Carotid artery intima-media thickness in Finnish families with familial combined hyperlipidemia

BACKGROUND: Familial combined hyperlipidemia (FCHL) is the most common hereditary lipid disorder that predisposes the patients to premature coronary heart disease. Members of FCHL families are categorised as affected or unaffected according to serum lipid levels. This study is aimed to evaluate whether there is a difference in carotid artery wall thickness between asymptomatic FCHL family members who are affected and those who are unaffected according to the currently used lipid criteria. METHODS AND RESULTS: Carotid artery ultrasonography with intima-media thickness (IMT) measurements was performed for 148 members of 39 Finnish FCHL families. Study subjects who had no history of coronary heart disease or stroke were divided into two groups according to their serum total cholesterol and/or triglyceride levels. The average carotid IMT of the affected subjects (0.75+/-0.15 mm) was not significantly different from that of their unaffected relatives (0.73+/-0.13 mm), P=0.90. In multivariate analysis, age, gender, and pulse pressure, but no lipid variables, contributed significantly to the variation of carotid IMT. CONCLUSIONS: The IMT findings in FCHL family members indicate that the current lipid criteria alone are of limited value in predicting long-term risk of cardiovascular disease in asymptomatic members of FCHL families.     

血浆apoB100水平升高不宜作为家族性混合型高脂血症与家族性高胆固醇血症鉴别诊断的指标

目的 探讨家族性混合型高脂血症与家族性高胆固醇血症血浆载脂蛋白A1（apoA1)、载脂蛋白B100（apoB100)水平的异同。方法 病例－对照／家系设计,家族性混合型高脂血症家系15个（93人）;家族性高胆固醇血症家系11个（94人）;对照家系12个（67人）。比较家系间及家系内受累组与未受累组血浆apoA1与apoB100水平。结果 两种高脂血症家系间及两种家系内受累组间血浆apoA1与apoB100水平未见统计学显著性差异;与对照家系相比,两种高脂血症家系血浆apoB100水平均显著升高（P＜0．01）,同时,家系内受累组血浆apoB100水平显著高于未受累组（P＜0．01）。结论 两种高脂血症家系受累组血浆apoB100水平均显著升高,故血浆apoB100水平升高不宜作为家族性混合型高脂血症与家族性高胆固醇血症鉴别诊断的指标。     

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

Background and aimsHypoadiponectinemia 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 ResultsWe 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).ConclusionsFCHL 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.     

血浆apoB100水平升高不宜作为家族性混合型高脂血症 与家族性高胆固醇血症鉴别诊断的指标

目的探讨家族性混合型高脂血症与家族性高胆固醇血症血浆载脂蛋白A1(apoA1)、载脂蛋白B100(apoB100)水平的异同。方法病例-对照/家系设计,家族性混合型高脂血症家系15个（93人）;家族性高胆固醇血症家系11个（94人）;对照家系12个（67人）。比较家系间及家系内受累组与未受累组血浆apoA1与apoB100水平。结果两种高脂血症家系间及两种家系内受累组间血浆apoA1与apoB100水平未见统计学显著性差异;与对照家系相比,两种高脂血症家系血浆apoB100水平均显著升高（P<0.01）,同时,家系内受累组血浆apoB100水平显著高于未受累组（P<0.01）。结论两种高脂血症家系受累组血浆apoB100水平均显著升高,故血浆apoB100水平升高不宜作为家族性混合型高脂血症与家族性高胆固醇血症鉴别诊断的指标。     

Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia

Familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG) share pathogenic mechanisms and a high interaction with components of the metabolic syndrome. The metabolic syndrome associates increased serum ferritin concentration and high cardiovascular risk. The objective was to describe the frequency of iron overload and the relationship between serum ferritin and the phenotype in patients with FCH and FHTG. The study was composed of 211 consecutive unrelated patients aged at least 18 years with primary hypertriglyceridemia, 149 with FCH, and 62 with FHTG. The prevalence of the metabolic syndrome and hyperferritinemia was very high in both hypertriglyceridemic groups (51.7% and 20.1% in FCH and 62.9% and 16.1% in FHTG, respectively), without significant statistical differences between them. Serum ferritin concentration did not show any significant association with the number of metabolic syndrome criteria. Subjects in the highest tertile of ferritin concentration (ferritin >200 μg/L) presented higher concentrations of triglycerides and liver enzymes than subjects in the first tertile of ferritin concentration (ferritin <90 μg/L). The highest positive correlation coefficient for triglycerides was found with ferritin in FCH and in FHTG subjects (R = 0.317 [P < .001] when combined). Ferritin was also the covariate that showed the highest independent association with triglycerides in FCH and FHTG. In contrast, ferritin was not associated with carotid intima-media thickness. In summary, serum ferritin is commonly increased in FCH and in FHTG, it is not related with the presence of metabolic syndrome, and it is highly correlated with liver enzymes.     

Serum insulinlike growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor

Insulinlike growth factor 1 (IGF-1) has growth-promoting effects on myeloma cells in vitro as well as in vivo. In this study, we measured the concentration of IGF-1 and its major binding protein, IGF- binding protein 3 (IGFBP-3), in serum from 127 patients with multiple myeloma. Serum had been drawn at the time of diagnosis, before treatment with high-dose melphalan. IGFBP-3 in myeloma patients (1.6 +/- 0.73 microg/mL; mean +/- SD) was significantly decreased compared to healthy age- and sex-matched controls (2.2 +/- 0.42 microg/mL). However, IGFBP-3 had no prognostic value in this study. The mean IGF-1 level did not differ between myeloma patients (17.8 +/- 7.7 nM) and controls (17.3 +/- 5.6 nM). Nevertheless, IGF-1 was a strong indicator of prognosis. After 80 months of follow-up, myeloma patients with low levels (< 13 nM) of serum IGF-1 had not reached median survival. In the patient group with IGF-1 levels above 13 nM, median survival was 62 months (P =.006). These findings support the hypothesis of a role for IGF-1 in myeloma disease progression.     

Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression

The association between angiogenin and cancer progression and poor outcome in solid tumors has been documented, but its significance in leukemias has not been evaluated. Using an ELISA technique (Quantikine Human Angiogenin Immunoassay; R&D Systems), we measured serum angiogenin levels in 77 previously untreated Binet stage A B-cell chronic lymphocytic leukemia (CLL) patients. No difference in angiogenin serum levels could be found between patients (median: 295 ng/mL; range: 74-1700) and 15 age- and sex-matched healthy controls (median: 264 ng/mL; range: 29-1835) (P = NS; Mann-Whitney test). Increased angiogenin serum level was associated with higher LDH (P = 0.03) and beta2-m (P = 0.007) concentrations. However, angiogenin did not reflect the extent of bone marrow (BM) angiogenesis as evaluated by microvessel area (P = 0.611), circulating levels of vascular endothelial growth factor (VEGF) (P = 0.873) and basic fibroblastic growth factor (FGF-2) (P = 0.421). When the 25 patients with available data were stratified into the four major cytogenetic categories (normal karyotype, 13q as a sole aberration, 12q trisomy, 11q or 17p deletion) and aberrations were compared with angiogenin serum levels, no correlation was found (P = 0.651; Kruskall-Wallis test). A cut-off of angiogenin serum level corresponding to median (i.e. 330 ng/mL) or higher identified later upstaging and longer progression-free survival (PFS). The 5-yr PFS was 51.5% for patients with angiogenin levels lower than median and 85% for patients with higher values [P = 0.03; hazard ratio (HR) = 2.86; 95% CI: 1.08-6.72]. Although in multivariate analysis only Rai substages (P = 0.00001) and peripheral blood lymphocytosis (P = 0.009) retained their prognostic significance, angiogenin could be incorporated into the Rai substages thus leading to the identification of the following risk categories: (i) stage 0 (angionenin >330 ng/mL); (ii) stage 0 (angiogenin <330 ng/mL) + stage I-II (angiogenin >330 ng/mL); and (iii) stage I-II (angiogenin <330 ng/mL). The 40-month PFS were as follows: 85%, 65%, 25% (chi(2) for trend = 6.33; d.f. = 1; P = 0.01). In conclusion, serum angiogenin levels although not increased in comparison with healthy controls, may predict clinical outcome of patients with early CLL and help to refine Rai's stratification.     

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.     

In vivo modulation of plasma free fatty acids in patients with familial combined hyperlipidemia using lipid-lowering medication

One of the best studied aspects of the insulin resistance syndrome in familial combined hyperlipidemia (FCHL) is impaired insulin-mediated suppression of FFA by diminished inhibition of hormone-sensitive lipase (HSL). In vitro experiments have shown that stimulation of HSL activity by catecholamines is decreased in FCHL. The aim of this study was to investigate HSL inhibition by insulin and stimulation by endogenous catecholamines in vivo in FCHL patients. Twelve FCHL subjects using lipid-lowering medication and 12 controls underwent a mental stress test after random ingestion of either 50 g glucose or placebo. After ingestion of glucose, insulin concentrations increased from 76.8 +/- 21.5 pM to a maximum of 520.2 +/- 118.4 pM (P < 0.01) in FCHL and from 38.0 +/- 5.0 to 221.7 +/- 25.1 pM (P < 0.01) in controls. The percent decreases in plasma FFA during the first hour after glucose ingestion were similar in FCHL and controls (67 +/- 5% vs. 72 +/- 3%, respectively), suggesting a comparable inhibition of HSL in both. During the placebo test, FFA increased similarly in FCHL (56 +/- 9%) and controls (57 +/- 19%). In contrast, FFA concentrations did not change during mental stress after ingestion of glucose (from 0.17 +/- 0.02 to 0.15 +/- 0.02 mmol/liter in FCHL and from 0.11 +/- 0.02 to 0.12 +/- 0.02 mmol/liter in controls). In conclusion, the present study provides in vivo evidence for intact insulin-mediated suppression of FFA in FCHL, although this inhibition of HSL was achieved by higher insulin levels, suggesting insulin resistance at the level of HSL. Secondly, the induction of HSL activity by endogenous catecholamines in vivo is not decreased in FCHL, in contrast to earlier in vitro findings. Finally, catecholamine-induced HSL activation can be inhibited by insulin in a similar manner in both FCHL and controls.     

High plasma level of remnant-like particles cholesterol in familial combined hyperlipidemia

CONTEXT: The traditional lipid and lipoprotein levels in patients with familial combined hyperlipidemia (FCH) are relatively mildly elevated and do not fully explain the increased risk of cardiovascular disease (CVD). In other populations, high remnant-like particles cholesterol (RLP-C) levels are an independent risk factor for CVD. OBJECTIVE: The objective of the study was to investigate whether plasma RLP-C concentrations are elevated in patients with FCH and contribute to the increased prevalence of CVD. DESIGN, SETTING, PARTICIPANTS: In this cross-sectional study, we studied RLP-C levels in 37 FCH families comprising 582 subjects, of whom 134 subjects were diagnosed FCH based on total cholesterol, triglyceride, and apolipoprotein-B levels. Plasma RLP-C concentrations were determined using an immune-separation technique. RESULTS: For both men and women, the mean plasma RLP-C concentration (mmol/liter) was 2-fold elevated in FCH patients [0.59 (0.54-0.66) and 0.40 (0.37-0.43), respectively] compared with both normolipidemic relatives [0.27 (0.26-0.29) in male and 0.22 (0.21-0.23) in female, all P<0.000]; and spouses [0.27 (0.23-0.31) in male and 0.24 (0.21-0.27) in female, all P<0.000]. Plasma RLP-C levels above the 90th percentile predicted prevalent CVD, independently of nonlipid cardiovascular risk factors [odds ratio 2.18 (1.02-4.66)] and triglyceride levels [odds ratio 2.35 (1.15-4.83)]. However, in both FCH patients and controls, RLP-C did not provide additional information about prevalent CVD over and above non-high-density lipoprotein cholesterol levels. CONCLUSIONS: Patients with FCH have 2-fold elevated plasma RLP-C levels, which add to the atherogenic lipid profile and contribute to the increased risk for CVD. However, for clinical practice, non-high-density lipoprotein cholesterol is the best predictor of prevalent CVD.     

Bimodality of plasma apolipoprotein B levels in familial combined hyperlipidemia.

To investigate possible genetic influences on plasma apolipoprotein (apo) B levels in familial combined hyperlipidemia (FCHL), commingling analysis was performed on data from seven large kindreds, including 183 individuals. The overall frequency distribution of apo B was skewed and was compatible with the presence of two normally distributed subdistributions (mean values, 117 and 172 mg/dl). The analysis was repeated after stratification of individuals by low density lipoprotein (LDL) subclass phenotype. Among subjects with phenotype A (predominance of large, buoyant LDL), a single apo B distribution was found (mean, 115 mg/dl). Among subjects with phenotype B (predominance of small, dense LDL), the distribution was bimodal, with mean values, 116 and 167 mg/dl, similar to the unstratified data set. Thus the skewing of the overall apo B distribution in FCHL family members may be due to a distinct subset of individuals with phenotype B who are genetically susceptible to even higher elevations of apo B. The higher apo B/phenotype B subjects also showed significantly higher levels of triglyceride and LDL-cholesterol than the lower apo B/phenotype B subjects. The lower apo B/phenotype B subjects had higher triglyceride and lower LDL-cholesterol than the phenotype A subjects. The enhanced information regarding apo B and lipid levels in the three subgroups of individuals identified here may facilitate a better understanding of genetic susceptibility to coronary heart disease.     

Plasma homocysteine in subjects with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia and/or hypertriglyceridemia and associated with an increased risk of cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects with FCH are relatively moderately elevated and do not fully explain the increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine metabolism and also a well-known independent risk factor for CVD. We investigated whether subjects with FCH have higher plasma homocysteine concentrations than controls, and whether homocysteine contributes to the increased risk of CVD in FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein metabolism and/or insulin resistance are associated with the homocysteine level. In total 667 subjects, including 161 subjects with FCH, 109 spouses who referenced as control group and 397 normolipidemic relatives were studied. FCH was defined by the presence of plasma total cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. The mean homocysteine concentration of the FCH group did not significantly differ from the control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH was not higher than in subjects without FCH. No associations were observed between plasma homocysteine concentration and plasma lipid and lipoprotein levels, including small dense low density lipoprotein, nor between homocysteine concentration and insulin resistance.     

Serum C-reactive protein correlates with survival in colorectal cancer patients but is not an independent prognostic indicator

BACKGROUND: C-reactive protein (CRP) is an acute-phase protein synthesized in liver and up-regulated by pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor (TNF). Elevated CRP has been reported to be associated with reduced crude survival rates in patients with colorectal cancer. OBJECTIVE: To investigate the prognostic significance of preoperative serum CRP in relation to the disease-specific survival rate and expression of different cytokines. METHODS: One hundred and seventy-two consecutive patients with colorectal cancer, whose primary lesions were resected, were selected from April 1995 to December 1999. Preoperative serum CRP levels were measured, and the relationship between the elevation of CRP and clinicopathological factors was investigated. Prognostic significance was analysed by univariate and multivariate tests. RESULTS: One-third of patients had increased CRP levels, and this was associated with larger tumour size, lymph node or liver metastasis, and advanced Dukes' stage. Higher CRP levels were also related to the elevation of IL-6 and IL-8. The most important prognostic factor predicting survival was Dukes' stage (P < 0.001). Multivariate analysis indicated that CRP level is not an independent factor predicting survival. CONCLUSIONS: A preoperative elevation of serum CRP does not have the independent prognostic significance reported by earlier studies. Whether the elevated CRP can predict the development of cachexia or whether this association characterizes a pattern in tumour behaviour remains to be determined.     

TXNIP gene not associated with familial combined hyperlipidemia in the NHLBI Family Heart Study

Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, and is implicated in up to 20% of cases of premature coronary heart disease. Positive linkage to chromosome 1q was found in FCHL families participating in the NHLBI Family Heart Study (FHS), replicating linkage found in other studies. The HcB-19 mouse, which shares phenotypes with FCHL, was shown in other studies to have a nonsense mutation in the thioredoxin interacting protein gene (txnip). txnip is a gene on mouse chromosome 3 in a region syntenic with the 1q human FCHL linkage region. We re-sequenced the human homolog of mouse txnip in the FHS sample and identified nine single nucleotide polymorphisms (SNPs). We did not observe the nonsense mutation found in the HcB-19 mouse, and only three of the SNPs discovered were sufficiently polymorphic for analysis. No association between FCHL and the TXNIP gene was found. Within FCHL cases, presence of variants also did not significantly affect body mass index or levels of lipids, insulin, or glucose. Our results suggest that in this sample, TXNIP does not play a major role in FCHL or related traits, and is unlikely to account for the positive evidence of linkage in this region.     

Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol

Familial defective apolipoprotein B-100 is a genetic disorder which is associated with elevated plasma LDL levels. It appears to result from a G----A mutation at nucleotide 10,708 in exon 26 of the apolipoprotein B-100 gene leading to a substitution of glutamine for arginine at amino acid residue 3500. We explored the possible role of this point mutation as a cause of elevated plasma cholesterol among the Finns, a genetically isolated population in which both hypercholesterolemia and coronary heart disease are common: 552 hyperlipidemic patients from Western and Southern Finland were screened either by assaying patient sera with monoclonal antibody MB47 or by amplifying the region of the apo B gene containing the nucleotide 10,708 followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes. Not a single individual with this particular mutation could be found. We conclude that familial defective apo B-100 is not a common cause of elevated plasma cholesterol in this population.     

Apolipoprotein B is associated with metabolic syndrome in Chinese families with familial combined hyperlipidemia, familial hypertriglyceridemia and familial hypercholesterolemia

There is a paucity of data concerning the metabolic syndrome (MetS) in families with familial combined hyperlipidemia (FCHL), familial hypertriglyceridemia (FHTG), familial hypercholesterolemia (FH) and normolipidemic families in China. This study investigated the prevalence of MetS in these families and explored potential factors relevant to MetS. We recruited 70 families with 560 individuals > or = 20 years of age, including 43 FCHL families with 379 individuals, 3 FHTG families with 30 individuals, 16 FH families with 102 individuals and 8 normolipidemic families with 49 individuals. The definition of MetS is determined using modified criteria of National Cholesterol Education Program substituting body mass index for waist circumference. MetS is identified in 60.7% of FCHL patients and 71.4% of FHTG patients. The prevalence of MetS in family members is 36.7% for FCHL, 33.3% for FHTG, 17.6% for FH and 16.3% for normolipidemic families, with an odds ratio (OR) of 2.97 (95% CI 1.29-7.07, P=0.007) in FCHL families compared with normolipidemic families. Apolipoprotein B (apoB) is associated with MetS by multiple logistic analysis with an OR of 1.05 (1.03-1.07, P<0.001) in FCHL families, OR of 1.26 (1.03-1.55, P=0.026) in FHTG and OR of 1.07 (1.01-1.12, P=0.014) in FH families, independent of variables including age, gender, apolipoprotein A1, and low density lipoprotein cholesterol. Apolipoprotein A1 provided an OR of 0.95 (0.94-0.97, P<0.001) in FCHL families and OR of 0.94 (0.90-0.97, P=0.011) in FH families, but neither in FHTG nor in normolipidemic families (both P>0.05). Thus, apoB may be regarded as a relevant factor in the assessment of MetS in FCHL, FHTG and FH families. However, this finding needs to be verified by prospective studies in diverse ethnicities and warrants additional studies to elucidate possible mechanisms linking apoB to MetS.     

Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia

Apolipoprotein A-II (apoA-II) is a major protein on high-density lipoprotein (HDL) particles, and in mice, its levels are associated with triglyceride and glucose metabolism. In particular, transgenic mice overexpressing apoA-II exhibit hypertriglyceridemia, increased body fat, and insulin resistance, whereas apoA-II-null mice have decreased triglycerides and increased insulin sensitivity. Given the phenotypic overlap between familial combined hyperlipidemia (FCH) and apoA-II transgenic mice, we investigated the relationship of apoA-II to this disorder. Despite having lower HDL-cholesterol (HDL-C), FCH subjects had higher apoA-II levels compared with unaffected relatives (P<0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II, demonstrating that apoA-II variation is associated with several FCH-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h2=0.15; P<0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (LOD=3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (LOD score=1.4). Thus, this locus may have pleiotropic effects on apoA-II and FCH traits. Our results demonstrate that apoA-II is biochemically and genetically associated with FCH and may serve as a useful marker for understanding the mechanism by which FCH develops.     

An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia

A remarkable reduction of plasma concentrations of high-density lipoproteins (HDL), especially of the HDL(2) subfraction, is one of the typical lipoprotein alterations found in patients with familial combined hyperlipidemia (FCHL). Fourteen FCHL patients received 4 capsules daily of Omacor (an omega-3 polyunsaturated fatty acid [omega3 FA] concentrate providing 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day; Pronova Biocare, Oslo, Norway) or placebo for 8 weeks in a randomized, double-blind, crossover study. Plasma triglycerides were 44% lower, and LDL cholesterol and apoliporpotein (apo)B were 25% and 7% higher after Omacor than placebo. HDL cholesterol was higher (+8%) after Omacor than placebo, but this difference did not achieve statistical significance. Omacor caused a selective increase of the more buoyant HDL(2) subfraction; plasma HDL(2) cholesterol and total mass increased by 40% and 26%, respectively, whereas HDL(3) cholesterol and total mass decreased by 4% and 6%. Both HDL(2) and HDL(3) were enriched in cholesteryl esters and depleted of triglycerides after Omacor. No changes were observed in the plasma concentration of major HDL apolipoproteins, LpA-I and LpA-I:A-II particles, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP). The plasma concentration of the HDL-bound antioxidant enzyme paraoxonase increased by 10% after Omacor. Omacor may be helpful in correcting multiple lipoprotein abnormalities and reducing cardiovascular risk in FCHL patients.     

Genetic evidence from 7 families that the apolipoprotein B gene is not involved in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is the most common genetic form of hyperlipidemia in which affected individuals manifest multiple lipoprotein phenotypes. Although the molecular defect is still unknown, several kinetic studies have demonstrated increased turnover rates of apolipoprotein B (apo B) in patients with FCHL, irrespective of their lipoprotein phenotype. Using 3 restriction fragment length polymorphisms (RFLPs) of the apo B gene (XbaI, MspI and EcoRI) we have investigated 33 families which fulfill the diagnostic criteria of FCHL. No significant difference in allele frequency was found between 33 unrelated individuals with FCHL and 107 normolipidemic controls. 3-RFLP haplotypes were constructed in each pedigree. A co-segregation analysis was performed in 7 informative families. In no family was co-segregation observed between the haplotype of the apo B gene and the phenotype of FCHL. These data are not compatible with the hypothesis that FCHL is caused by mutations of the apo B gene acting as a simple mendelian trait.