Interaction between variant apolipoproteins C-II and E that affects plasma lipoprotein concentrations.

Hegele, Robert A.; Breckenridge, W. C.; Cox, Diane W.; Maguire, Graham F.; Little, J. A.; Connelly, Philip W.

doi:10.1161/01.atv.11.5.1303

Cited by 35 publications

(18 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 Furthermore, the presence of a single APOE E4 allele occurring in individuals with a single, mutant apo CII-T allele has been associated with higher plasma concentrations of cholesterol, TGs, and VLDL cholesterol when compared with relatives who carried neither or only 1 variant allele. 21 The data from the current report suggest that although routine biochemical tests might have been adequate to detect the association of apo CII-T with elevated plasma TGs, only the more labor-intensive procedure of ultracentrifugation of plasma would have permitted detection of the more subtle finding of increased LDL TGs for both of these mutations.…”

Section: Discussionmentioning

confidence: 71%

“…18 Heterozygotes for apo CII-T have an Ϸ50% decrease in apo CII mass and capacity to activate LPL. 21 The association of heterozygosity for apo CII-T with higher total TGs and LDL TGs suggests that impairment of this pathway can affect lipoprotein quantity and composition. The absence of associations of lipoprotein phenotypes with compound heterozygosity for both mutations was likely due to small numbers.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Hegele

Breckenridge

Cox

et al. 1998

ATVB

View full text Add to dashboard Cite

Abstract-Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (Pϭ0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (Pϭ0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F. 10 -12 Studies in transgenic rabbits suggest that HL overexpression can result in reduced plasma HDL and IDL and in reduced atherosclerosis. 4 In contrast, disruption of HL in mice can result in increased HDL and, on an APOE-deficient background, increased ␤-migrating VLDL but reduced atherosclerosis. 13 The relevance of such results to human lipoprotein metabolism is unclear.Most patients with HL deficiency due to HL mutations have been ascertained on the basis of dyslipidemia. However, among carriers of HL mutations associated with loss of function, such as R186H, S267F, L334F, and T383M, there are disparities in both the biochemical phenotype and the association with atherosclerosis susceptibility.14 -17 For example, in a Canadian family, compound heterozygotes for HL S267F and T383M had (1) combined hyperlipidemia, (2) TG enrichment of LDL and HDL, (3) ␤-migrating VLDL, (4) impaired chylomicron remnant metabolism, and (5) early coronary heart disease.14 However, the limited number of subjects in this family made it difficult to conclude whether simple heterozygotes had a discrete phenotype. In a Finnish family, compound heterozygotes for L334F and T383M did not have ␤-migrating VLDL but did have TG enrichment of LDL and HDL.15 Also, Finnish heterozygotes for an HL allele that carried R186H and L334F appeared to have TG enrichment of LDL and HDL.16 Homozygosity for a splice-site mutation in HL intron I was associated with hypertriglyceridemia and coronary heart disease; however, there was no obvious biochemical phenotype among heterozygotes. 17The disparity among the results of studies of phenotype in heterozygotes for loss-of-function mutations in HL has many possible explanations. First, ...

show abstract

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Hegele

Breckenridge

Cox

et al. 1998

ATVB

View full text Add to dashboard Cite

show abstract

“…40 Similarly, analysis of pedigrees of probands with familial chylomicronemia attributable to mutant apoC-II isoforms suggested that obligate heterozygote carriers of APOC2 mutations had elevated plasma TG and high TG content in lipoprotein subfractions. 41 Finally, heterozygous relatives of probands homozygous for truncating mutations in APOA5 and severe HTG were variably found to have moderately elevated plasma TG. 42,43 Thus, evidence from the pre-and postgenomic eras, including findings from this study, indicates that heterozygosity for rare dysfunctional coding sequence mutations is strongly associated with severe HTG.…”

Section: Discussionmentioning

confidence: 99%

Resequencing Genomic DNA of Patients With Severe Hypertriglyceridemia (MIM 144650)

Wang

Cao

Ban

et al. 2007

ATVB

View full text Add to dashboard Cite

Objective-The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. Methods and Results-We resequenced Ͼ2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age-and sex-matched normolipidemic controls. We found: (1) Complex quantitative traits, such as plasma TG, do not conform to Mendelian inheritance patterns; instead their genetic basis represents the cumulative contribution of multiple DNA variants. 7 A promising new strategy in human genetics to understand common complex traits is called the "missense accumulation approach", which aims to detect enrichment of rare, deleterious missense DNA variants in cases taken from one extreme of the distribution of a quantitative trait versus a control group. 7 The cumulative frequency of missense mutations rather than their individual frequencies is then compared between cases and controls. 7 This method has proven to be successful for investigation of common disease traits that have a very heterogeneous spectrum of predisposing alleles. 7 For instance, the missense accumulation approach has been successfully used to evaluate the MC4R gene 8 and several other genes in obesity, 9 and the tyrosine phosphatome in colorectal cancers. 10 However, the most successful application of the missense accumulation strategy has been in lipoprotein metabolism, as evidenced by the pioneering work of Hobbs and Cohen. [11][12][13][14] They have found enrichment of missense mutations in individuals at the extremes of several plasma lipoprotein traits, including: (1) increased missense mutations in LCAT, APOA1, and ABCA1 among individuals with depressed highdensity lipoprotein (HDL) cholesterol 13 ; (2) increased PCSK9 missense or nonsense mutations among individuals with depressed low-density lipoprotein (LDL) cholesterol 14 ; (3) increased missense mutations in NPC1L1 in individuals with reduced sterol absorption and low plasma LDL cholesterol 12 ; and (4) increased missense mutations in ANGPTL4 in indi-

show abstract

“…When OHLD family members (excluding unrelated spouses) were classified 40.5 ±18.3 years), mean levels of HDL TG were not above the 95th percentile in carriers of T383M and S267F, whereas mean levels of LDL TG exceeded the 95th percentile for carriers of S267F but not for carriers of T383M. When "hyperbetatriglyceridemia" and "hyperalphatriglyceridemia" are used to define the phenotype in subjects with levels of LDL TG and HDL TG, respectively, that exceed the 95th percentile for age and sex, then all compound heterozygotes have hyperalphatriglyceridemia and hyperbetatriglyceridemia.…”

Section: Lipoprotein Phenotypes and Hl Genotypesmentioning

confidence: 99%

Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics.

Hegele

Little

Vézina

et al. 1993

Arterioscler Thromb

Self Cite

213

110

View full text Add to dashboard Cite

Hepatic lipase (HL) is an important enzyme in the metabolism of triglyceride-rich lipoproteins and high density lipoproteins. The clinical syndrome of HL deficiency is rare and difficult to identify. We studied carriers of mutant HL to ascertain whether there are distinctive clinical and/or biochemical characteristics of the heterozygous state. In an Ontario kindred, compound heterozygosity for two HL mutations, S267F and T383M, underlies the clinical syndrome of complete HL deficiency. We report that simple heterozygotes for either HL mutant do not have a discrete lipoprotein abnormality, except for relative triglyceride enrichment of lipoprotein fractions with d> 1.006 g/mL. Postheparin HL activity is depressed to a greater degree in carriers of S267F compared with carriers of T383M. Retinyl palmitate loading studies in a compound heterozygote revealed impaired clearance of chylomicron remnants. The dyslipoproteinemia in a compound heterozygote was ameliorated by lovastatin. There was no difference in the quantity and distribution of HL mRNA in the liver of a compound heterozygote when compared with that of a normal subject. Thus, HL deficiency associated with structural variation of the HL gene is characterized by premature atherosclerosis, triglyceride enrichment of lipoprotein fractions with d> 1.006 g/mL, the presence of circulating /3-very low density lipoproteins, and abnormal catabolism of postprandial triglyceride-rich lipoproteins. (Arteriosclerosis

show abstract

Interaction between variant apolipoproteins C-II and E that affects plasma lipoprotein concentrations.

Cited by 35 publications

References 37 publications

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Resequencing Genomic DNA of Patients With Severe Hypertriglyceridemia (MIM 144650)

Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics.

Contact Info

Product

Resources

About