Effect of the APOC3 Sst I SNP on fasting triglyceride levels in men heterozygous for the LPL P207L deficiency

Garenc, Christophe; Couillard, Charles; Laflamme, Nathalie; Cadelis, F.; Gagné, Claude; Couture, Patrick; Julien, Pierre; Bergeron, Jean

doi:10.1038/sj.ejhg.5201469

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…A recent study has observed that the apo CIII-SstI SNP increases fasting TG levels among carriers of the LPL P207L mutation. 30 Reilly et al 31 have also recently…”

Section: Discussionmentioning

confidence: 99%

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

et al. 2007

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Background: Abdominal obesity and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) increase cardiovascular risk. The very low-density lipoprotein (VLDL) is a triglyceride (TG)-rich particle. Frequent variations in the genes coding for enzymes and proteins involved in the VLDL catabolism have already been documented. The epistatic effect of such variants on the risk profile associated with abdominal obesity remains to be elucidated. Objective: This study aims to assess the effect of combinations of frequent single-nucleotide polymorphisms (SNPs) in the VLDL catabolic pathway on the relation between abdominal obesity and fasting TG. Method: Only gene variants in the lipoprotein lipase, apolipoprotein (apo) CIII, hepatic lipase and apo E genes known to be frequent in the general population (allele frequency45%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphisn in a sample of 640 non-diabetic French Canadians at high cardiovascular risk (405 obese, 235 non-obese). Results: Carrying more than two frequent gene variants involved in the VLDL catabolic pathway significantly increased the risk of hyperTG (odds ratio of TG41.7 mmol/l ¼ 4.15; P ¼ 0.001). This effect was proportional to the number of SNPs and genes involved and was significantly amplified by the presence of abdominal obesity defined on the basis of waist circumference. Conclusion: When combined with abdominal obesity, epistasis in the VLDL pathway has a deleterious effect on fasting TG and coronary artery disease risk profile according to the TG threshold (1.7 mmol/l) used in medical guidelines for the assessment of the metabolic syndrome and associated risk.

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“…A recent study has observed that the apo CIII-SstI SNP increases fasting TG levels among carriers of the LPL P207L mutation. 30 Reilly et al 31 have also recently…”

Section: Discussionmentioning

confidence: 99%

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

et al. 2007

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“…Examples of functional influence of single or multiple polymorphisms on the effect of a nearby mutated gene are rare, but nevertheless reported (15)(16)(17)(18)(19). For example, in hereditary thrombotic thrombocytopenic purpura due to mutation in the ADAMTS13 gene, the polymorphisms R7W and Q448E -that were shown to have positive modifying effect on the gene function in the absence of the mutation -enhanced the detrimental effect of the missense mutation (16).…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Raef¹,

Baitei²,

Zou³

et al. 2008

European Journal of Endocrinology

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Objective: Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-a (GR-a) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance. Design: The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype. Method: Three siblings were presented with clinical cortisol resistance, featuring severe hypertension, hypokalemia and hyperandrogenism. Three other siblings and both parents were asymptomatic. Genomic DNA from peripheral lymphocytes was isolated from family members. The entire GR-a coding sequence (exons 2-9) was amplified by PCR and sequenced. Results: A homozygous G679S mutation was present in the three clinically affected subjects. Heterozygous G66A (E22E) and G68A (R23K) polymorphisms and G2035A (G679S) mutation were found in the father and two siblings. Mother and one sibling had only heterozygous G679S mutation. The clinically unaffected subjects showed two different responses to dexamethason. Those with heterozygous G679S mutation and ER22/23EK polymorphism had normal cortisol suppression, whereas those with only heterozygous G679S mutation failed to suppress normally. Conclusions: A homozygous G679S mutation of the GR-a gene is associated with severe cortisol resistance, whereas a heterozygous mutation of the same gene can lead to subclinical cortisol resistance. The effect of the heterozygous mutation was abolished in subjects carrying the ER22/23EK polymorphism.

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“…However, in addition to these variants, the E255G proband was homozygous for the previously reported LPL W86G 15 and the H321L carrier was heterozygous for LPL P207L 18 suggesting that these variants in APOA5 are making a rather minor contribution to the disorder. We expressed these APOA5 variants together with those previously reported 1,2,5 and carried out functional studies in vitro obtaining novel insights into the structure: function relationship of apoAV.…”

Section: Discussionmentioning

confidence: 89%

“…LPL P207L has been well characterized in vitro 24 and in vivo. 18 In a study of 34 P207L carriers, in the presence of a APOC3 TG-raising SNP, mean TG were 10.31 mmol/L compared to 5.58 mmol/L in noncarriers of this SNP. 18 We propose that the presence of APOA5 H321L and S19W compound the effect of P207L, resulting in pretreatment TG levels reaching 63 mmol/L, considerably higher than that reported by Garenc et al 18 …”

Section: Apoav-l321mentioning

confidence: 99%

“…18 In a study of 34 P207L carriers, in the presence of a APOC3 TG-raising SNP, mean TG were 10.31 mmol/L compared to 5.58 mmol/L in noncarriers of this SNP. 18 We propose that the presence of APOA5 H321L and S19W compound the effect of P207L, resulting in pretreatment TG levels reaching 63 mmol/L, considerably higher than that reported by Garenc et al 18 ApoAV-X139, -X148, and ⌬139 to 147The structure-function studies of these 2 reported truncation variants reflect the disparity in their observed LPL activity in vivo. The Q139X proband had only 21% residual LPL activity (comparable to homozygous LPL deficiency) 1 whereas the Q148X homozygous proband had 60% residual LPL activity.…”

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confidence: 99%

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Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding

Dorfmeister

Zeng

Dichlberger

et al. 2008

ATVB

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Objective-The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. Methods and Results-We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -⌬139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (Ϫ25% [Pϭ0.005], Ϫ36% [PϽ0.0001], and Ϫ23% [Pϭ0.02]), respectively). ApoAV-C271, -X139, -X148, and ⌬139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. Key Words: apolipoprotein AV Ⅲ LDL-R family Ⅲ LR8 Ⅲ LRP1 Ⅲ HSPG-bound LPL P remature truncations of APOA5, Q139X, Q148X, and the IVS3ϩ3gϾc are associated with severe hypertriglyceridemia (HyperTG), 1-3 behaving as phenocopies of lipoprotein lipase (LPL) deficiency. These rare APOA5 variants do not always lead to a deficiency in circulating plasma apoAV, and carriers present with a range of apoAV levels (reviewed in 4 ). Kao et al 5 identified a common polymorphism G185C in a Taiwanese study which occurs at a minor allele frequency of 0.04 in controls but at a 6.3-fold higher frequency of 0.27 in hypertriglyceridemic patients (PϽ0.001). Conclusion-TheApoAV is present on chylomicrons, VLDL, and HDL, but not on IDL or LDL, suggesting that VLDL-containing apoAV is cleared before the lipolytic cascade. 6 One function of apoAV is to activate LPL, and Apoa5 knockout mice have 4-fold higher TG levels than wild type. [7][8][9] Whereas LPL transgenic mice can rescue Apoa5 knockout mice from HyperTG, this is not entirely reciprocal 8 suggesting that the effect of apoAV on plasma TG is dependent on heparinsulfate proteoglycan (HSPGs)-bound LPL. 7,8 In addition, apoAV-dependent TG catabolism acts by enhancing receptormediated endocytosis via members of the LDL-receptor (LDLR) family. 10,11 We have identified 3 novel APOA5 missense variants (E255G, G271C, H321L) in patients with TG levels Ͼ10 mmol/L. Although LPL and APOC2 variants had been excluded for the G271C carrier, the coding exons of LPL and APOC2 were sequenced in the 2 other probands. Because family studies were not possible, the APOA5 variants were expressed in vitro together with G185C, Q139X, Q148X. 1,2,5 In addition we designed a deletion construct ⌬139 to 147, to MethodsSee supplemental methods (available online at http://atvb.ahajournals. org) for full details. PatientsIn total 130 patients with TG levels Ͼ10 mmol/L were recruited into the study; seven patients from the UK, 28 patients from the Netherlands with LPL and APOC2 mutations excluded, and 95 p...

show abstract

Effect of the APOC3 Sst I SNP on fasting triglyceride levels in men heterozygous for the LPL P207L deficiency

Cited by 9 publications

References 33 publications

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding

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