposition of cholesterol and other lipoproteins is the culprit of atherosclerotic lesions leading to a range of cardiovascular diseases which together represent the most frequent causes of death in the industrialized world. The balance between plasma levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) is critical for disease development. A high level of LDL-C is atherogenic whereas a high level of HDL-C is cardio protective. Heritability of LDL-C and HDL-C levels in humans are estimated to be up to 70%. However, loci identified by large-scale genome-wide screens in humans explain only a small fraction of the genetic variation. Few GWAS and QTL mapping studies have been performed in mice to identify loci affecting blood lipid levels. More often, spontaneous dyslipidemic and genetically engineered mice models have been used to study the effect of dyslipidemia associated genes identified in human GWAS studies. Here we employ the pig as a full size animal model for atherosclerosis. The pig has a close similarity to humans in physiology, organ development and disease progression. We have established F2 pedigrees using Göttingen Minipig as the parental boar line and Duroc and Yorkshire as parental sow lines. Whereas Duroc and Yorkshire represent lean, fast growing production breeds, the Göttingen Minipig is an obesity prone pig breed often used in studies of obesity, diabetes and metabolic syndrome. Levels of LDL-C, HDL-C and several other blood lipids were measured at two age points in a total of 564 F2 animals. GWAS, LD and haplotype analyses identified seven loci with effect on different blood lipid levels. Five of these loci are clustered in a 12 Mb region on chromosome 3. Interestingly, the haplotypes associated with an atherosclerosis protective blood lipid profile are in general found to originate from the Göttingen Minipig.