Linking genotype to aorto-coronary atherosclerosis: a model using familialhypercholesterolemia and aorto-coronary calcification

Most studies of the pathogenesis of coronary heart disease occur between ge ne variants and biochemical or physiological variables known to be atheroge nic. In many situations, however, the gene products are not necessarily kno wn. We studied 17 families (n = 122) with mutations in the lon density lipo protein (LDL) receptor gene as a model in which to test formally for linkag e directly between an atherogenic genotype and ischemic heart disease (IHD) or aorto-coronary calcified atherosclerosis. In each family one of three d ifferent mutations was found: the Trp(66)-Gly mutation, the Trp(23)-Stop mu tation, or a tell kilobase deletion removing exons 3-6 of the LDL receptor gene. Genomic DNA was used to determine these mutations by either enzymatic cleavage assays or Southern blotting. Aorto-coronary calcification n as si gnificantly associated with age and plasma cholesterol. Sex, hypertension, BMI and smoking were not, associated with aorta-coronary calcification. Non parametric analysis indicated significant linkage of the LDL receptor gene locus to aortic (p < 0.00005) and to aorto-coronary calcified atheroscleros is (p < 0.00001), Assuming a dominant mode of inheritance, significant link age n as detected for aortic (LOD = 3.89) and aorto-coronary calcified athe rosclerosis (LOD = 4.10). We suggest that the at atherogenicity of variatio ns in other genes could be assessed LS a similar approach.