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.