2009 Robert Levy Memorial Lecture—LDL and Atherosclerosis: What Simple Genetics Tell Us About a Complex Disease
Complex diseases result from interactions among multiple genetic and environmental factors. We have used DNA sequencing in individuals with extreme phenotypes to identify low-frequency alleles with large effects on gene function. This strategy has revealed that mutations with large effects on protein function are more common than was previously recognized and can provide important insights into phenotype and mechanism. By screening candidate genes involved in low-density lipoprotein metabolism, we identified sequence variants present in 2% to 3% of individuals in the general population that cause moderate (15% to 30%) reductions in low-density lipoprotein levels yet confer substantial protection against coronary heart disease. This finding suggests that complex diseases may not be so complex, either in etiology or prevention.