Abstract 468: Genetic Variation Within The Human Gp130 Gene Is Associated With Coronary Artery Diseases
Introduction: Liver-derived acute phase proteins such as C-reactive protein (CRP) or serum amyloid A (SAA) emerged as powerful predictors of cardiovascular diseases and future cardiovascular events. We previously demonstrated that a hepatocyte-specific knockout of the gp130 gene on an atherosclerotic background (apoE−/−) exhibits less aortic atherosclerosis with significantly decreased number of macrophages in the lesion.
Methods and results: To translate these findings to human diseases, we performed genetic association studies to evaluate, whether genetic variation in the human ortholog, IL6ST, contributes to the disease process. Therefore, single nucleotide polymorphisms (SNP) in IL6ST were analysed in two large study samples (513 MI families (Broeckel et al., Nat. Genetics, 2002)) and 1090 patients with documented coronary artery disease (CAD) (Popgen (www.popgen.de)).We tested a total of 11 SNPs located in the IL6ST gene, capturing 95% of the genetic variance within this linkage disequilibrium block. Single point analysis identified one SNP (rs10940495) that was significantly associated with CAD before and after adjustement for age, sex, smoking, diabetes, CAD , lipid medication and SNPs in the CRP gene, which were previously associated with CRP levels.We subsequently analyzed clinical subphenotypes of CAD as determined by angiography and detected a particularly high heritability for the disease manifestation in the proximal part of coronary arteries including lesions at the coronary ostium
Conclusion: The genetic analysis strengthens the impact of knock-out models plus comparative genetics approaches to identify susceptibility genes for common, complex diseases in humans i.e. atherosclerosis. This approach enables us to translate information from knock-out models directly to clinical relevance.