Abstract
Background . The discovery of new genes responsible for regulation of high-density lipoprotein cholesterol (HDL) has great clinical relevance since increases in HDL can reduce cardiovascular disease risk. Quantitative trait locus (QTL) analysis is a means of finding novel genes that regulate complex traits, such as atherosclerosis and HDL. Hdlq14 and Hdlq15 , two closely linked QTLs for HDL on mouse Chr 1, have been detected by using an intercross between strains C57BL/6 (B6) and 129S1/SvImJ (129). Apoa2 is the gene for Hdlq15 locus, but the gene for Hdlq14 is unknown. Methods: To confirm the Hdlq14 and identify the candidate gene, we performed QTL analysis in a F2 population generated from strains NZB and NZW, which are same at Apoa2 to avoid its strong effect on the nearby QTL. Hdlq14 was further narrowed by several strategies including combining crosses, comparative genomics, and haplotype analysis. The reduced lists of candidate genes were evaluated by their expression or sequence differences between the strains that caused the Hdlq14 . Finally, other HDL crosses, including NZOxNON, B6xC3H, and Pera x D2, were examined to point out the QTL gene. The relationship between the polymorphism at the Hdlq14 gene and HDL was analyzed in 43 genetically diverse mouse strains. Results: Hdlq14 was proved in cross NZBxNZW and the critical interval was reduced from 45 Mb harboring 271 genes to 1.65 Mb containing 15 genes by using bioinformatics tools. Six of these 15 genes have polymorphisms that changed an amino acid; and two genes were found have a significant expression difference between strains B6 and 129. The Hdlq14 gene was further pointed out using HDL QTL identified in crosses including NZOxNON, B6xC3H, and PeraxDBA. In 43 genetically diverse mouse strains, we found that strains with one allele of the Hdlq14 had significantly higher plasma HDL levels than those with the other variant. Conclusions: The Hdlq14 was identified as a new HDL-regulating gene.
Published Version
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