Unraveling the complex genetics of familial combined hyperlipidemia.

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.