Oligopolygenic complex genetic hyperlipidemias

Familial combined hyperlipidemia (FCHL)

Combined hyperlipidemia, characterized by increased serum triglyceride and/or cholesterol and decreased HDL cholesterol is the most common disorder of lipid metabolism affecting 1-2% of individuals in Western societies.

The term familial combined hyperlipidemia (FCHL) was coined by Goldstein et al. to describe a pattern of lipid abnormalities (Goldstein et al., 1973) in survivors of myocardial infarction who had raised blood cholesterol and triglyceride levels. Originally, FCHL was described as a dominant disorder with a primary effect on blood triglyceride levels, a secondary effect on cholesterol levels, and with incomplete penetrance until the third decade (Goldstein et al., 1973). However subsequent segregation analyses (Austin, 1992;

Cullen et al., 1994) and three genome-wide studies (Aouizerat et al., 1999; Naoumova et al., 2003; Pajukanta et al., 1999) have suggested a more complex inheritance pattern (Shoulders et al., 2004).

The molecular basis of FCHL is still unknown. The evidence for major genes acting on apoB, insulin and triglyceride levels in FCHL is consistent with the metabolic finding of increased production of VLDL and apoB100 (Kissebah et al., 1984; Venkatesan et al., 1993), defective catabolism of VLDL and chylomicrons (Babirak et al., 1992; Cabezas et al., 1993) and increased production of apoCIIIand insulin resistance (Aitman etal., 1997a; Dallinga-Thie etal., 1996; Ito etal., 1990).

Candidate gene approaches to identify the primary metabolic defects underlying FCHL have been largely unrewarding. Genome-wide studies in FCHL-implicated regions on chromosome 1q, 6q, 8p and 11p (Aouizerat et al.,1999; Naoumova et al., 2003; Pajukanta et al., 1999). Apo A5, a newly discovered gene involved in lipid metabolism (Pennacchio et al., 2001), was found to contribute to the transmission of FCHL in a proportion of British FCHL families (Eichenbaum-Voline et al., 2004).

Type III hyperlipoproteinemia (dysbetalipoproteinemia or broad p disease)

Polymorphism of the apoE gene has been detected in all populations. The most common allele in Europe is apoE3 (frequency 0.75) followed by apoE4 (0.13) and apoE2 (0.1) (Motulsky et al., 2002). ApoE3 binds with high affinity to the LDLR, whereas apoE2 has much reduced binding. About 1% of the population are homozygous for apoE2 but only 1% of these individuals will have the additional genetic or acquired factors (obesity, diabetes, hypothyroidism, FCHL, alcohol abuse) that lead to type III hyperlipidaemia. This rare disorder, which results from the presence in the circulation of large amounts of CM remnants and VLDL remnants (collectively termed b VLDL) is characterized by markedly raised serum cholesterol and triglyceride, palmar striae and tuberoeruptive xanthomata. If left untreated patients have strikingly increased risk for premature CHD and peripheral vascular disease (Mahley et al., 2001).

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