Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population

Knoblauch, Hans; Bauerfeind, Anja; Krähenbühl, Christine; Daury, Aurelie; Rohde, Klaus; Bejanin, Stéphane; Essioux, Laurent; Schuster, Herbert; Luft, Friedrich C.; Reich, Jens

doi:10.1093/hmg/11.12.1477

Cited by 65 publications

(40 citation statements)

References 33 publications

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“…32 In a large family study on the impact of genetic variants and the effect of SNPs and haplotypes on baseline lipid levels, a similar observation was made for several genes involved in lipid metabolism, including the CETP gene, where haplotypes derived from SNP combinations resulted in stronger significance of the genotypephenotype association than did individual SNPs. 24 CETP protein mass and activity are intermediate phenoypes much closer to the CETP genotype than any other biochemical phenotype (i.e. lipid concentrations).…”

Section: Discussionmentioning

confidence: 97%

“…Analyses that employ haplotypes, the ordered array of SNP combinations in individual alleles, may enable more consistent and relevant associations. 23,24 In this study, we sought to determine and compare the contribution of individual SNPs and haplotypes in the CETP gene to plasma CETP levels and activity, to lipid levels and to the response to treatment with 3-hydroxy-3-methylglutaray coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with previously untreated dyslipidemias.…”

Section: Introductionmentioning

confidence: 99%

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Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Winkelmann¹,

Hoffmann

Nauck

et al. 2003

Pharmacogenomics J

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Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P¼0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P¼0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins. The Pharmacogenomics Journal (2003) 3, 284-296, doi:10.1038/sj.tpj.6500195Keywords: cholesteryl ester transfer protein; HDL-cholesterol; triglycerides; haplotype; single nucleotide polymorphism; statin INTRODUCTION Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and plays a central role in high-density lipoprotein (HDL) metabolism. CETP transfers cholesteryl esters associated with HDL to triglyceride-rich lipoproteins, facilitating the clearance of cholesteryl esters from plasma. 1 Although the potential contribution of CETP to reverse cholesterol transport suggests an antiatherogenic mode of action, knowledge of the physiologic role of CETP in lipoprotein metabolism remains incomplete. The overall effect of CETP on atherogenesis may vary depending on both metabolic context and molecular variation in the CETP gene. 2 Investigations of associations between genetic variants in CETP and cardiovascular phenotypes are numerous, but often conflicting in their findings. The Taq1B polymorphism of the CETP gene has been associated with plasma levels of CETP and HDL cholesterol (HDL-C) and with the risk of coronary heart disease (CHD). 3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Winkelmann¹,

Hoffmann

Nauck

et al. 2003

Pharmacogenomics J

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“…7,[21][22][23][24] Furthermore, other genes such as the ApoE, ApoA1, ApoB, hepatic lipase and PPAR genes have been investigated for their association with lipid levels and/or cardiovascular disease outcomes. 4,10,[25][26][27] Since weight gain and BMI are significantly correlated with serum triglycerides and cholesterol levels, it is possible that genetic variants which may influence the extent of weight gain during treatment with antipsychotics, such as the polymorphisms in the 5-HT2C receptor (À759 T/C), 28,29 polymorphisms of the leptin gene, 28,30 and polymorphisms in the a2A receptor (À1291 C/G) 31 may also be related to deferential drug Â gene effects on serum lipids. In this initial study, we could only investigate a few polymorphisms which previous studies suggested may have significant effects on plasma or serum triglycerides or cholesterol; we also chose SNPs with a minor allele frequency of at least 10% in some prior studies.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms in these genes have been shown to influence serum or plasma triglyceride levels [6][7][8] and some of these variations have also been shown to influence cholesterol and other serum lipid parameters. 9 Several studies have revealed pharmacogenetic interactions of polymorphisms in lipid genes and metabolic response to statin drug treatment (for a review see Knoblauch et al 10 ; Schmitz et al 11 ).…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

et al. 2007

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Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug Â gene and drug Â haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine-or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.

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“…They did. 24 We then expanded this analysis to 7 additional genes. With common single nucleotide polymorphisms in 13 genes, we were able to construct haplotypes that account for approximately two-thirds of the Luft Geneticismgenetic variance for LDL and HLD.…”

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confidence: 99%

Geneticism of Essential Hypertension

Luft

2004

Hypertension

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T he idea that a person's genetic constitution is allimportant and that genetic knowledge is sufficiently advanced so that we can make judgments on our past or future health was called geneticism by Medawar. 1 He termed geneticism as the application to the human condition of a genetic knowledge or understanding that is assumed to be very much greater than it really is. Proponents of geneticism have promised us that the sequencing of the human genome will offer limitless insights into the pathogenesis of essential hypertension and, moreover, will provide bountiful access to new drug targets and facilitate pharmacological therapy. In terms of citations, only "hypertension and sodium" provokes more "hits" than "hypertension and genetics." Nevertheless, with a few exceptions, the results appear disappointing. We might pause and reflect on the answers to the question, "Why?" In so doing, we should first examine the genetic differences that separate us from one another. The genetic differences between human beings seem to be of 3 types: those based on single gene mutations, those based on polymorphic genetic differences, and those resulting from a complex interaction of many genes.First, there are the differences that divide us into a great majority and a tiny minority. Essential hypertension clearly does not involve a tiny minority and not yet a great majority; however, this state-of-affairs was lost on early students of the subject. When Weitz first proposed the notion of genetic variance on blood pressure, he concluded that essential hypertension was inherited through the actions of a single gene. Because essential hypertension is common, were Weitz correct, we would expect 2 distinct blood pressure distributions in the population, the haves and the have-nots. Indeed, that very argument occupied Platt and Pickering. Platt studied family histories, measured blood pressure in normotensive probands, hypertensive propositi and their relatives, and argued as Weitz did. Pickering et al, however, studied systolic and diastolic blood pressure distributions from the second to eighth decades in first-degree relatives of normotensive probands and hypertensive propositi. 2 They found that the frequency distribution moved upward as age advanced. At no age was there a clear-cut blood pressure distribution into normal and high blood pressures. Moreover, others found subsequently that the relationship between blood pressures of parents and sons was linear for both probands and propositi. As a matter of fact, the relationships were no different than those for height. Pickering concluded that blood pressure is inherited as a graded character over the entire blood pressure range, whether this value is regarded as hypotension, normotension, or hypertension. Nevertheless, disorders that separate us into the great majority and the tiny minority indeed exist. Methods to elucidate these monogenic disorders are at hand and a series of these hypertensive (or hypotensive) disorders have been elucidated. 3

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Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population

Cited by 65 publications

References 33 publications

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

Geneticism of Essential Hypertension

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