Paso 2: Medida del Mecanismo de Cobertura

Familial combined hyperlipidaemia (FCHL) was first described by Goldstein and his colleagues based on the study of MI survivors from the Seattle area and their relatives, whose cholesterol and triglyceride levels had been measured (Goldstein et al., 1973b). FCHL was common in this cohort accounting for 11 % of premature CHD cases (before age 60). The disorder is classically defined by elevated plasma levels o f either cholesterol or triglycerides or both, in the proband and in at least one relative, with a relatively late age of onset (3rd-4th decade) (Goldstein et al., 1973a,b; Nikkila and Aro,

1973). Multiple lipid phenotypes (Fredrickson and Lees classification - Ila, lib and IV) are expected within a family and these often change over time (Grundy et al., 1987). A positive family history for CHD should also be found.

The common metabolic defect in FCHL appears to be overproduction of Tg-rich apoB-containing particles from the liver (Sniderman et al., 1980; Janus et al., 1980a & b; Grundy et al., 1987) which accounts both for HTG and raised apo B levels (Venkatesan et al. 1993). This may be accompanied by increased number of small dense LDL particles in the blood (LDL pattern B, Austin et al., 1990a; Hokanson et al., 1993). Castro-Cabezas et al. (1993) and Sniderman et al. (1992b) have additionally proposed that defective free fatty acid (FFA) metabolism and hyperinsulinaemia are involved in the etiology of FCHL.

Although FCHL was originally described as a monogenic disorder with an autosomal dominant mode of inheritance, it is now widely believed to be a genetically heterogeneous condition (reviewed in Kwiterovich, 1993b). Several conditions which display a degree of overlap with FCHL may share a common genetic defect. Hyperabobetalipoproteinaemia (hyperapo B) is defined by an increase in apo B relative to LDL cholesterol (Sniderman et al. 1982 and 1992b). It is characterised by a very

similar, if slightly milder, lipid profile compared to FCHL (LDL cholesterol may be normal but Tg may be elevated) as well as premature atherosclerosis (Sniderman et al., 1980) and may not be a distinct entity from FCHL. In familial dyslipidaemic hypertension (FDH), early hypertension is associated with elevated LDL-cholesterol, low HDL-cholesterol or raised Tg (Williams RR et al., 1992). Of 63 individuals with FDH studied by Hunt et al. (1989), almost a third could be classified as having FCHL. FDH probands are often obese and hyperinsulinaemic. Taken together, the features of hypertension, obesity, hyperinsulinaemia and hyperlipidaemia are reminiscent of a disorder described by Reaven (1988) called syndrome X where a clustering of these conditions is observed.

1.2.2.3.1 Candidate genes for FCHL.

A number of potential causative genes for FCHL have been investigated. Given the metabolic abnormalities in FCHL, the apo B gene was a prime candidate for study but it has been ruled out through family and sib-pair linkage analysis studies (Rauh et al., 1990; Coresh et al., 1992; Nishina et al., 1992). Complex segregation analysis in FCHL families suggests that a major gene locus determines apo B levels (Jarvik et al.,

1993) while in other pedigrees a major gene has been proposed to determine Tg levels (Cullen et al., 1994). These data do not unfortunately provide any additional information as to the identity of the gene involved. Kwiterovich (1993b) has recently put forward a ’two-hit’ hypothesis whereby two genes with Tg and apo B raising effects might be necessary for full expression of FCHL. This pattern has been observed in the animal model for FCHL, the St.Thomas Hospital hyperlipidaemic rabbit (Beaty et al., 1989).

The proposed locus for the atherogenic lipoprotein phenotype (Austin et a l., 1990b), characterised by predominance of small dense LDL, elevated Tg and elevated apo B, is linked to the LDL-receptor locus (Nishina et al., 1992). However, earlier studies indicate that mutations at this locus are unlikely to cause FCHL (Goldstein et al.,

1973b; Janus et al., 1980a). Preliminary evidence suggests that another gene in close proximity to the LDL-receptor, the insulin receptor gene, may in fact be involved (Nishina et al., 1992).

Cianflone and co-workers (1989, 1990a) have isolated a small basic plasma protein which they named acylation-stimulating protein (ASP) as it stimulates Tg synthesis from FFA in fibroblasts from normal individuals. Importantly, the presence of ASP did not activate Tg synthesis to the same extent in cells from subjects with hyperapobetalipoproteinaemia (Cianflone et al., 1990a). This defective stimulation has been replicated by another group who had independently isolated ASP and termed it BP I (basic protein I)(Kwiterovich et al., 1994). Based on their results, Sniderman et al. (1992a) proposed that a receptor for ASP exists which is defective in patients with hyperapobetalipoproteinaemia. These authors further suggested that this causes an increase influx of FFA to the liver, thereby increasing VLDL apo B secretion, the major metabolic abnormality observed in FCHL (Sniderman et al., 1992b).

Co-segregation of variation at the AI-CIII-AIV gene cluster with FCHL has been reported in seven families (Wojciechowski et al., 1991). The peak LOD score of 6 . 8 6 at a recombination frequency of 0 suggested that the defect was in or very near this gene cluster. Of the three genes in the cluster, overproduction of apoCIII would appear to be the most likely cause of hypertriglyceridemia, as apoCIII is known to inhibit lipoprotein lipase (LPL) and hepatic lipase and to interfere with clearance of remnant lipoproteins (Brown and Baginsky, 1970) (see section 1.5.3.1). Other workers have not detected this linkage between FCHL and the apo AI-CIII-AIV gene cluster in other families (Wijsman et al., 1992; Xu et al., 1994) so that the involvement of this gene cluster remains to be confirmed.

One of the key factors determining the metabolism of triglyceride-rich lipoproteins is the activity of LPL. Patients who are homozygous for a mutation in the LPL gene causing LPL deficiency occur at a frequency of roughly one per million, and

have Type I hyperlipoproteinaemia with fasting chylomicronaemia (section 1.2.1.1); thus, carriers for such mutations may be as frequent as 1/500. The study of a large Type I kindred has shown that some relatives who are heterozygous for LPL deficiency have high plasma triglyceride concentrations and that this is most marked in individuals over 40 years (Wilson et al., 1990). In another report, Babirak et al. (1989) have noted the presence of hyperlipidaemia in obligate heterozygotes for mutations in the LPL gene, with multiple lipoprotein phenotypes reminiscent of FCHL. Recently, these workers have also demonstrated that a proportion (1/5 - 1/3) of FCHL patients have levels of post­ heparin LPL activity and mass below the 10th percentile for the general population (Babirak et al., 1992). These data suggest that partial LPL deficiency, either genetic or acquired, may underlie the phenotype of FCHL in some patients. Based on observations made with HepG2 cells in culture, Williams et al. (1991) have proposed a mechanism linking partial LPL deficiency and FCHL. In the presence of LPL, a large porportion of newly secreted VLDL are rapidly re-absorbed by the cells. In vivo, this phenomenon might take place in the space of Disse (Williams et a l., 1991) where active LPL has been detected. Thus, LPL deficiency would result in apparent apo B overproduction, as observed in FCHL. Additional evidence for this hypothesis is provided by the finding that LPL can act as a bridge between lipoproteins and the cell surface (see section 1.3.3.4).

In summary, several candidate genes have been proposed which may contribute to the FCHL phenotype in individuals and further studies are required to clarify their roles and the relationship between them.