Familial Combined Hyperlipidemia Phenotype Research Articles

Genetic Architecture and Cardiovascular Risk of Familial Combined Hyperlipidemia

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Familial combined hyperlipidemia (FCHL) is one of most common inherited lipid phenotypes and is characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. However, many aspects of FCHL remain incompletely understood, such as its genetic basis and the magnitude of cardiovascular risk with which it is associated. <h3>Objective/Purpose</h3> The goals of this study were to investigate the genetic architecture and cardiovascular risk associated with FCHL. <h3>Methods</h3> We identified individuals with a FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n=39,961), 5.01% (n=17,485), 1.48% (n=5,153), 1.10% (n=3,838), and 0.48% (n=1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein clinical criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria. <h3>Results</h3> We identified 175 independent loci associated with FCHL at genome-wide significance. All loci have known associations with plasma lipid levels. We investigated the combined impact of genetic and environmental risk on FCHL and found that the combination of polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome was associated wa ith greater prevalence of FCHL. Lastly, we observed that individuals with an FCHL phenotype had a comparable risk of incident coronary artery disease compared to individuals with monogenic Familial Hypercholesterolemia (FH) (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31-3.21] and 1.90 [1.30-2.78]) <h3>Conclusions</h3> Our results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. Importantly, the cardiovascular of the FCHL phenotype is similar to that of monogenic FH, despite being at least 5 times more common.

Comparative assessment of LDL-C and VLDL-C estimation in familial combined hyperlipidemia using Sampson\u2019s, Martin\u2019s and Friedewald\u2019s equations

BackgroundSampson et al. developed a novel method to estimate very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) in the setting of hypertriglyceridemia. Familial Combined Hyperlipidemia (FCHL) is a common primary dyslipidemia in which lipoprotein composition interferes with LDL-C estimation. This study aimed to evaluate performance of LDL-C using this new method (LDL-S) compared with LDL-C estimated by Friedewald’s and Martin eq. (LDL-F, LDL-M) in FCHL.MethodsData were collected from 340 subjects with confirmed FCHL. Concordance for VLDL-C measured by ultracentrifugation and LDL-C estimated using these measures compared to Sampson’s, Martin’s and Friedewald’s equations was performed using correlation coefficients, root mean squared error (RMSE) and bias. Also, concordance of misclassified metrics according to LDL-C (< 70 and < 100 mg/dL) and Apo B (< 80 and < 65 mg/dL) thresholds were assessed.ResultsSampson’s equation was more accurate (RMSE 11.21 mg/dL; R2 = 0.88) compared to Martin’s (RMSE 13.15 mg/dL; R2 = 0.875) and the Friedewald’s equation (RMSE 13.7 mg/dL; R2 = 0.869). When assessing performance according to LDL-C, Sampson’s had highest correlation and lowest RMSE compared to other equations (RMSE 19.99 mg/dL; R2 = 0.840). Comparing performance strength across triglyceride levels, Sampson’s showed consistently improved correlations compared to Martin’s and Friedewald’s formulas for increasing triglycerides and for the FCHL phenotype of mixed dyslipidemia. Sampson’s also had improved concordance with treatment goals.ConclusionsIn FCHL, VLDL-C and LDL-C estimation using Sampson’s formula showed higher concordance with lipid targets assessed using VLDL-C obtained by ultracentrifugation compared with Friedewald’s and Martin’s equations. Implementation of Sampson’s formula could improve treatment monitoring in FCHL.

Molecular and Metabolic Pathogenesis of Familial Combined Hyperlipidemia and Association with Metabolic Syndrome

Background The objective of this review is to unify the various genetic defects along with elaborating metabolic pathways in Familial Combined Hyperlipidemia(FCHL) and also to differentiate the phenotype of FCHL from metabolic syndrome. Methods PubMed and Cochrane’s library was searched for keyword “Familial combined hyperlipidemia” and latter with “Familial combined hyperlipidemia genes” to finally shortlist 23 articles. Further search with key words “molecular pathogenesis of familial combined hyperlipidemia” and “metabolic syndrome and familial combined hyperlipidemia” was carried out for finding molecular defects in FCHL, non-molecular findings distinguishing FCHL from metabolic syndrome and overlapping features between FCHL and metabolic syndrome. Results Major culprit regions identified included Chromosome-1q21-q24(USF1 and FOXA2) , Ch-11q (APOA5), Ch-16q24, Ch-20q12-q13.1, Ch.4q32.3 (rs6829588), and Ch-19q13.32 containing PVRL-2 gene (Also known as Nectin-2). The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of Apo-B containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction. FCHL phenotype showed close resemblance with metabolic syndrome clinical and biochemical features with slight differences. Conclusion The reviewed data suggested that FCHL phenotype is the resultant end outcome from multiple molecular defects and thus underlying genetic defect identification in the index case is important for personalized medicine and incoming gene therapy. Further research is warranted to explore specific genetic defects.

The genetics of familial combined hyperlipidaemia

Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes.

FABP4 plasma levels are increased in familial combined hyperlipidemia

FABP4 plasma levels are increased in familial combined hyperlipidemia

Serum adiponectin is decreased in patients with familial combined hyperlipidemia and normolipaemic relatives and is influenced by lipid-lowering treatment

Background and aims Hypoadiponectinemia has been reported in patients with familial combined hyperlipidemia (FCHL) presenting increased waist circumference and insulin resistance. However, no studies have evaluated this association in non-obese FCHL patients. Moreover, it is unclear whether correction of lipoprotein abnormalities may influence adiponectin levels in FCHL. Methods and Results We have compared serum levels of adiponectin in 199 non-obese FCHL patients (BMI 25.96 ± 3.7), 116 normolipaemic (NL) non-affected relatives (BMI 24.4 ± 4.0) and 192 controls (BMI 28.0 ± 7.4). In a subgroup of FCHL patients, changes in adiponectin levels after treatment with atorvastatin ( n = 22) or fenofibrate ( n = 26) were also evaluated. FCHL patients as well as their NL relatives showed lower serum adiponectin levels compared to controls (9.7 ± 5.4 μg/mL, 10.7 ± 5.3 μg/mL and 17.3 ± 13.7 μg/mL, respectively; p < 0.0001 for all comparisons). After controlling for confounders, the strongest association with hypoadiponectinemia was observed with family history of FCHL, followed by HDL-C (negatively) and age (positively). These variables jointly explained 15% of the total variance of serum adiponectin levels. After 24-week of treatment, adiponectin was increased by 12.5% ( p < 0.05) by atorvastatin and was reduced by 10% by fenofibrate, resulting in a treatment difference of 22.5% in favor of atorvastatin ( p < 0.017). Conclusions FCHL patients showed lower serum adiponectin levels compared to controls. Also normolipaemic relatives of FCHL patients presented decreased levels of adiponectin, suggesting a possible common background in the determination of this abnormality. Overall, these observations indicate that hypoadiponectinemia may be an inherent characteristic of the FCHL phenotype. In FCHL patients hypoadiponectinemia may be partially corrected by atorvastatin but not by fenofibrate treatment.

Familial-combined hyperlipidaemia in very young myocardial infarction survivors (&lt;=40 years of age)

Myocardial infarction (MI) in very young individuals is a rare disease associated with an unfavourable prognosis. Familial-combined hyperlipidaemia (FCHL) increases the risk for MI in individuals below 60 years; however, its role in very young MI patients below 40 years is not as well established. We investigated the prevalence and impact of FCHL in these very young MI patients. We prospectively enrolled 102 consecutive MI survivors (< or =40 years) from two high-volume cardiac catheterization centres. Patients were frequency-matched for age, gender, and centre to 200 hospital controls free from coronary heart disease. Myocardial infarction patients were invited to send family members for FCHL screening. Overall, 37 families were screened. Familial-combined hyperlipidaemia was diagnosed using a nomogram, which takes into account total cholesterol, triglycerides, and Apo B(100) levels. Thirty-eight acute myocardial infarction (AMI) patients (38%) and five controls (2.5%) displayed the FCHL phenotype, 21 of these MI patients sent family members for screening, and FCHL was confirmed in 16 families (76%). The FCHL phenotype was associated with a 24-fold increased adjusted risk for MI (95% CI 7.5-81, P < 0.001). Of all lipid parameters, VLDL-cholesterol, and non-HDL-cholesterol were most strongly associated with MI. The present study suggests that the FCHL phenotype seems to be a major risk factor for the occurrence of MI at a very young age. It remains to be determined whether this excessively increased risk can be favourably modified by therapeutic interventions.

A PCSK9 variant and familial combined hyperlipidaemia

Background:Our discovery in 2003 of the first mutations of PCSK9 gene causing autosomal dominant hypercholesterolaemia (ADH) shed light on an unknown factor that strongly influences the level of circulating low...

Paraoxonase (PON1) is associated with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder of which the molecular basis still remains to be elucidated. Since the HDL-associated enzyme serum paraoxonase (PON1) is associated with variation in serum lipids and lipoproteins, we determined whether variation in PON1 also contributes to the FCH phenotype. The study population consisted of 32 well-defined families with FCH, including 103 FCH patients and 240 normolipidemic relatives (NLR). In addition to plasma lipids and lipoproteins we determined PON1 activity (arylesterase- and paraoxonase activity) as well as the common genetic variants −107C > T, 55L > M and 192Q > R in the PON1 gene. The arylesterase activity was significantly higher in FCH patients when compared to NLR ( P < 0.001). In the total population, the PON1 genetic variants associated with the highest arylesterase activity (−107CC and 55LL) also associated with higher levels of total cholesterol, apolipoprotein B, triglycerides and VLDL-cholesterol and decreased levels of HDL-cholesterol. In support, the combination of the −107CC with the 55LL genotype associated with a significant increased risk for FCH when compared to the −107TT/55MM genotype (odds ratio 5.0 (95% CI, 1.3–19.1, P = 0.02)). In conclusion, in this population of subjects from well-defined families with FCH, PON1 is biochemically and genetically associated with FCH.

Fatty liver–based identification of two distinct hypertriglyceridemic subgroups in familial combined hyperlipidemia

The present study was conducted to investigate whether the fatty liver phenotype could be helpful in the identification of subgroups with distinct metabolic properties and lipid profiles within familial combined hyperlipidemia (FCHL). One hundred eighty-five FCHL family members participated in the current study; 38 subjects were found to be hypertriglyceridemic, of whom 66% showed evidence of fatty liver as measured with ultrasound. A detailed comparison between the hypertriglyceridemic FCHL subjects with (n = 25) and without (n = 13) fatty liver revealed that, despite very similar plasma triglyceride levels (3.5 vs 3.2 mmol/L in subjects with and without fatty liver, respectively), the fatty liver subgroup presented with significantly higher body mass index, visceral adipose tissue (ultrasound), insulin, and alanine aminotransferase levels. Moreover, very low-density lipoprotein (VLDL) subclass analysis showed that the VLDL2 fraction of the fatty liver subgroup contained significantly less cholesterol and triglycerides ( P = .02 for both parameters), which was likely explained by a decreased VLDL2 particle number because VLDL2 apolipoprotein B levels tended to be lower ( P = .08). These data indicate that hypertriglyceridemic FCHL subjects may belong to metabolically distinct subgroups and suggest that a refinement of the hypertriglyceridemic FCHL phenotype by adding information on fatty liver will eventually facilitate the elucidation of its complex genetic background.

Endothelial function in familial combined hyperlipidaemia

Familial combined hyperlipidaemia (FCH) is characterized by dyslipidaemia, visceral obesity and insulin resistance, and is associated with an increased intima-media thickness (IMT) and an increased risk for cardiovascular disease. In the present study, we investigated whether FCH is associated with early functional vascular wall changes, as represented by endothelial dysfunction, and we determined whether endothelial function in FCH is related to any of the cardiovascular risk factors associated with the FCH phenotype, or to the (increased) IMT. In 98 patients with FCH [mean age 51 (48-54) years, 43% male] and 230 unaffected relatives [mean age 44 (42-46) years, 48% male], venous blood was drawn in the fasting state after discontinuation of lipid lowering drugs for at least 4 weeks (if used). IMT was measured by B-mode ultrasound and endothelial function was assessed by determination of flow mediated dilation (FMD) and by measurement of plasma concentrations of various soluble adhesion molecules, including soluble vascular cell adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin. There were no significant differences between FCH patients and their non-affected relatives in FMD [2.9 (2.3-3.6%) vs. 2.8 (2.5-3.2%)] or in the plasma concentrations of the various adhesion molecules. None of the individual clinical and biochemical cardiovascular risk factors was an independent predictor of endothelial function in patients with FCH, nor was IMT. However, subgroup analysis revealed that IMT was an independent and powerful predictor of FMD in subjects with carotid artery plaques (St. beta = 4.11, P < 0.004), whereas IMT was no significant predictor in subjects without plaques. FCH patients have no impaired endothelial function when compared to their unaffected relatives. IMT is an important predictor of FMD when advanced morphological wall changes are present. Our results question the value of FMD measurements for cardiovascular risk stratification in populations with an anticipated high cardiovascular risk.

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.

Up‐regulation of CD36/FAT in preadipocytes in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) shows many features of the metabolic syndrome. The strong genetic component makes it an excellent model to study the genetic background of metabolic syndrome and insulin resistance. Adipose tissue is believed to contribute to, or even underlie, the FCHL phenotype and is an interesting target tissue for gene expression studies. However, interpretation of adipose tissue gene expression experiments is complex since expression differences cannot only arise as a direct consequence of a genetic trait, but may also reflect an adaptation to metabolic influences at the cellular level. In the present study, we measured gene expression levels in cultured primary human preadipocytes from FCHL and control subjects. Since isolated preadipocytes were allowed to replicate for weeks under standardized conditions, the contribution of previous metabolic influences is rather small whereas genetic defects are preserved and expressed in vitro. The main finding was up-regulation of CD36/FAT in FCHL preadipocytes, confirmed in two independent groups of subjects, and a concomitant increase in CD36/FAT-mediated fatty acid uptake. CD36/FAT overexpression has previously been shown to be associated with other insulin-resistant states. The present data suggest that CD36/FAT overexpression in FCHL occurs very early in adipocyte differentiation and may be of genetic origin.

Elevated leptin levels in subjects with familial combined hyperlipidemia are associated with the increased risk for CVD

Familial combined hyperlipidemia (FCH) is characterized by hypercholesterolemia and/or hypertriglyceridemia and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have been associated with obesity, insulin resistance and CVD. The aim of this study was to determine whether increased leptin levels contribute to the FCH phenotype and its increased risk for CVD. The study population comprised 644 subjects, including 158 FCH patients. Leptin levels were determined, using a commercially available ELISA. For both males and females, the mean leptin level (ng/ml) was higher in FCH patients compared to normolipidemic relatives and spouses. However, after standardization for BMI and insulin resistance, these differences disappeared. The 90th percentile of the leptin level, standardized for BMI, insulin resistance and gender, was associated with an increased risk for CVD in FCH patients (odds ratio = 2.9, 95% CI = 1.1–8.0) and in non-FCH subjects (odds ratio = 3.4, 95% CI = 1.3–9.0). The overall increased risk for CVD, associated with a leptin level >90th percentile, was 3.3 (95% CI = 1.7–6.4). We conclude that in patients with FCH, leptin levels are increased in proportion to their higher BMI and the presence of insulin resistance. These increased leptin levels are associated with an increased risk for CVD both in FCH patients and non-FCH subjects, independent of BMI, insulin resistance and gender.

Contribution of chromosome 1q21-q23 to familial combined hyperlipidemia in Mexican families.

Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, with a prevalence of 1-2% in the general population. A major locus for FCHL has been mapped to chromosome 1q21-q23 in Finnish, Chinese, German and US families. We studied seven extended Mexican families with 153 members, including 64 affected subjects. A total of 11 markers were genotyped, including D1S104 which has been linked to FCHL in other studies. Two point linkage analysis for the FCHL phenotype, and for the elevated triglyceride (TG) trait, allowing for heterogeneity, gave a maximum HLOD of 1.67 (alpha = 0.49) and 1.93 (alpha = 0.43) at D1S2768 (2.69 cM proximal to D1S104) respectively. Heterogeneity and non-parametric (NPL) multipoint analyses for the FCHL phenotype and the TG trait showed maximum HLODs of 1.27 (alpha = 0.46) and 1.64 (alpha = 0.38), and NPLs of 4.00 (P = 0.0001) and 3.68 (P = 0.0003) near D1S2768, respectively. In addition, analysis of four candidate genes putatively involved in the expression of FCHL showed no evidence of linkage for the LCAT gene or the APOA1/C3/A4/A5 gene cluster. However, we cannot exclude the participation of these genes, or the LIPC and LPL genes, as minor susceptibility loci in the expression of FCHL, or the TG or elevated total cholesterol (TC) traits in our families. In conclusion, our data confirm the involvement of a major susceptibility locus on chromosome 1q21-q23 in FCHL Mexican families, consistent with findings in other populations.

Thioredoxin interacting protein in Dutch families with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH), characterized by multiple lipoprotein phenotypes, is the most common hereditary lipid disorder in humans. A mutant mouse strain, HcB-19, with similar biochemical features as FCH patients, has recently been identified. The mutation causing the FCH phenotype in these mice is located in the thioredoxin interacting protein (TXNIP) gene. The TXNIP gene in mice is located on chromosome 3F2.2, which is syntenic to chromosome 1q21 in humans, a region where several groups have positioned a locus for FCH. To evaluate the potential role of TXNIP in the FCH phenotype in humans, we analyzed the coding region, 5' UTR and introns of the TXNIP gene by direct sequencing in 10 well-defined patients with FCH and 5 healthy controls. We did not find any sequence variants in these regions of the TXNIP gene in patients with FCH. Our results suggest that different genes are involved in the FCH phenotype in humans compared to mice. We conclude that in our Dutch FCH patients, the TXNIP gene, based on its intronic, exonic, and 5' UTR sequences, is not involved as a major contributor to the FCH phenotype. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that is present in 10% of patients with premature coronary artery disease (CAD). It was the objective of the present study to evaluate the possible involvement of the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of the six coding PPARA exons resulted in the identification of four novel variants, [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3 ′ UTR in three FCHL probands, whereas no novel variants were identified in spouses. In a case-control study, markers D22S275 and D22S928 were shown not to be associated with FCHL. However, D22S928, mapped within 1 Mb of the PPARA gene, was shown to have a modifying effect on plasma apoCIII concentrations ( P=0.011) and the combined hyperlipidemic FCHL phenotype ( P=0.038). In addition two PPARA polymorphisms in intron 2 and 7 were studied, but these were not associated with FCHL. The frequency of the L162V variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%). These results clearly demonstrate the genetically complex nature of FCHL and identify the PPARA gene as a modifier of the FCHL phenotype.

Locus for elevated apolipoprotein B levels on chromosome 1p31 in families with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH), a common cause of premature coronary artery disease, is genetically complex and poorly understood. Recently, a major locus on chromosome 1q21-23 exhibiting highly significant linkage was identified in Finnish FCH families by use of a parametric analysis. We now report highly significant evidence of linkage (maximum LOD score 3.8, recombination fraction 0) of an important FCH phenotype, elevated apolipoprotein B (apoB) levels, to a distinctly separate locus on chromosome 1p31 in Dutch pedigrees. ApoB is the major protein on very low density and low density lipoproteins, and elevated apoB levels have been used as a surrogate trait for FCH. Additional microsatellite markers in the 1p31 region were genotyped, and evidence of linkage improved (maximum LOD score 4.7) in a multipoint analysis of two markers in the peak region. The leptin receptor gene resides within this locus and is involved in obesity and insulin/glucose homeostasis. However, there was no evidence of an association between leptin receptor and apoB levels, raising the possibility that another gene on this chromosomal region contributes to elevated apoB levels in this Dutch population. This is one of the first loci identified for apoB levels in humans and is the second major locus implicated in the genetic etiology of FCH.

Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study

In order to characterize the lipoprotein abnormalities in familial combined hyperlipidemia (FCHL) and to describe factors associated with the stability of the FCHL phenotype during 20-year follow-up, 287 individuals from 48 families with FCHL originally identified in the early 1970s (baseline) were studied. Hyperlipidemia was defined as lipid-lowering medication use, or ⩾age- and sex-specific 90th percentile for triglycerides or cholesterol. Triglyceride, cholesterol and medical history data were obtained at baseline and 20-year follow-up. Additional follow-up measures included HDL-C, LDL-C, LDL particle size, lipoprotein(a), apolipoprotein (apo) A-I, apoB, and apoE polymorphism. Longitudinally, two-thirds of relatives were consistently normolipidemic or hyperlipidemic, and one third were discordant for hyperlipidemic status at baseline and 20-year follow-up. Individuals with hyperlipidemia at baseline and/or follow-up had higher apoB levels than those with consistently normal lipids ( P<0.05), whereas small LDL size was associated with concurrent hyperlipidemia. Among individuals who were normolipidemic at baseline, the following variables were independently associated with development of hyperlipidemia over 20 years: older age at baseline, male sex, greater increase in BMI during follow-up, and apoE alleles epsilon 2 or epsilon 4. In conclusion, apoB is associated with hyperlipidemia and apoE polymorphism is associated with later onset of hyperlipidemia in FCHL.

Genetic Dissection of Familial Combined Hyperlipidemia

Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia in man. FCHL is characterized by familial clustering of hyperlipidemia and clinical manifestations of premature coronary heart disease, i.e., before the age of 60. Although FCHL was delineated about 25 years ago, at present the FCHL phenotype and its complex genetics are not fully understood. Initially, the familial aggregation of high plasma total cholesterol and triglyceride levels, with a bimodal distribution of triglycerides, was taken as evidence of a dominant mode of inheritance. However, it is now clear that the genetics of FCHL is more complex, and it has been suggested that FCHL is heterogeneous. Several approaches can be taken to identify genes contributing to the disease phenotype in complex genetic disorders either by studying the disease in the human situation or by using animal models. Recent reports have shown that a combination of genetic linkage studies, association studies, and differential gene expression studies provides a useful tool for the genetic dissection of complex diseases. Therefore, the genetic strategies that will be used to dissect the genetic background of FCHL are reviewed.