Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease.

Wang, X. L.; Liu, S.-X.; McCredie, R. M.; Wilcken, D. E. L.

doi:10.1172/jci118802

Cited by 59 publications

(56 citation statements)

References 30 publications

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“…In another study, Cohen et al recently reported that multiple rare alleles contribute to low plasma levels of HDL cholesterol (Cohen et al 2004). Furthermore, a rare SNP in the apolipoprotein Al gene, +83C→T, f (−)=0.041, has been shown to be associated with the severity of coronary artery disease (Wang et al 1996). Finally, a rare synapsin III SNP, S470N, f(−)≈0.02, has been reported to have a possible relationship to schizophrenia (Porton et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function

Lei

Morris

Smith

et al. 2005

Naunyn-Schmiedeberg's Arch Pharmacol

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We identified nine naturally-occurring human single nucleotide polymorphisms (SNPs) in the α 1a -adrenoceptor (α 1a AR) coding region, seven of which result in amino acid change. Utilizing rat-1 fibroblasts stably expressing wild type α 1a AR or each SNP at both high and low levels, we investigated the effect of these SNPs on receptor function. Compared with wild type, two SNPs (R166K, V311I) cause a decrease in binding affinity for agonists norepinephrine, epinephrine, and phenylephrine, and also shift the dose-response curve for norepinephrine stimulation of inositol phosphate (IP) production to the right (reduced potency) without altering maximal IP activity. In addition, SNP V311I and I200S display altered antagonist binding. Interestingly, a receptor with SNP G247R (located in the third intracellular loop) displays increased maximal receptor IP activity and stimulates cell growth. The increased receptor signaling for α 1a AR G247R is not mediated by altered ligand binding or a deficiency in agonist-mediated desensitization, but appears to be related to enhanced receptor-G protein coupling. In conclusion, four naturally-occurring human α 1a AR SNPs induce altered receptor pharmacology and/or biological activity. This finding has potentially important implications in many areas of medicine and can be used to guide α 1a AR SNP choice for future clinical studies.

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Section: Discussionmentioning

confidence: 99%

Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function

Lei

Morris

Smith

et al. 2005

Naunyn-Schmiedeberg's Arch Pharmacol

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“…These sequence variations were shown to be associated with increased HDLC levels (29,30). Both the Ϫ75 bp and ϩ83 bp sites were significantly predictive of CAD severity in terms of the number of diseased vessels in a case-control study (31). There was another report of higher A allele frequency in myocardial infarction patients relative to healthy control subjects (32) but not for alleles at the ϩ83 bp.…”

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confidence: 94%

Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(a) Levels in Asian Indian Neonates from Singapore

2001

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We studied the influence of two DNA polymorphisms (-75 bp G/A and +83 bp C/T) in the promoter region of the apolipoprotein A-1 (apoA1) gene on cord plasma level of lipoprotein(a) [Lp(a)] in 1076 newborns of both genders from the three major ethnic groups in Singapore-Chinese, Malays, and Asian Indians. The frequency of the A: allele at -75 bp in the Indians was significantly lower than the Chinese and Malays. There was no linkage disequilibrium between the two sites studied. Both polymorphic sites were not significantly associated with any lipid factors except for Lp(a) levels in the Asian Indians. The AA and CC homozygotes were significantly associated with lower Lp(a) levels. These associations were specific only to the male Indian neonates. The genetic variations at the -75 and +83 bp explained 6.9% and 7.2%, respectively, of the total variability of plasma Lp(a) levels at birth in the Asian Indians. The Lp(a) levels were also significantly different between composite genotypes in the order GG/TT > GA/CT > GG/CT > GA/CC > GG/CC > AA/CC. The effects of the two polymorphisms seem to be additive as the composite genotypes were able to explain 14% of the Lp(a) variance, equivalent to the sum of the two constituent sites. Our results showed that there is significant ethnic- and gender-specific influence of the apoA1 gene on plasma Lp(a) levels at birth that is inherent and independent of known gene-environment interactions.

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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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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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Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease.

Cited by 59 publications

References 30 publications

Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function

Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function

Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(a) Levels in Asian Indian Neonates from Singapore

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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