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PubMed2006

Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.

Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

ATP Binding Cassette Transporter 1↗
PubMed1976

Distribution of G6PD types in the population of southwest France: common variants and new variants.

Glucose-6-phosphate dehydrogenase was purified from blood samples originating from 33 subjects living in the 'Midi-Pyrenees' region (Southwest France). Biochemical and electrophoretic characteristics of several enzymatic variants were revealed. The distribution of the mutations in the subjects studied gave the following results: (1) Meditteranean Gd(-) and Gd(-)A identified variants; they constitute the main part of our observations. (2) Two original variants confirmed by the WHO International Reference Laboratory, that is: Gd(-) Toulouse and Gd(+) Luz-Saint-Sauveur; the latter mutation did not produce any haematological disorder. Absence of chronic haemolytic anaemia as well as a high rate of favism could be found in the families studied. As it is generally observed in Mediterranean regions, Southwest France population is characterized by a certain heterogeneity in biochemical and genetic mutations.

Erythrocytes↗
PubMed1995

A common variant in the gene for lipoprotein lipase (Asp9-->Asn). Functional implications and prevalence in normal and hyperlipidemic subjects.

Subjects with combined hyperlipidemia (CHL) were screened for mutations in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G-->A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identified in 2 individuals. Because this substitution destroys a recognition site for Taq I, pooling of DNA samples, amplification, and digest with Taq I allowed the rapid screening of 1563 healthy individuals and patients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation were detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed atherosclerosis; the frequency was consistently higher in each patient group compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozygotes for the mutation were identified. In these 27, plasma triglyceride but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P < .02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL activity data were available for some carriers and for 7 of 9 individuals from the patient groups, and 6 of 6 individuals from the control groups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that compared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by 20% to 30% in the culture media. Overall however, LPL-Asn9 had only slightly reduced specific activity (by 18%). Thus, although the precise mechanism of the effect is unclear, the data strongly suggest that the LPL-Asn9 variant is associated with and may play a direct role in predisposing carriers to develop hypertriglyceridemia.

Adult↗
PubMed1999

Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure.

BACKGROUND: This study was undertaken to identify gene(s) that may be associated with improved clinical outcome in patients with congestive heart failure (CHF). The adenosine monophosphate deaminase locus (AMPD1) was selected for study. We hypothesized that inheritance of the mutant AMPD1 allele is associated with increased probability of survival without cardiac transplantation in patients with CHF. METHODS AND RESULTS: AMPD1 genotype was determined in 132 patients with advanced CHF and 91 control reference subjects by use of a polymerase chain reaction-based, allele-specific oligonucleotide detection assay. In patients with CHF, those heterozygous (n=20) or homozygous (n=1) for the mutant AMPD1 allele (AMPD1 +/- or -/-, respectively) experienced a significantly longer duration of heart failure symptoms before referral for transplantation evaluation than CHF patients homozygous for the wild-type allele (AMPD1 +/+; n=111; 7.6+/-6.5 versus 3.2+/-3.6 years; P<0.001). The OR of surviving without cardiac transplantation >/=5 years after initial hospitalization for CHF symptoms was 8.6 times greater (95% CI: 3.05, 23.87) in those patients carrying >/=1 mutant AMPD1 allele than in those carrying 2 wild-type AMPD1 +/+ alleles. CONCLUSIONS: After the onset of CHF symptoms, the mutant AMPD1 allele is associated with prolonged probability of survival without cardiac transplantation. The mechanism by which the presence of the mutant AMPD1 allele may modify the clinical phenotype of heart failure remains to be determined.

AMP Deaminase↗
PubMed2006

Association analysis of common variants of ELN, NOS2A, APOE and ACE2 to intracranial aneurysm.

BACKGROUND AND PURPOSE: Previous studies have shown positive evidence of linkage of the intracranial aneurysm (IA) at chromosome 7q11, 17cen, 19q13, and Xp22. These regions contain elastin (ELN), nitric oxide synthetase 2A (NOS2A), apolipoprotein E (APOE), and angiotensin-I converting enzyme 2 (ACE2), which are considered to be promising candidate genes for IA. We aimed to examine the association of single-nucleotide polymorphisms (SNPs) with IA in these candidate genes. METHODS: To identify polymorphisms in NOS2A and ACE2, all exons and exon-intron boundaries were screened by direct sequencing in 30 randomly selected controls. The program tagSNPs was used to select an optimal set of haplotype-tagging SNPs. For ELN and APOE, SNPs were selected from previous reports. These selected SNPs were then genotyped in 362 cases with IA and 332 residential area matched controls. THESIAS software was used to investigate the association of alleles and haplotypes with IA by adjusting with covariates. RESULTS: We genotyped 8 SNPs in ELN, 8 SNPs in NOS2A, 3 epsilon alleles in APOE and 1 SNP in ACE2. No alleles or haplotypes of 4 candidate genes revealed any significant association with IA. CONCLUSIONS: Investigated polymorphisms in this study were not associated with IA.

Adult↗
PubMed2003

Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD.

BACKGROUND: Current evidence demonstrates that positive family history and several alterations in lipid metabolism are all important risk factors for coronary artery disease (CAD). All lipid abnormalities themselves have genetic determinants. Thus, objective of this study was to determine whether 6 genetic variants potentially related to altered lipid metabolism were associated with CAD and with lipid abnormalities in an Italian population. These genetic variables were: apolipoprotein E (Apo E), Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and the hepatic lipase (LIPC) genes. Furthermore, an 8 years prospective analysis of clinical cardiovascular events was related to the various genetic markers. METHODS: 102 subjects with established coronary artery disease and 104 unrelated normal subjects were studied. CAD Patients were followed up for 8 years, and clinical CAD outcomes (a second coronary angioplasty (PTCA), myocardial infarction, coronary artery by-pass graft (CABG), cardiovascular deaths), available from 60 subjects, were related to the genetic variants by multiple regression analysis. Results. Of the six lipid loci studied (for a total of 11 polymorphisms) only the apolipoprotein E, Apo B and LIPC polymorphisms distinguished between case and controls. However, multivariate analysis accounting for clinical and metabolic predictors of CAD showed that only the ApoB Xba1 and ApoE4 polymorphism associated with CAD in this Italian population. When lipid parameters were related to genotypes, the ApoE, ApoB, and LIPC gene polymorphisms were associated to various markers of dyslipidaemia in the CAD patients, confirming previous reports. When the occurrence of a second cardiovascular event was related to genotypes, an independent role was observed for the LIPC gene T202T variant. CONCLUSIONS: variation in LIPC (hepatic lipase) gene associates with clinical outcomes in Italian patients with established CAD. Further studies on the LIPC gene in CAD patients are warranted, in particular looking at the possible influences on clinical outcomes.

Apolipoprotein A-I↗
PubMed2005

Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.

INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.

Adult↗
PubMed2003

Common variants in the lipoprotein lipase gene in Brazil: association with lipids and angiographically assessed coronary atherosclerosis.

Lipoprotein lipase is the rate-limiting enzyme in the lipolysis of plasma triglyceride-rich lipoproteins. We studied six variants (T-93G, D9N, N291S, PvuII, HindIII and S447X) in the lipoprotein lipase (LPL) gene in 309 non-diabetic patients with angiographically assessed coronary artery disease and in 197 controls in a southern Brazilian population of European descent. The HindIII H-allele was associated with lower triglycerides (p < 0.01) and higher high-density lipoprotein cholesterol (p = 0.03) levels, and the S447X mutation was associated with lower triglyceride levels (p < 0.01) in males, but not females. No other significant lipid associations were observed. Haplotypes were derived from these two sites (HindIII/S447X), and carriers of H-S and H-X haplotypes showed lower triglycerides (p < 0.01) and increased high-density lipoprotein cholesterol (p = 0.01) levels when compared to the H+S haplotype in males. In this gender, the H-X haplotype was associated with a protective effect (OR = 0.36, 95%CI = 0.13-0.97) for significant disease (> or = 60% of luminal coronary stenosis), even controlling for other classical risk factors.

Aged↗
PubMed2005

Apolipoprotein A5 and triglyceridemia. Focus on the effects of the common variants.

High plasma levels of triglycerides are an independent risk factor for the development of cardiovascular disease. Apolipoprotein A5 (APOA5) is a new member of the apolipoprotein APOA1/C3/A4 gene cluster, found by comparative sequencing analysis. The importance of the APOA5 gene for determination of plasma triglyceride levels has been suggested by the creation of transgenic and knock-out mice (transgenic mice displayed significantly reduced triglycerides, whereas knock-out mice had a high level of triglycerides). It has now been clearly established that distinct polymorphisms in the APOA5 gene consistently influence plasma triglycerides in a wide range of human populations, although some differences between ethnic groups and males and females were described. The possible roles of APOA5 variants in determining the risk of myocardial infarction and coronary artery disease development, as well as in the determination of low-density lipoprotein-particle size or plasma concentrations of C-reactive protein and high-density lipoprotein-cholesterol, are also summarized.

Animals↗
PubMed2006

Common variants of the endothelial nitric oxide synthase gene and the risk of coronary heart disease among U.S. diabetic men.

Endothelial nitric oxide synthase (eNOS) gene represents a promising candidate gene for coronary heart disease (CHD) because of its impact on eNOS activity. We systematically examined the associations of eight variants of the eNOS gene (two potentially functional variants [-786T>C and Glu298Asp] and six tagging single nucleotide polymorphisms) with CHD risk in a large cohort of diabetic patients. Among 861 diabetic men (>97% Caucasian) from the Health Professionals Follow-Up Study, 220 developed CHD, and 641 men without cardiovascular disease were used as control subjects. Genotype distributions of -786T>C and Glu298Asp polymorphisms were not significantly different between case and control subjects. CHD risk was significantly higher among men with the variant allele at the rs1541861 locus (intron 8 A/C) than men without it (adjusted odds ratio 1.5 [95% confidence interval 1.1-2.1]). Moreover, among control subjects, plasma soluble vascular cell adhesion molecule concentrations were significantly higher among carriers of this allele (P 0.019) and carriers of the variant allele of the -786T>C (P 0.010), or the Glu298Asp polymorphism (P 0.002), compared with noncarriers. In conclusion, our data suggested that -786T>C, Glu298Asp, and an intron 8 polymorphism of the eNOS gene are potentially involved in the atherogenic pathway among U.S. diabetic men.

Aged↗
PubMed2000

A common variant of the angiotensinogen gene and the risk of coronary artery disease in a German population.

The thymidine to cytosine transition at position 704 in exon 2 of the angiotensinogen gene leads to the amino acid substitution of threonine for methionine (T235 variant) and is responsible for elevated plasma levels of angiotensinogen. To examine the influence of T235 on the risk of coronary artery disease (CAD) we genotyped 184 CAD patients, 77 controls in whom CAD was excluded angiographically, and 155 healthy controls without signs of CAD by polymerase chain amplification and restriction enzyme digestion. Allele frequencies for A (wildtype) and a (mutant allele) in the total study population were 0.538 and 0.462, 0.536 and 0.464 in the healthy controls, and 0.481 and 0.519 in patients with excluded CAD, respectively. The allele frequencies and the genotype distribution in these groups did not show a significant difference. In conclusion, we did not observe an association between the T235 variant of the angiotensinogen gene and the risk of CAD.

Amino Acid Substitution↗
PubMed2004

[Common variants in beta 3-adrenergic-receptor and uncoupling protein-2 genes are associated with type 2 diabetes and obesity].

OBJECTIVE: To investigate the effects of uncoupling protein-2 (UCP2) gene Ala55Val variation and beta(3)-adrenergic-receptor (beta(3)-AR) gene Trp64Arg variation on type 2 diabetes and obesity, as well as the combined effects between the two variations. METHODS: The peripheral blood samples of 173 type 2 diabetics, 119 obese persons, and 177 control subjects were collected. PCR-RFLP was used to detect the UCP2 gene Ala55Val variation and beta(3)-AR gene Trp64Arg variation. The haplotype and allele frequency distributions among the three groups were analyzed. The combined effect of the two gene mutations was analyzed too. RESULTS: (1) The frequencies of homozygote of UCP2 gene Ala55Val variation in the diabetes and obesity patients were both significantly higher than that in the control subjects (OR = 4.62, P = 0.001; OR = 3.71, P = 0.001). The Ala55Val variation carriers had higher BMI in the control subjects. (2) The gene frequency of homozygote of beta(3)-AR gene Trp64Arg variation was significantly higher in the diabetes patients than in the control subjects. The Trp64Arg variation carriers had higher fasting and 2-hour postgrandual glucose levels than the non-carriers in the control subjects. (3) When there was only UCP2 gene mutation or beta(3)-AR gene mutation, their frequencies in diabetes and obesity patients were not significantly different from that in the control subjects (both P > 0.05). However, the frequencies of the combined mutations of these two genes in either the diabetes patients or in the obesity patients were both significantly higher than in the control subjects (OR = 3.69, P = 0.000; OR = 2.57, P = 0.009). (4) The Val/Val + Trp/Arg carriers had the greatest relation with diabetes (OR = 10.43, P = 0.000) and obesity (OR = 8.58, P = 0.002). CONCLUSION: The homozygote of UCP2 gene Ala55Val mutation significantly enhances the risks of diabetes and obesity. The homozygote of beta(3)-AR gene Trp64Arg mutation is related with diabetes. The accumulation of the effects of two micro-genes creates obvious phenotypic effects.

Aged↗
PubMed2004

Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo.

OBJECTIVE: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. RESULTS: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 +/- 0.6 ng/mL) compared with wild-types (8.8 +/- 0.4 ng/mL) and heterozygotes (9.1 +/- 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 +/- 1.1 micromol/L) compared with homozygous subjects (10.9 +/- 0.4 micromol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 +/- 6.3 ng/mL) compared with wild-types (112.2 +/- 5.2 ng/mL) and heterozygous individuals (125.1 +/- 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. CONCLUSION: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.

Adult↗
PubMed2005

[Study on the association of ABCA1 gene common variants with the risk of coronary atherosclerotic heart disease].

OBJECTIVE: To investigate the association of R219K and M883I polymorphisms of ATP binding cassette transporter 1 gene with lipid metabolism and the susceptibility to coronary atherosclerotic heart disease in Chinese population. METHODS: Genotypes were determined by PCR-restriction fragment length polymorphism and Primer introduced restriction analysis-PCR techniques, respectively, in 248 unrelated CHD-free controls and 224 CHD cases. RESULTS: Smoking, high blood pressure and high serum glucose were independent risk factors for CHD. Multivariate logistic regression analysis revealed that individuals carrying at least one 219K variant allele (RK + KK genotypes) had a significantly decreased risk for CHD (adjusted OR = 0.41; 95% CI = 0.27-0.61) compared with the wild-type genotype (219RR) and only 883II homozygotes displayed a decreased risk for CHD (adjusted OR = 0.54; 95% CI = 0.26-1.11) compared with 883MM and 883MI genotypes. Furthermore, compared with individuals with both wild genotypes (219 RR and 883 MM or 883 MI) other individuals with all other assembly genotypes had a significantly decreased risk (adjusted OR = 0.39, 95% CI = 0.26-0.60). Plasma HDL-C in 219K allele carriers were markedly higher than those in 219 K non-carriers in controls (P = 0.037). CONCLUSION: The ABCA1 R219K polymorphism may be involved in the variability of serum HDL-C and the susceptibility to coronary artery disease.

ATP Binding Cassette Transporter 1↗