Familial combined hyperlipidaemia: under - defined and under - diagnosed?

Area of Science:

• Genetics
• Cardiovascular Disease
• Lipid Metabolism

Background:

• Familial combined hyperlipidaemia (FCH) is a dominant genetic disorder associated with mixed hyperlipidaemia and early-onset coronary heart disease.
• FCH is sensitive to environmental influences, complicating its genetic basis.
• Unlike familial hypercholesterolaemia, FCH genetics are complex with few identified genes.

Purpose of the Study:

• To review the definitions, animal models, and genetics of Familial Combined Hyperlipidaemia (FCH).
• To highlight recent advances in identifying candidate genes for FCH.
• To discuss the challenges in resolving the genetic architecture of FCH.

Main Methods:

• Review of existing literature on FCH definitions, animal models, and genetic studies.
• Analysis of genetic associations, including quantitative trait mapping.
• Examination of candidate genes such as apoA-I cluster, USF-1, and CD-36.

Main Results:

• Early studies linked FCH to the apoA-I, A-IV, A-V, C-III gene cluster on chromosome 11.
• Quantitative trait mapping identified upstream transcription factor-1 (USF-1) on 1q21 as a strong candidate gene.
• Intronic variants in USF-1 show the strongest association with FCH lipid components, but links to diabetes and metabolic syndrome are unclear.

Conclusions:

• The genetics of FCH are complex and likely heterogeneous.
• Upstream transcription factor-1 (USF-1) variants are strongly associated with FCH lipid profiles.
• Environmental factors, obesity, and metabolic syndrome significantly confound FCH genetics, posing a major research challenge.