Cardiometabolic Disease's Risk through Population Genetic Studies: Historical, Present and Future Resources of the Brisighella Biobank

Cardiovascular diseases (CVD) comprise the most common chronic disease worldwide. High lipid levels are a strong risk factor, making lipid-lowering statin therapy an important preventive measure. Here we explore the effects of common variants at the KIF6 and HMGCR loci on a range of cardio-metabolic traits and on response to statin therapy. While HMGCR is a well-established lipid-related locus, the role of KIF6 in response to statin therapy is controversial, and its contribution to related phenotype variability has not been clarified. We genotyped a coding KIF6 variant (p.W719R, rs20455) and two intronic ones in high LD to the former (rs9462535,rs9471077), as well as two non-coding variants in HMGCR (rs3761740 and rs3846662). Effects on 14 quantitative and 5 categorical cardiometabolic phenotypes including lipid-lowering therapy response were tested in a sample of 1,645 individuals from the Genetics in Brisighella Health Study (GBHS) from Italy and replicated in 10,662 individuals from the Estonian Genome Center (EGCUT). In GBHS the established HMGCR variant rs3846662 affects LDL cholesterol levels (P=8.5x10-4) while the intronic KIF6 variant rs9471077 modifies APOB levels (P=8.2x10-4). The latter association was confirmed in EGCUT. No significant association between KIF6 variants and response to statin therapy was observed. In the first genetic study involving GBHS we confirm the HMGCR effect on LDL-Cholesterol and demonstrate a novel KIF6 effect on APOB. The latter association needs to be evaluated for its predictive value for overall CVD risk and its potential contribution to stratified patient care.