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Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23
P Pajukanta1, I Nuotio, J D Terwilliger
1Department of Human Molecular Genetics, National Public Health Institute and Institute of Biomedicine, University of Helsinki, Finland.
Insights
Familial combined hyperlipidaemia (FCHL), a common genetic disorder, is linked to premature coronary heart disease (CHD). Researchers identified a novel FCHL gene locus on chromosome 1q21-q23 in Finnish families.
Area of Science:
- Human Genetics
- Cardiovascular Disease
- Metabolic Disorders
Background:
- Familial combined hyperlipidaemia (FCHL) is the most common genetic dyslipidemia, affecting 1.0-2.0% of the population.
- FCHL is a significant contributor to premature coronary heart disease (CHD), causing an estimated 10-20% of cases.
- Genetic heterogeneity and unclear inheritance patterns have hindered the identification of FCHL-predisposing genes.
Purpose of the Study:
- To identify novel genetic loci associated with familial combined hyperlipidaemia (FCHL).
- To minimize genetic heterogeneity by studying families from an isolated population with strict phenotype criteria.
Main Methods:
- Linkage analysis was performed on 31 extended FCHL families from the Finnish population.
- Markers from ten chromosomal regions containing lipid-metabolism candidate genes were analyzed.
- Lod scores were calculated to assess the linkage between markers and the FCHL phenotype.
Main Results:
- A significant linkage was detected with marker D1S104 on chromosome 1, adjacent to the apolipoprotein A-II (APOA2) gene (lod score Z = 3.50).
- Multipoint analysis combining D1S104 and D1S1677 yielded a lod score of 5.93, strongly suggesting linkage.
- The identified locus on chromosome 1q21-q23 is distinct from the physical locations of known lipid-related genes in the vicinity, indicating a novel FCHL locus.
Conclusions:
- A novel locus for familial combined hyperlipidaemia (FCHL) has been identified on chromosome 1q21-q23.
- This finding provides a new target for understanding the genetic basis of FCHL and its role in premature coronary heart disease.
- Further research, including studies in syntenic regions of other species, supports the etiological significance of this chromosomal region in hyperlipidaemia.
Abstract:
More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.