Familial hyper-alpha-lipoproteinemia: Studies in eighteen kindreds

Glueck, Charles J.; Fallat, R.; Millett, Frank; Gartside, Peter S.; Elston, Robert C.; Go, Rodney C.P.

doi:10.1016/0026-0495(75)90063-3

Cited by 196 publications

(49 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…25 The frequency of this haplotype is more common in blacks, possibly accounting for (at least in part) the higher HDL-C levels seen in this population. 26 The phenotype of elevated HDL-C is often dominantly inherited, 27 but the molecular pathogenesis in most subjects is unknown. Only homozygous deficiency of HL or of the cholesteryl ester transfer protein (CETP) 28 has been shown to cause genetic high HDL-C, and both are recessive conditions.…”

mentioning

confidence: 99%

Identification of Genetic Variants in Endothelial Lipase in Persons With Elevated High-Density Lipoprotein Cholesterol

et al. 2002

View full text Add to dashboard Cite

Background-Elevated high-density lipoprotein cholesterol (HDL-C) is associated with reduced risk of cardiovascular disease, and variation in HDL-C levels has been shown to be Ϸ50% heritable. Overexpression of endothelial lipase (EL), a member of the lipoprotein lipase gene family, markedly reduces HDL-C levels in mouse models. We hypothesized that genetic variation in EL might be associated with elevated HDL-C. Methods and Results-All exons and 1.2 kilobase of promoter of the EL gene were sequenced in 20 unrelated human subjects with high HDL-C levels. A total of 17 variants were identified. Six of these were potentially functional and were confirmed by restriction enzyme analysis. Four variants result in amino acid changes (Gly26Ser, Thr111Ile, Thr298Ser, and Asn396Ser,) and 2 variants were in the promoter (Ϫ303A/C and Ϫ410C/G). The genotype frequencies of each variant were determined in 176 black controls, 165 white controls, and 123 whites with high HDL-C. The Thr111Ile variant was the most common, with an allele frequency of 10.3% in blacks, 31.2% in white controls, and 32.6% in the high HDL-C group. The remaining variants all had allele frequencies Ͻ5.0% but differed in frequency among the 3 groups. Interestingly, Gly26Ser, Thr298Ser, and Ϫ303A/C were found in the black and high HDL-C white cohorts but were absent in the control white group. Conclusions-Six new potentially functional variants in EL were discovered through sequencing of the EL gene in subjects with high HDL-C levels. Differences in allele frequencies exist between blacks and whites and between control subjects and those with high HDL-C levels. 2 Endothelial lipase (EL) is the most recently discovered member of the LPL, or triglyceride (TG) lipase, gene family. Cloned independently by 2 groups using distinct methods, 3,4 the EL gene spans 10 exons and 9 introns and encodes a polypeptide of 500 amino acids. The EL cDNA is 45% homologous to LPL and 40% to HL. Many of the regulatory domains found in LPL and HL, such as the lipoprotein and heparin-binding domains, are highly conserved in EL. 5 Unlike LPL and HL, EL is synthesized by endothelial cells and primarily acts as a phospholipase. 6 Whereas LPL activity indirectly influences the metabolism of high-density lipoprotein cholesterol (HDL-C) levels, 7 HL directly modulates the metabolism of HDL in vivo by converting larger HDL to smaller HDL. 2 Because EL acts predominantly as a phospholipase and the phospholipid content of HDL is a major factor in determining apolipoprotein A-I (apoA-I) conformation 8 and HDL function, 9 -11 we hypothesized that HDL might be a major substrate for EL. We showed that HDL is an excellent and preferred substrate for EL ex vivo. 6 Furthermore, we demonstrated that HDL-C and apoA-I levels were markedly reduced in mice injected with an adenoviral vector encoding human EL. 3 These results suggested that EL may play a central role in HDL metabolism.At least 50% of the variation in HDL-C is genetically determined. 12,13 Genetic diversity at both the LPL and HL loci ha...

show abstract

mentioning

confidence: 99%

Identification of Genetic Variants in Endothelial Lipase in Persons With Elevated High-Density Lipoprotein Cholesterol

et al. 2002

View full text Add to dashboard Cite

show abstract

“…4 Genetic syndromes of high HDL are associated with longevity and decreased incidence of CHD. 5,6 Thus, the concept of intervention targeted toward HDL as a method of preventing or treating atherosclerotic cardiovascular disease is attractive. 7,8 …”

mentioning

confidence: 99%

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

et al. 1999

View full text Add to dashboard Cite

Background-The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported. Methods and Results-LDL receptor-deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I-expressing adenovirus were 216Ϯ16.0 mg/dL, compared with 68.0Ϯ3.0 mg/dL in control virus-injected mice (PϽ0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189Ϯ21.0 mg/dL, compared with 123Ϯ8.0 mg/dL in control virus-injected mice (PϽ0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and cross-sectional analysis of the aortic root. Compared with baseline mice, atherosclerosis progressed in mice injected with the control adenovirus. In contrast, in mice expressing apoA-I compared with baseline mice, total en face aortic lesion area was reduced by 70% and aortic root lesion was reduced by 46%. Expression of apoA-I was associated with a significant reduction in the fraction of lesions occupied by macrophages and macrophage-derived foam cells. Conclusions-Liver-directed gene transfer of human apoA-I resulted in significant regression of preexisting atherosclerotic lesions in LDL receptor-deficient mice as assessed by 2 independent methods. (Circulation. 1999;100:1816-1822.)

show abstract

“…had severe calcification of major arteries. One report indicates a relative paucity of coronary artery morbidity and mortality among first-degree relatives of patients with heterozygous HBLP 26 ; furthermore, the virtual absence of atherosclerosis was reported in a 76-year-old subject with HBLP. 27 According to her medical history, K.H.…”

Section: Discussionmentioning

confidence: 99%

A Truncated Species of Apolipoprotein B (B-38.7) in a Patient With Homozygous Hypobetalipoproteinemia Associated With Diabetes Mellitus

Ohashi

Ishibashi

Yamamoto

et al. 1998

ATVB

View full text Add to dashboard Cite

Abstract-Familial hypobetalipoproteinemia is caused by mutations in the apolipoprotein (apo) B gene. We identified a 57-year-old woman whose plasma total cholesterol and apoB levels were 2.17 mmol/L and 0.03 g/L, respectively. Separation of plasma lipoproteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the absence of apoB-100 and the presence of a faster-migrating form of apoB with an apparent M r of 195 kDa. Direct sequencing of a polymerase chain reaction-amplified fragment of the patient's apoB gene DNA revealed a single C3 T transition at nucleotide 5472 that converts glutamine 1755 (CAA) to a stop codon (TAA). We predict this novel nonsense mutation of the apoB gene to produce a truncated protein that contains 1754 amino-terminal amino acid residues of apoB-100. We designated this mutant form of apoB apoB-38.7 by following the centile nomenclature of the apoB species. The same mutation was found in both of her children. The proband revealed clinical findings of retinitis pigmentosa, acanthocytosis, and loss of deep tendon reflexes that are characteristic of severe hypobetalipoproteinemia. In addition, the proband had type II diabetes mellitus with nephropathy, anemia, cholelithiasis, hepatic hemangioma, bronchiectasis, and extensive calcification of major arteries including, the celiac, splenic, and renal. In summary, we have found a novel truncated apoB, apoB-38.7, in a patient with an unusual presentation of hypobetalipoproteinemia that includes diabetes mellitus and extensive arterial calcification. (Arterioscler Thromb Vasc Biol. 1998;18:1330-1334.)

show abstract

Familial hyper-alpha-lipoproteinemia: Studies in eighteen kindreds

Cited by 196 publications

References 14 publications

Identification of Genetic Variants in Endothelial Lipase in Persons With Elevated High-Density Lipoprotein Cholesterol

Identification of Genetic Variants in Endothelial Lipase in Persons With Elevated High-Density Lipoprotein Cholesterol

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

A Truncated Species of Apolipoprotein B (B-38.7) in a Patient With Homozygous Hypobetalipoproteinemia Associated With Diabetes Mellitus

Contact Info

Product

Resources

About