Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies.
We aim to assess the unknown genetic background of CHD by investigating the most common familial dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL). The population prevalence of FCHL is estimated to be 1-2 percent and the disorder affects 10-20 percent of families with premature CHD. In FCHL, serum cholesterol, triglycerides, or both are elevated. Both environmental and genetic factors are suggested to affect the complex FCHL phenotype. Since the molecular basis of FCHL is unknown, a significant number of genetically predisposed individuals remain unidentified and exposed to premature CHD. We will use our unique study samples from the genetically isolated population of Finland and apply molecular genetic tools to first restrict the genetic locus we have identified and then to characterize the causative gene underlying the FCHL disorder on chromosome 1q21. Specifically, we first aim to further restrict the region by dissecting the different component traits. We will genotype an extended study sample consisting of all available family members of 61 FCHL families with dense sets of microsatellite markers and single nucleotide polymorphisms to fully utilize the refined quantitative phenotype information in fine mapping. Second, we aim to build a transcript map over the critical region on 1q21-q23 and to identify the causative FCHL gene among the regional candidate genes. This region on 1q21-q23 is orthologous to a region on mouse chromosome 3, where a locus (Hyplip 1) for combined hyperlipidemia has been identified. We have analyzed the human homolog of the Hyplip 1 gene but disappointingly, the human Hyplip 1 gene was found 10 Mb from the peak linkage markers and no evidence emerged for Hyplip 1 as a causative gene for FCHL. Our targets to identify the FCHL gene are currently the genes showing strongest association near the linkage peak. The FCHL gene will then be functionally characterized to prove the biological dysfunction. Characterizing one gene for FCHL would improve our understanding of molecular mechanisms of cardiovascular disease, and potentially lead to more accurate diagnosis, treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL070150-01A1
Application #
6580595
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2003-03-15
Project End
2007-02-28
Budget Start
2003-03-15
Budget End
2004-02-29
Support Year
1
Fiscal Year
2003
Total Cost
$379,226
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Auro, Kirsi; Alanne, Mervi; Kristiansson, Kati et al. (2007) Combined effects of thrombosis pathway gene variants predict cardiovascular events. PLoS Genet 3:e120
Lee, Jenny C; Weissglas-Volkov, Daphna; Kyttala, Mira et al. (2007) USF1 contributes to high serum lipid levels in Dutch FCHL families and U.S. whites with coronary artery disease. Arterioscler Thromb Vasc Biol 27:2222-7
Komulainen, Kati; Alanne, Mervi; Auro, Kirsi et al. (2006) Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies. PLoS Genet 2:e69
Suviolahti, Elina; Lilja, Heidi E; Pajukanta, Paivi (2006) Unraveling the complex genetics of familial combined hyperlipidemia. Ann Med 38:337-51
Dastani, Zari; Quiogue, Leigh; Plaisier, Christopher et al. (2006) Evidence for a gene influencing high-density lipoprotein cholesterol on chromosome 4q31.21. Arterioscler Thromb Vasc Biol 26:392-7
Auro, K; Komulainen, K; Alanne, M et al. (2006) Thrombomodulin gene polymorphisms and haplotypes and the risk of cardiovascular events: a prospective follow-up study. Arterioscler Thromb Vasc Biol 26:942-7
Suviolahti, Elina; Reue, Karen; Cantor, Rita M et al. (2006) Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism. Hum Mol Genet 15:377-86
Weissglas-Volkov, Daphna; Huertas-Vazquez, Adriana; Suviolahti, Elina et al. (2006) Common hepatic nuclear factor-4alpha variants are associated with high serum lipid levels and the metabolic syndrome. Diabetes 55:1970-7
Lee, Jenny C; Lusis, Aldons J; Pajukanta, Paivi (2006) Familial combined hyperlipidemia: upstream transcription factor 1 and beyond. Curr Opin Lipidol 17:101-9

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