Characterization of 𝘈𝘵𝘩𝘴𝘲1, an Atherosclerosis Modifier Locus on Mouse Chromosome 4:

Atherosclerosis, the primary cause of heart attack, stroke, and peripheral vascular disease, is genetically complex and the genes that confer cardiovascular risk remain largely unknown. Attempts to map common atherosclerosis susceptibility loci in humans have resulted in limited success. Mouse models provide an excellent tool for dissecting genetic complexity, and testing the role of candidate genes and pathways. While recent genome-wide association studies in humans have identified multiple genetic variants associated with atherosclerosis related traits- such as circulating lipid levels and hypertension- as well as myocardial infarction and stroke, few of the causal variants or underlying mechanisms are known. The work presented in this thesis identifies genetic loci contributing to atherosclerosis susceptibility in a murine model and, based on mechanistic data obtained in mouse, strongly suggests a mechanism underlying a coronary heart disease susceptibility locus on chromosome 9p21 identified by genome-wide association studies in humans. In this study we have used congenic mice that were previously constructed to isolate 𝘈𝘵𝘩𝘴𝘲1, an atherosclerosis susceptibility locus identified in a cross between MOLF/Ei and C57BL/6J-𝘓𝘥𝘭𝘳⁻⸍⁻. Atherosclerosis studies performed in congenic mice carrying the MOLF-derived susceptibility allele from chromosome 4, in the C57BL/6J-𝘓𝘥𝘭𝘳⁻⸍⁻ background, confirmed the existence of the 𝘈𝘵𝘩𝘴𝘲1 locus and BM-derived cells were shown to play an important role. Refined mapping of the 𝘈𝘵𝘩𝘴𝘲1 locus identified at least two susceptibility loci within the interval. A proximal locus was narrowed to a region containing 8-21 genes, including the region of homology with the human coronary heart disease risk interval on chromosome 9p21. Interestingly, mRNA expression analyses in macrophages revealed markedly decreased 𝘊𝘥𝘬𝘯2𝘢 transcript expression in cells derived from congenic mice compared to the controls. 𝘊𝘥𝘬𝘯2𝘢 is a candidate locus associated with the 9p21 locus in humans. The potential role of bone marrow -derived 𝘊𝘥𝘬𝘯2𝘢 expression in atherogenesis was tested using a bone marrow transplantation approach with 𝘊𝘥𝘬𝘯2𝘢-deficient donor cells. Mice receiving 𝘊𝘥𝘬𝘯2𝘢⁺⸍⁻deficient bone marrow exhibited accelerated atherosclerosis, increased inflammatory monocyte subsets and increased monocyte/macrophage proliferation compared to the controls. This study provides a mechanistic link between decreased 𝘊𝘥𝘬𝘯2𝘢 expression, increased monocytes/macrophages proliferation with the expansion of an inflammatory monocyte subset and increased atherosclerosis. Together, these data illustrate the utilization of mouse models as tools to elucidate causal gene(s)/loci and potential pathophysiologic mechanisms underlying genome-wide association studies-identified loci for human disease.

Author dc:creator

• Kuo, Chao-Ling

• Medical sciences
• Atherosclerosis--Genetic aspects
• Cardiovascular system--Diseases--Genetic aspects
• Molecular biology
• Mice--Genetics
• Macrophages
• Messenger RNA

Language dc:language

English

DOI dc:identifier

https://doi.org/10.7916/D8CV4QXC

OAI identifier oai:identifier

oai:academiccommons.columbia.edu:10.7916/D8CV4QXC