Faculty Bibliography

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.

Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.

The relationship between mitochondrial genotype and clinical phenotype is complicated in most instances by the heteroplasmic nature of pathogenic mitochondrial mutations. We have previously shown that maternally inherited hearing loss in a large Arab-Israeli kindred is due to the homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with this mutation have phenotypes ranging from profound hearing loss to completely normal hearing, and we have shown that there is genetic and biochemical evidence for nuclear gene involvement in this family [Bu et al., 1993: Genet Epidemiol 9:27-44; Guan et al., 1996: Hum Mol Genet 5:963-971]. To identify such a nuclear locus, two candidate genes were excluded through linkage analysis and sequencing, and a genome-wide linkage search in family members who all have the identical homoplasmic mitochondrial mutation, but differ in their hearing status, was performed. In two stages a total of 560 polymorphic genetic markers was genotyped, and the data were analyzed under model-dependent and model-free assumptions. No chromosomal region was identified as a major contributor to the phenotypic expression of the mitochondrial mutation. Thus, in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in the similar environment of a small village, the penetrance of the mitochondrial mutation appears to depend on the interaction of multiple nuclear genes.