Linking genotype to aorto-coronary atherosclerosis: a model using familial hypercholesterolemia and aorto-coronary...

Most studies of the pathogenesis of coronary heart disease occur between gene variants and biochemical or physiological variables known to be atherogenic. In many situations, however, the gene products are not necessarily known. We studied 17 families (n = 122) with mutations in the low density lipoprotein (LDL) receptor gene as a model in which to test formally for linkage directly between an atherogenic genotype and ischemic heart disease (IHD) or aorto-coronary calcified atherosclerosis. In each family one of three different mutations was found: the Trp66-Gly mutation, the Trp23-Stop mutation, or a ten 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 was significantly associated with age and plasma cholesterol. Sex, hypertension, BMI and smoking were not associated with aorto-coronary calcification. Nonparametric analysis indicated significant linkage of the LDL receptor gene locus to aortic (p < 0.00005) and to aorto-coronary calcified atherosclerosis (p < 0.00001). Assuming a dominant mode of inheritance, significant linkage was detected for aortic (LOD = 3.89) and aorto-coronary calcified atherosclerosis (LOD = 4.10). We suggest that the atherogenicity of variations in other genes could be assessed by a similar approach.