G→A Substitution at Position −75 of the Apolipoprotein A-I Gene Promoter

Minnich, Anne; DeLangavant, Ghislaine; Lavigne, Jacques; Roederer, Ghislaine O.; Lussier‐Cacan, Suzanne; Davignon, Jean

doi:10.1161/01.atv.15.10.1740

Cited by 40 publications

(14 citation statements)

References 29 publications

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“…The apo A-1 and HDL cholesterol levels were significantly higher in some studies in men with the A allele compared with GG individuals, but not in women [10,[13][14][15][16]. In other studies these levels were significantly higher in women with the A allele but not in men [17][18][19]. Furthermore, some reports failed to find any lipid difference between apo A-1 gene promoter genotypes [20][21][22].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, ethnic heterogeneity among American study populations [20][21][22] may obscure differences between genotypes detected in more homogeneous populations. For example, linkage disequilibrium may exist between the A allele and a yet unknown HDL-raising allele in some populations [19] but not in others. Moreover, apo B and apo E gene polymorphisms, known to contribute to the regulation of lipid levels and lipid responses [34][35][36], could have confounded the results in apo A-1 genotype studies, which did not use adjustment for other polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a number of studies have investigated the association between a common G\A genetic variation at position k75 bp (relative to the transcription start site) in the promoter region of the apo A-1 gene and plasma apo A-1 and HDL cholesterol levels. However, the results have been inconsistent and sometimes conflicting [10,[13][14][15][16][17][18][19][20][21][22][23]. Even less is known about the effect of the apo A-1 promoter polymorphism on lipid responses during dietary modification [15,23].…”

Section: Introductionmentioning

confidence: 99%

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Influence of apolipoprotein A‐1 promoter polymorphism on lipid levels and responses to dietary change in Finnish adults

Meng

Pajukanta

Valsta

et al. 1997

Journal of Internal Medicine

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of apolipoprotein A‐1 promoter polymorphism on lipid levels and responses to dietary change in Finnish adults

Meng

Pajukanta

Valsta

et al. 1997

Journal of Internal Medicine

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“…Other examples of discrepancies between apparent effects of gene deletions as assessed by in vitro studies and by phenotypic expression of a naturally occurring deletion is seen when domain 3 (O-linked sugar domain) is deleted in vitro by site-directed mutagenesis resulting in no defect in receptor activity (27), while a homozygote for such a mutation expresses FH (28,29). A variant of lipoprotein lipase containing an Asn2913 Ser substitution which is functionally mildly abnormal in vitro (30) is associated with type IV hypertriglyceridemia in French Canadians (31). In the case of lipoprotein lipase, the unexpectedly profound clinical effect of heterozygosity for a mildly defective variant may be attributable to a dominant negative mechanism, wherein the defective variant would interfere with lipoprotein lipase dimerization, which is necessary for function.…”

Section: Fig 2 Ldl-r Mrna From Ldl-r ⌬5kb and Normal Allelementioning

confidence: 99%

Unexpected Consequences of Deletion of the First Two Repeats of the Ligand-binding Domain from the Low Density Lipoprotein Receptor

Sass

Giroux

Lussier‐Cacan

et al. 1995

Journal of Biological Chemistry

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Heterozygosity for a 5-kilobase (kb) deletion of the first two ligand-binding repeats (exons 2 and 3) of the low density lipoprotein (LDL) receptor (R) gene (LDL-R ⌬5kb) confers familial hypercholesterolemia (FH).The FH phenotype is unexpected based on previous sitedirected mutagenesis showing that deletion of exons 2 and 3 resulted in little or no defect in LDL-R activity. In the present study, we took unique advantage of the ability to distinguish the LDL-R ⌬5kb from the normal receptor on the basis of size, in order to resolve this apparent discrepancy. Fibroblasts from heterozygotes for the LDL-R ⌬5kb displayed 50% of normal capacity to bind LDL and ␤-VLDL, apparently due to lower receptor number. Cellular mRNA for the ⌬5kb allele was at least as abundant as that for the normal allele. Immunoblotting and cell binding assays with anti-LDL-R antibody IgG-4A4 demonstrated normal synthesis and transport of the ⌬5kb receptor. Ligand blotting demonstrated that the ⌬5kb receptor displayed minimal or no ability to bind LDL or ␤-VLDL. Thus, in contrast to transfected cell lines, in human fibroblasts, the first two cysteinerich repeats of the LDL-R appear functionally necessary. These characteristics of the LDL-R ⌬5kb in human fibroblasts explain the in vivo phenotype of carriers. The low density lipoprotein (LDL)1 receptor (R) binds and catabolizes apolipoprotein E-containing chylomicron and VLDL remnants and LDL. In the liver, LDL-R functions to remove these lipoproteins from plasma for eventual excretion of the cholesterol into the bile. In peripheral cells, it functions to provide the cell with cholesterol needed for membrane synthesis. The LDL-R contains five major structural domains: a seven-repeat, cysteine-rich ligand binding domain encoded by exons 2-6, an epidermal growth factor-precursor homology domain (exons 7-14), a glycosylation domain (exon 15), a membrane-spanning domain (exon 16), and a cytoplasmic tail (exon 17) (1). The LDL-R is one of the few proteins for which knowledge of the structure-function relationship has been generated both from site-directed mutagenesis and from numerous naturally occurring human mutations.Mutations in the LDL-R gene resulting in a dysfunctional receptor cause a codominantly inherited disorder of plasma cholesterol catabolism known as familial hypercholesterolemia (FH). Human LDL-R mutations have been assigned to five classes of defects based on their phenotypic effects on the receptor protein (1). We have previously described a deletion of approximately 5 kb, which removes exons 2 and 3 of the LDL-R gene (LDL-R ⌬5kb) (2). In site-directed mutagenesis experiments, deletion of the first repeat (exon 2) has no effect on the binding or internalization of LDL or ␤-VLDL or recycling of receptors in transfected mammalian cells (3). Simultaneous deletion of exons 2 and 3 has resulted in a receptor which binds LDL 70% as well as the normal receptor and which binds ␤-VLDL equally as well (4). These results have led to the suggestion that the first two repeats of the LDL-R ligandb...

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“…Polymorphisms at Ϫ75 and ϩ83 bp of the apo(a1) gene have been related to elevated levels of HDL cholesterol and apo(a1) in nondiabetic subjects (5-7), although not confirmed in all studies (8,9). Association of the ϩ83-bp polymorphism with elevated levels of HDL cholesterol has been stronger than that with the Ϫ75-bp polymorphism (6).…”

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confidence: 99%

MspI polymorphism at +83 bp in intron 1 of the human apolipoprotein A1 gene is associated with elevated levels of HDL cholesterol and apolipoprotein A1 in nondiabetic subjects but not in type 2 diabetic patients with coronary heart disease.

et al. 2000

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T he protective effect of HDL cholesterol and apolipoprotein A1 [apo(a1)] on the risk of coronary heart disease (CHD) is mediated mainly through the promotion of cholesterol efflux from peripheral cells (1). In addition, both HDL cholesterol and apo(a1) may have antioxidant, antithrombotic, and anti-inflammatory properties, which could have important antiatherogenic effects (1). The level of circulating HDL cholesterol and apo(a1) is dependent on sex, BMI, age (2), smoking (3), alcohol intake, and lipid-lowering medication (4). In addition, different variants in the apo(a1) gene can modify its expression and affect HDL cholesterol and apo(a1) levels (5,6).Restriction site polymorphisms have been identified at Ϫ75 bp in the promoter region and ϩ37 and ϩ83 bp in intron 1 of the apo(a1) gene. Polymorphisms at Ϫ75 and ϩ83 bp of the apo(a1) gene have been related to elevated levels of HDL cholesterol and apo(a1) in nondiabetic subjects (5-7), although not confirmed in all studies (8,9). Association of the ϩ83-bp polymorphism with elevated levels of HDL cholesterol has been stronger than that with the Ϫ75-bp polymorphism (6). The genotype effect on circulating apo(a1) and HDL cholesterol levels is modulated by sex and environmental factors such as smoking (3,7,10). The differences in HDL cholesterol and apo(a1) levels among various genotypes of the apo(a1) gene are not modified by different diets, suggesting that the possible benefit is independent of fat and cholesterol intake (11).So far, no studies have been published on the impact of the Ϫ75-and/or ϩ83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes. To this aim, we screened nondiabetic and type 2 diabetic subjects with CHD for the Ϫ75-and ϩ83-bp polymorphisms of the apo(a1) gene. RESEARCH DESIGN AND METHODS SubjectsAll unrelated subjects (n = 641: 469 men, 172 women) participating in this study were R I G I N A L A R T I C L EOBJECTIVE -Elevated HDL cholesterol and its principal carrier protein apolipoprotein A1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the Ϫ75-bp and/or ϩ83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -We determined the prevalence of the Ϫ75-bp and ϩ83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD Ϫ ). RESULTS-The rare M1 Ϫ and M2 Ϫ allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2 ϩϪ genotype had higher HDL cholesterol (1.48 ± 0.19 vs. 1.23 ± 0.02 mmol/l, P Ͻ 0.01) and apo(a1) (1.43...

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G→A Substitution at Position −75 of the Apolipoprotein A-I Gene Promoter

Cited by 40 publications

References 29 publications

Influence of apolipoprotein A‐1 promoter polymorphism on lipid levels and responses to dietary change in Finnish adults

Influence of apolipoprotein A‐1 promoter polymorphism on lipid levels and responses to dietary change in Finnish adults

Unexpected Consequences of Deletion of the First Two Repeats of the Ligand-binding Domain from the Low Density Lipoprotein Receptor

MspI polymorphism at +83 bp in intron 1 of the human apolipoprotein A1 gene is associated with elevated levels of HDL cholesterol and apolipoprotein A1 in nondiabetic subjects but not in type 2 diabetic patients with coronary heart disease.

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