Genetic and functional studies of susceptibility genes in familial combined hyperlipidemia and hypoalphalipoproteinemia. Jenny Chin-Hyun Lee

ISBN: 9780549724582

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123 pages


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Genetic and functional studies of susceptibility genes in familial combined hyperlipidemia and hypoalphalipoproteinemia.  by  Jenny Chin-Hyun Lee

Genetic and functional studies of susceptibility genes in familial combined hyperlipidemia and hypoalphalipoproteinemia. by Jenny Chin-Hyun Lee
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Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol (TC) and/or triglycerides (TGs) is the most common form of familial dyslipidemia that predisposes to premature coronary heart disease (CHD).MoreFamilial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol (TC) and/or triglycerides (TGs) is the most common form of familial dyslipidemia that predisposes to premature coronary heart disease (CHD). Hypoalphalipoproteinemia (HA), characterized by elevated high density lipoprotein cholesterol (HCL-C) levels is an independent risk factor for CHD and a component trait of FCHL.

Both FCHL and HA are common complex disorders with the interplay of numerous genetic and environmental factors that contribute to the etiology. Genome-wide linkage analysis for both FCHL and HA have identified a number of linked loci- of which some overlap. The focus of this dissertation was to utilize human sequence variation to follow up regions of linkage in order to identify the genes and variants associated with the disease traits. In addition, a variant previously associated with FCHL was investigated in a replication study.-The upstream transcription factor I (USF 1) located on chromosome 1q23 was previously shown to be associated in Finnish FCHL families, with the strongest association observed for TGs in males.

We investigated the previously associated SNP rs3737787 for association in Dutch FCHL families and a cohort of U.S. Whites. Consistent with the original study, we observed significant sex-dependent associations for TGs and related metabolic traits, with the rare allele associated in females of the U.S. Whites and the common allele conferring risk in males of the Dutch FCHL families and the U.S. Whites. Moreover, a highly significant genotype x sex interaction was observed for TGs in the Dutch FCHL families and TGs and BMI in the U.S.

Whites.-A locus on chromosome 16q23-34 has been significantly linked to low levels of HDL-C in several genome-wide linkage studies. We employed a two-stage design to follow up this region of linkage using a tag-SNP strategy and identified one variant rs2548861 within the WWOX gene that was significantly associated in the stage I and 2 study samples and their combined analysis.

Furthermore, we replicated the association in two independent population based cohorts, a cross-sectional cohort of Finnish males of age 50-70 (METSIM) and a prospective cohort of young Finns (LASERI). We observed a significant association between rs2548861 and HDL-C levels in the METSIM cohort. In the LASERI cohort, we observed significant associations with both the mean of four HDL-C measurements and the longitudinal HDL-C levels obtained over a span of 21 years.-The rs2548861 SNP is located within a computationally predicted cis-regulatory element in intron 8 of WWOX and investigation of the potential enhancer/silencer function of this element by a reporter gene assay showed that the region functions as a transcriptional silencer.

Furthermore, a significant allelic effect of the rs2548861 SNP was observed with the risk allele resulting in even further suppression of the reporter activity. We also quantified the HDL-C levels in mice with a targeted deletion of the Wwox gene and observed a statistically significant difference in HDL-C levels between the knockout mice compared to heterozygous and wildtype littermates. Taken together, our genetic and functional data show that rs2548861 within WWOX influences serum HDL-C levels.-We utilized a tagSNP strategy to survey all of the common variants within a candidate gene myocardin-like 2 (MKL2) located in a region of suggestive linkage.

The mouse Mk12 was shown to interact with Hnf1A and Hnf4A, both genes known to have critical metabolic functions in the liver of mice. We identified a SNP rs30144 that was significantly associated with TG levels in Finnish and Dutch FCHL families.

Microarray expression analysis of Finnish fat biopsy samples showed that the myocardin-like 2 (MKL2) gene had the most significant evidence of differential expression according to TG affection of all the transcripts arrayed in this region of suggestive linkage.



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