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.

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL.

No abstract

Objective-Oxidized low-density lipoprotein (Ox-LDL)is implicated in the pathogenesis of atherosclerosis. Circulating oxidation-specific epitopes on plasma Ox-LDL has been linked with coronary artery disease, but its determinants and its association with early development of atherosclerosis in familial combined hyperlipidemia (FCHL) has not been very well studied. This study aimed to investigate the determinants of the circulating Ox-LDL and the association between Ox-LDL and carotid intima-media thickness (IMT) in asymptomatic members of FCHL families. Methods and Results-Ox-LDL, susceptibility of LDL to oxidation in vitro, plasma 8-isoprostane and antioxidants, lipids and lipoproteins, LDL particle size, and carotid IMT were measured in 150 asymptomatic FCHL family members. Affected FCHL family members had reduced LDL particle size and lag time for LDL oxidation, increased plasma levels of Ox-LDL, increased plasma urate and ␣-tocopherol, and a trend for the increase of 8-isoprostane as compared with nonaffected FCHL. Ox-LDL was independently associated with serum LDL cholesterol, apoB, and 8-isoprostane in multivariate analysis but only univariately correlated with LDL particle size and lag time for LDL oxidation. In addition, Ox-LDL was significantly associated with carotid mean IMT independently of other clinical and biochemical variables in a multivariate model. Conclusion-Serum LDL cholesterol, apoB levels, and 8-isoprostane were the most important determinants of Ox-LDL.Ox-LDL is independently associated with carotid IMT in asymptomatic FCHL family members and can be used as a marker of early atherosclerosis in FCHL. Key Words: carotid arteries Ⅲ hyperlipoproteinemia Ⅲ familial combined Ⅲ lipoproteins Ⅲ low-denisty lipoprotein Ⅲ oxygen radical Ⅲ ultrasonography T here is substantial evidence that oxidized low-density lipoprotein (Ox-LDL) is present in vivo within atherosclerotic lesions of arteries. 1 Under the oxidative stress, oxidative modification of LDL may take place in the subendothelial space of the arterial wall, 1 and a small amount of Ox-LDL may also be released into the circulation. 2 When "fully oxidized LDL" enters the circulation in minor quantities, it will be rapidly cleared by the reticuloendothelial system, particularly in the liver, or it will be removed by the preexisting circulating autoantibodies to In contrast, the "minimally modified LDL," in which oxidative modification has not been sufficient to cause changes recognized by scavenger receptors, can be found in circulation. 4,5 Other studies have defined the presence of oxidationspecific epitopes on plasma LDL 6 -8 or baseline levels of conjugated dienes in lipids extracted from LDL (LDL-BDC) as measures of LDL oxidation in vivo. 9 Recently, several groups have developed several specific methods to measure circulating Ox-LDL using different anti-Ox-LDL antibodies. 6 -8 As a sensitive biochemical marker, Ox-LDL has been related to coronary artery disease (CAD) in several clinical studies. 6,10 -12 Plasma Ox-LDL has also been associ...

Background and Purpose-In addition to low-density lipoprotein (LDL) cholesterol, small, dense LDL particles and oxidative modification of LDL have been linked to the pathogenesis of atherosclerosis. The present study was aimed at investigating the association between carotid artery intima-media thickness (IMT) and LDL particle size and susceptibility of LDL to oxidation in vitro in asymptomatic members of familial combined hyperlipidemia (FCHL) families. Methods-LDL particle size, susceptibility of LDL to oxidation in vitro, and carotid IMT were measured in 148 asymptomatic FCHL family members. Results-LDL particle size and lag time for LDL oxidation were reduced in hyperlipidemic compared with normolipidemic family members. LDL particle size, serum total cholesterol, and ␣-tocopherol in LDL were independently associated with lag time for LDL oxidation in multivariate analysis. LDL particle size was associated with carotid mean IMT independently of clinical, lipid, and antioxidant variables in multivariate analysis. Although the susceptibility of LDL to oxidation in vitro was correlated with mean IMT, it did not have a significant independent contribution to variation in mean IMT in the multivariate model. Conclusions-We conclude that LDL particle size but not susceptibility of LDL to oxidation in vitro is independently associated with carotid IMT in asymptomatic FCHL family members. These results imply that small, dense LDL as an inherent feature of FCHL is an important diagnostic indicator for coronary artery disease risk in FCHL.

No abstract

Abstract-A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial combined hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (PϽ0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially. Key Words: acylation-stimulating protein Ⅲ complement Ⅲ familial hyperlipidemia Ⅲ postprandial Ⅲ atherosclerosis F amilial combined hyperlipidemia (FCHL) is a common hereditary dyslipidemia that predisposes the patients to premature coronary heart disease (CHD). 1,2 The affected members of FCHL families present different lipid phenotypes: hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia, as well as high serum levels of apolipoprotein B (apoB). Insulin resistance with impaired free fatty acid (FFA) suppression is also commonly encountered. 3,4 It has been proposed that the failure of adipose tissue to efficiently "trap" FFA would result in an excessive FFA flux to liver and increased VLDL apoB production. 5 Acylation-stimulating protein (ASP) is, in vitro, a potent stimulator of triglyceride (TG) synthesis in human adipocytes. 6,7 ASP mediates its effect by stimulating diacylglycerol acyltransferase, a key enzyme in TG synthesis, 8 and by enhancing glucose uptake. 9 Reduced capacity of TG esterification and resistance to the action of ASP 10 -12 have been reported in vitro in patients with hyperapobetalipoproteinemia, a lipid disorder closely related to FCHL. So far, only a few in vivo studies have investigated the effect of ASP on lipid metabolism.Interestingly, the primary structure of ASP is identical to the inactive cleavage product of complement C3a, C3a-desArg. 7 Adipocytes are able to secrete complement factors, including C3, from which ASP is generated through activation of the alternative complement pathway. 13 We have previously shown that Finnish male FCHL patients have higher serum levels of complement C3 than their unaffected relatives. 14 No data exist, however, on plasma ASP in FCHL patients.The aim of this study was to examine the role of plasma ASP in Finnish FCHL families. The...