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Abstract
Familial combined hyperlipidemia (FCHL) constitutes a substantial risk factor for atherosclerosis since it is observed in about 20% of coronary heart disease (CHD) patients under 60 years. FCHL, characterized by elevated levels of total cholesterol (TC) and triglycerides (TGs), or both, is also one of the most common familial hyperlipidemias with a prevalence of 1%–6% in Western populations. Numerous studies have been performed to identify genes contributing to FCHL. The recent linkage and association studies and their replications are beginning to elucidate the genetic variations underlying the susceptibility to FCHL. Three chromosomal regions on 1q21–23, 11p and 16q22–24.1 have been replicated in different study samples, offering targets for gene hunting. In addition, several candidate gene studies have replicated the influence of the lipoprotein lipase (LPL) gene and apolipoprotein A1/C3/A4/A5 (APOA1/C3/A4/A5) gene cluster in FCHL. Recently, the linked region on chromosome 1q21 was successfully fine‐mapped and the upstream transcription factor 1 (USF1) gene identified as the underlying gene for FCHL. This finding has now been replicated in independent FCHL samples. However, the total number of variants, the risk related to each variant and their relative contributions to the disease susceptibility are not known yet.
| Abbreviations | ||
| APOA1 | = | apolipoprotein A1 |
| APOA2 | = | apolipoprotein A2 |
| APOA5 | = | apolipoprotein A5 |
| APOB | = | apolipoprotein B |
| APOC3 | = | apolipoprotein C3 |
| APOE | = | apolipoprotein E |
| APOA1/C3/A4/A5 | = | apolipoprotein A1/C3/A4/A5 |
| CHD | = | coronary heart disease |
| FCHL | = | familial combined hyperlipidemia |
| HDL‐C | = | high‐density lipoprotein cholesterol |
| HNF4A | = | hepatic nuclear factor 4 alpha |
| LD | = | linkage disequilibrium |
| LDL‐C | = | low‐density lipoprotein cholesterol |
| LEPR | = | leptin receptor |
| LIPC | = | hepatic lipase |
| LPL | = | lipoprotein lipase |
| SNP | = | single nucleotide polymorphism |
| TC | = | total cholesterol |
| TG | = | triglycerides |
| TNFRSF1B | = | tumor necrosis factor receptor superfamily, member 1B |
| TXNIP | = | thioredoxin interacting protein |
| T2DM | = | type 2 diabetes mellitus |
| USF1 | = | upstream transcription factor 1 |
| Abbreviations | ||
| APOA1 | = | apolipoprotein A1 |
| APOA2 | = | apolipoprotein A2 |
| APOA5 | = | apolipoprotein A5 |
| APOB | = | apolipoprotein B |
| APOC3 | = | apolipoprotein C3 |
| APOE | = | apolipoprotein E |
| APOA1/C3/A4/A5 | = | apolipoprotein A1/C3/A4/A5 |
| CHD | = | coronary heart disease |
| FCHL | = | familial combined hyperlipidemia |
| HDL‐C | = | high‐density lipoprotein cholesterol |
| HNF4A | = | hepatic nuclear factor 4 alpha |
| LD | = | linkage disequilibrium |
| LDL‐C | = | low‐density lipoprotein cholesterol |
| LEPR | = | leptin receptor |
| LIPC | = | hepatic lipase |
| LPL | = | lipoprotein lipase |
| SNP | = | single nucleotide polymorphism |
| TC | = | total cholesterol |
| TG | = | triglycerides |
| TNFRSF1B | = | tumor necrosis factor receptor superfamily, member 1B |
| TXNIP | = | thioredoxin interacting protein |
| T2DM | = | type 2 diabetes mellitus |
| USF1 | = | upstream transcription factor 1 |
Acknowledgements
Many students and collaborators contributed to the work and ideas presented in this review and we would like to thank them. Work in the laboratory of PP is supported by the National Institutes of Health grants HL‐28481, HL‐82762 and HL‐70150, as well as the American Heart Association grant 0430180N.