Novel genes for familial combined hyperlipidemia

Aouizerat, Brad; Allayee, Hooman; Bodnar, Jackie; Krass, Kelly L.; Peltonen, Leena; Bruin, T.W.A. de; Rotter, J.L.; Lusis, Aldons J.

doi:10.1097/00041433-199904000-00005

Cited by 51 publications

(44 citation statements)

References 66 publications

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“…In Ͼ80% of the FCHL subjects, apoB levels were higher than the 90th percentile of controls at any level of Si or amount of IAF. These data provide support for genetic models describing a major, but separate, gene(s) for elevated apoB 34 distinct from genes with effects on triglyceride and small dense LDL 13,14,47,48 in subjects with FCHL. To date, no candidate genes, including the apoB gene, 49,50 have been found to account for the increased apoB in FCHL.…”

Section: Purnell Et Alsupporting

confidence: 54%

“…On the other hand, many genes seem to contribute to the increase in triglyceride and other lipid levels in FCHL. 48 In summary, subjects with FCHL are viscerally obese and insulin resistant compared with the age-matched control subjects. However, when compared with age-, weight-, and IAF-matched control subjects, their insulin resistance is appropriate for their degree of visceral obesity.…”

Section: Purnell Et Almentioning

confidence: 95%

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Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Purnell

Kahn

Schwartz

et al. 2001

ATVB

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Abstract-Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age-and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.

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Section: Purnell Et Alsupporting

confidence: 54%

Section: Purnell Et Almentioning

confidence: 95%

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Purnell

Kahn

Schwartz

et al. 2001

ATVB

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“…1 The lipoprotein profile in FCH patients is characterized by increased levels of plasma VLDL and LDL, which have been postulated to result from either increased VLDL secretion, decreased lipoprotein clearance, insulin resistance, and/or altered fatty acid metabolism. [2][3][4] Because FCH is not a monogenic disorder, it is also possible that FCH families have multiple or even different alterations in lipoprotein metabolism rather than just a single defect in one of these abnormalities.…”

Section: F Amilial Combined Hyperlipidemia (Fch) (See Mendelianmentioning

confidence: 99%

“…Although several candidate genes have been implicated, these genes appear to have only subtle effects and most probably modify the elevated lipid phenotype rather than represent the primary cause. 4 Two genome scans for FCH in Dutch and Finnish families have also been recently reported. 8,9 These studies identified several loci in each FCH population, but there was no obvious overlap between the loci in the two studies.…”

mentioning

confidence: 99%

Locus for Elevated Apolipoprotein B Levels on Chromosome 1p31 in Families With Familial Combined Hyperlipidemia

Allayee¹,

Krass²,

Pajukanta³

et al. 2002

Circulation Research

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Abstract-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. Because FCH is not a monogenic disorder, it is also possible that FCH families have multiple or even different alterations in lipoprotein metabolism rather than just a single defect in one of these abnormalities.To date, hypotheses regarding the underlying mode of inheritance of FCH, which was originally thought to be dominant, have been based on linkage and segregation analyses 5-7 and remain to be corroborated by identification of the causative genes. A number of genetic studies have been conducted in various ethnic populations to identify susceptibility loci for FCH. Although several candidate genes have been implicated, these genes appear to have only subtle effects and most probably modify the elevated lipid phenotype rather than represent the primary cause. 4 Two genome scans for FCH in Dutch and Finnish families have also been recently reported. 8,9 These studies identified several loci in each FCH population, but there was no obvious overlap between the loci in the two studies. In particular, evidence for a major FCH locus was observed on chromosome 1q21-23 in the Finnish families. 10 This locus has since also been observed with modest levels of significance in the US, Chinese, and German FCH populations as well 11,12 but was not apparent in the initial analyses of Dutch data. Some explanation for this observation is provided by differences in the genetic background between the Finnish and Dutch populations. However, the use of different analytic methods can also contribute to these findings, because nonparametric affected sibling-pair linkage methods were used in the Dutch genome scan, whereas model-based parametric linkage analysis was used in the Finnish study.In the present...

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“…The apolipoprotein gene cluster ( APOAI-CIII-AIV ) on human chromosome 11q23 is known to harbor at least three genes that affect the metabolism of plasma lipoproteins (9). The relationship between variations in the gene cluster and plasma lipids has been studied for nearly two decades (9)(10)(11)(12). The majority of studies have focused on either apolipoprotein A-I (apoA-I), because of its influence on HDL production, or on apoC-III for its modulation of plasma triglyceride (TG).…”

mentioning

confidence: 99%

Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids

Aouizerat

Kulkarni

Heilbron

et al. 2003

Journal of Lipid Research

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109

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Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population ( P ‫؍‬ 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG ( P ‫؍‬ 0.012), VLDL cholesterol ( P ‫؍‬ 0.0007), and VLDL TG ( P ‫؍‬ 0.012), LDL TG ( P ‫؍‬ 0.003), and HDL TG ( P ‫؍‬ 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl ( P ‫؍‬ 0.009) and VLDL cholesterol by 8 mg/dl ( P ‫؍‬ 0.0001), and reduces HDL cholesterol by 2 mg/dl ( P ‫؍‬ 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease. -Aouizerat, B.

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Novel genes for familial combined hyperlipidemia

Cited by 51 publications

References 66 publications

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Locus for Elevated Apolipoprotein B Levels on Chromosome 1p31 in Families With Familial Combined Hyperlipidemia

Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids

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