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PubMed1991

Identification of common variant alleles of the human guanosine monophosphate reductase gene.

Examination of nucleotide sequences of genomic DNA samples obtained from several unrelated Caucasians and orientals revealed the existence of four variant alleles in the chromosome 6-linked quanosine monophosphate reductase locus. The wild-type gene has T at position 42 (counting from A of the chain initiation codon), C at 630, G at 700, and T at 766, i.e., its structure is T(42)-C(630)-G(700)-T(766). The variant gene, T-T-G-T, was found in about 10% of the loci examined. The C-to-T change at 630 was silent and did not induce any amino acid substitution (His at amino acid residue 210), but it created an additional NcoI cleavage site in the variant gene. The frequency of another variant, the T-C-G-A gene, was about 30%. The T-to-A change at 766 caused an amino acid substitution Phe----Ile at amino acid residue 256 in the variant protein. Frequencies of the C-C-G-T variant and the T-C-A-T variant were probably lower than 5% in Caucasians and orientals.

Alleles↗
PubMed1978

Catalytic properties and stability of three common variants of placental alkaline phosphatase.

Three placental alkaline phosphatases purified to homogeneity, i.e., the F, I, and S variants, were investigated for catalytic and stability properties. All three forms of the enzyme were found to have almost identical pH optima (10.7--10.8), similar sensitivity to the uncompetitive inhibitors L-phenylalanine (70%) and L-leucine (30%), and identical Km values against p-nitrophenylphosphate, beta-glycerophosphate, and alpha-naphthylphosphate. Significant differences among the three types were observed in thermal stability. The F variant was found to be most stable and the I variant most labile at 79 C. At 70 C all three forms were stable.

Alkaline Phosphatase↗
PubMed2001

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.

Adult↗
PubMed2004

Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease.

Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the epsilon4 allele of APOE in relation to Alzheimer's disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme ( ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 ( P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 ( P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE epsilon4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.

Age of Onset↗
PubMed2001

Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men.

Physical activity has been identified as a protective factor against the occurrence and progression of coronary heart disease. The lipoprotein lipase (LPL) HindIII polymorphism has been associated with changes in triglyceride and high density lipoprotein (HDL)-cholesterol levels. We have investigated whether the association between the LPL HindIII genetic polymorphism and lipid levels is modified by physical activity. We have also tested the hypothesis that physical activity may interact with smoking and the LPL HindIII polymorphism to determine an individual's plasma lipid concentrations. A total of 520 men were selected from a representative sample used in a population study conducted in Gerona, Spain. The median value (291 kcal/day) of energy expenditure in leisure-time physical activity of the studied sample was selected as a cut-off to define sedentary or active subjects. Serum HDL-cholesterol was positively and significantly associated with the amount of daily energy expenditure in physical activity, whereas inverse associations were seen between physical activity and triglyceride concentration and with the triglyceride to HDL-cholesterol ratio. These effects were consistent across LPL HindIII genotypes. There was a statistically significant interaction between LPL genotype and smoking on lipid concentrations. No statistically significant differences were observed in lipid levels of active or sedentary non-smokers between H- carriers and H+H+ homozygotes for the LPL HindIII polymorphism. In smokers, sedentary H+H+ homozygotes showed significantly higher triglyceride and lower HDL-cholesterol concentrations than sedentary H- carriers. These differences were smaller and not statistically significant when lipid values of active H+H+ homozygotes were compared with active H- carriers. Among all subgroups, sedentary smokers with the H+H+ genotype had the most adverse lipid profile, which was considerably less adverse in H+H+ smokers who were physically active. These findings suggest that the presence of the H+H+ genotype has a deleterious effect on lipid profile in an adverse environment such as smoking, and that the expenditure of more than 291 kcal/day in physical activity attenuates this effect.

Cholesterol, HDL↗
PubMed2004

Glucose-6-phosphate dehydrogenase (G6PD) mutations in Myanmar: G6PD Mahidol (487G>A) is the most common variant in the Myanmar population.

We conducted a survey of malaria diagnoses and treatments in remote areas of Myanmar. Blood specimens from more than 1,000 people were collected by the finger-prick method, and 121 (11%) of these people were found to be glucose-6-phosphate dehydrogenase (G6PD) deficient. Of these 121, 50 consented to analysis of the G6PD genome. We read the G6PD sequences of these subjects and found 45 cases of G6PD Mahidol (487G>A), two of G6PD Coimbra (592C>T), two of G6PD Union (1360C>T), and one of G6PD Canton (1376G>T). Taken together with data from our previous report, 91.3% (73/80) of G6PD variants were G6PD Mahidol. This finding suggests that the Myanmar population is derived from homogeneous ancestries and are different from Thai, Malaysian, and Indonesian populations.

Ethnicity↗
PubMed2005

A common variant in the glutathione S transferase gene is associated with elevated markers of inflammation and lipid peroxidation in subjects with diabetes mellitus.

INTRODUCTION: Glutathione S transferases (GST) are enzymes responsible for the metabolism of numerous xenobiotics and play a major cellular antioxidant role. Our aim was firstly, to examine the association between the GST M1/GST mu-1 (GSTM1) and GST T1/GST theta-1 (GSTT1) gene variants with markers of oxidative stress and inflammation in diabetic patients, and secondly to examine the association and potential interaction between these variants and cigarette smoking. METHODS: Seven hundred and seventy-three Caucasian subjects with diabetes and 2592 Caucasian non-diabetic subjects were successfully genotyped. Plasma total antioxidant status, C-reactive protein (CRP), oxidized-LDL (Ox-LDL) and LDL-mean/peak particle diameter were recorded in the diabetes sample. RESULTS: No association was seen between genotype and cardiovascular disease (CVD) risk. In the diabetic subjects, GSTT1-1 compared to GSTT1-0 subjects had significantly higher CRP (p=0.001), Ox-LDL (p=0.004) and smaller LDL particles (p=0.01). In subjects without CVD, there was a significant interaction between the GSTT1-1 variant and smoking in determining Ox-LDL (p=0.04). Furthermore, CVD risk was higher in smokers compared to non-smokers with GSTT1-1. No significant associations were observed by GSTM1. Within the non-diabetic sample, no association was observed between genotype and prospective coronary heart disease (CHD) risk. Of note, the frequency of the GSTT1-1 variant was significantly lower in the diabetes subjects compared to the non-diabetic sample (p=0.01). CONCLUSIONS: This study demonstrates an association between the GSTT1-1 variant and markers of inflammation and lipid peroxidation. Furthermore this variant interacts with smoking to increase lipid peroxidation.

Aged↗
PubMed2004

A common variant of the AMPD1 gene predicts improved survival in patients with ischemic left ventricular dysfunction.

BACKGROUND: A recent retrospective study suggested that the adenosine monophosphate deaminase (AMPD)-1 gene variant C34T predicts outcome in heart failure patients. This variant might lead to ischemic preconditioning by increasing tissue adenosine. We tested whether the survival benefit of C34T occurs preferentially in the setting of ischemic left ventricular dysfunction. METHODS AND RESULTS: A consecutive cohort of patients (n=390) with left ventricular ejection fraction <40% was evaluated. In the ischemic patient subgroup (n=210) multivariate analysis identified AMPD1 T allele carriage (hazard ratio=0.43, confidence interval=0.20-0.94, P=.035) as an independent predictor of transplant-free cardiovascular survival. No benefit was found in the nonischemic group although the number of events was too small to reliably exclude a benefit by genotype. CONCLUSION: The AMPD1 C34T polymorphism influences transplant-free cardiovascular survival in the setting of ischemic left ventricular dysfunction.

AMP Deaminase↗
PubMed2006

Common variants of Cholesteryl ester transfer protein gene and their association with lipid parameters in healthy volunteers of Tamilian population.

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in a key pathway of reverse cholesterol transport implicated in atherosclerosis and coronary heart disease. CETP gene is known to have many single nucleotide polymorphisms which have been associated with CETP activity and plasma high density lipoprotein cholesterol (HDL-C) concentrations. No data on the prevalence of these polymorphisms and their phenotypic association is available in South Indian population. METHODS: Three CETP polymorphisms: TaqIB, -629C/A and I405V were studied in 171 healthy volunteers from Tamilnadu, a major population of South India. Subjects were clinically examined and lipid profile was estimated. Genotyping was performed by PCR-RFLP and genotype frequencies estimated. RESULTS: The allele frequencies of TaqIB: B1 allele was 0.51; -629C/A: C allele was 0.36; and that of I405V: I allele was 0.47. Study of association between these three polymorphisms and plasma lipid concentrations revealed no significant differences in lipid parameters between genotypes. A gender based subgroup analysis revealed a significant increase in HDL-C in men with B2B2 genotype and decrease in TG in B1B2 genotype. Analysis of the combined effect of multiple mutant genotypes revealed that as the number of mutant genotypes increased, the concentrations of low density lipoprotein-cholesterol (LDL-C), HDL-C and total cholesterol (TC) increased whereas that of triglyceride (TG) decreased in the group of three mutant genotypes significantly. CONCLUSION: The frequency of B2 and A alleles of TaqIB and -629C/A polymorphisms were highest in Tamilian population when compared to other major ethnic groups while that of V allele of I405V polymorphism is between Caucasians and African Americans. Taq1B polymorphism was associated with HDL-C and TG concentrations only in men. Combination of these three polymorphisms was significantly associated with lipid profile than the individual polymorphisms.

Cholesterol Ester Transfer Proteins↗
PubMed2004

Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects.

To assess the contribution of OATP-C to the hepatobiliary transport of bilirubin, a pharmacogenomic evaluation with regard to polymorphisms of three candidate genes, OATP-C, MRP2, and UGT1A1, was performed. Serum total and direct (conjugated) bilirubin levels were used as phenotypic indexes. Pharmacokinetic variables of pravastatin, a typical substrate for OATP-C, were obtained from our previous study. Among 23 volunteers, two variants (Val417Ile and Ser789Phe) were observed in the MRP2 gene. While there was no apparent effect of these two variants and the UGT1A1*28 on direct bilirubin levels, the OATP-C variants were associated with differences in unconjugated bilirubin levels. Subjects with the OATP-C*15 allele had higher bilirubin levels; unconjugated bilirubin levels in *1b/*1b (n = 3), *1b/*15 (n= 7), and *15/*15 (n = 1) subjects were 0.40 +/- 0.10, 0.77 +/- 0.35, and 0.70 (mg/dL), respectively. In addition, the correlation between unconjugated bilirubin levels and pharmacokinetic parameters of pravastatin revealed that the subjects with higher bilirubin levels had lower non-renal clearance values, and then higher serum concentrations of pravastatin. Large clinical studies are needed to confirm a role of OATP-C in the carrier-mediated uptake of bilirubin in the human liver.

Journal Article↗
PubMed2005

Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes.

BACKGROUND: Immune responses characterized by T H 2 type cells and IgE are important for the development of asthma and atopy. The transcription factors STAT6, GATA3, and STAT4 mediate the cytokine-induced development of naive CD4 + T cells into either T H 1 or T H 2 type. OBJECTIVE: We studied genetic variation of the STAT6, GATA3, and STAT4 genes and examined whether single nucleotide polymorphisms (SNPs) in these loci were associated with asthma or serum high IgE levels in the Finnish asthmatic families. METHODS: With denaturing high-performance liquid chromatography we screened all exons and exon-intron boundaries of the genes in 14 to 22 patients. All identified SNPs were genotyped in 120 nuclear families, and the haplotypes were analyzed by Haplotype Pattern Mining based statistical analysis. When potential association was observed, the analysis was replicated among 245 asthmatic patients and 405 population-based control subjects. RESULTS: A total of 23 SNPs were identified, of which 8 were not previously listed in the SNP database. Interestingly, a haplotype analysis of GATA3 showed 3 related haplotypes that associated with different asthma and atopy related phenotypes among both the family and case-control data sets. For STAT6 and STAT4, no significant association to asthma or serum total IgE levels was observed. CONCLUSIONS: We identified a panel of novel SNPs in genes coding for proteins important in the T H 1/T H 2 cell differentiation. SNPs of the GATA3 gene showed an initial association to asthma-related phenotypes. Elucidation of the importance of the identified panel of SNPs in other T H 1/T H 2 mediated diseases will be of great interest.

Adult↗
PubMedDate not supplied

A common variant in the ACE gene is associated with peripheral neuropathy in women with type 2 diabetes mellitus.

AIMS: The D allele of the ACE I/D gene variant is associated with higher tissue and serum ACE activity. Previously, studies have suggested an association between the D allele with the microvascular complications of diabetes. The aim of this study was to explore the impact of this genotype in relation to clinically manifest peripheral neuropathy (PN) in a cohort of subjects with type 2 diabetes mellitus (type 2 DM). METHODS: Five hundred and seventy-two Caucasian subjects (230 females, 342 males) with type 2 DM were recruited from the diabetes clinic at University College London Hospitals NHS Trust. Clinically manifest PN was determined from a standardized clinical examination. RESULTS: The ACE I/D genotype distribution was in Hardy-Weinberg equilibrium. In the whole group, no significant association was seen between genotype and PN; however, when stratified by sex, the D allele was associated with PN in females but not in males. The odds ratio (OR) for PN in the D allele carriers compared to those homozygous for the I allele was significantly higher in females [OR 2.93 (1.09-7.63), P=.027] but not in males [OR 1.2 (0.61-2.36), P=.60]. CONCLUSIONS: The presence of the D allele is associated with increased risk of peripheral neuropathy in females but not in male subjects with type 2 DM, suggesting a role for the renin-angiotensin system in the development of PN.

Aged↗
PubMed2004

Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance.

BACKGROUND AND PURPOSE: The type-III EGFR variant (EGFRvIII) is known to promote enhanced tumorigenicity. We have previously defined the importance of EGFRvIII in cellular radiation responses using Chinese hamster ovary cells (CHO). In the current study, we have extended our investigations of EGFRvIII to human tumor cells in vitro and in vivo and further verified the important role of EGFRvIII in modulating radiosensitivity. MATERIAL AND METHODS: The cell lines MDA-MB-231, U-87 MG, A-431 and U-373 MG were used. Adenoviral (Ad) vectors were produced to overexpress EGFRvIII in vitro or in xenograft tumors in vivo. The EGFR, EGFRvIII expression and tyrosine phosphorylation (Tyr-P) levels were quantified by Western blotting. The relative radiosensitivities were assessed in vitro by standard colony formation and in vivo by tumor growth delay assays. RESULTS: The presence of EGFRvIII was verified in all xenograft tumors tested with no detectable expression in the corresponding cells under in vitro culture conditions. MDA-MB-231 xenograft tumors demonstrated EGFRvIII expression levels, which were 1.9-fold higher relative to EGFRwt compared to a 14.5-fold higher Tyr-P. Ionizing radiation of these tumors at 4 Gy induced an average 3.2-fold increase in EGFRvIII Tyr-P. EGFRvIII expression in U-373 MG cells significantly enhanced survival after 4Gy, which was completely abolished by dominant-negative EGFR-CD533. Finally, the ability of EGFRvIII to accelerate tumor growth during irradiation was confirmed in vivo. CONCLUSION: EGFRvIII is frequently expressed in a variety of different tumor types and can confer significant radioresistance, thus further providing evidence for EGFRvIII as an additional important target in our approaches to radiosensitize malignant solid tumors.

Animals↗
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 &#xd7; 10(-9), joint analysis P (P(J)) = 1.7 &#xd7; 10(-9); stages 1, 2 and 3, P(M) = 8.2 &#xd7; 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 &#xd7; 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 &#xd7; 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 &#xd7; 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 &#xd7; 10(-10), P(J) = 5.2 &#xd7; 10(-11)), CLU (rs1532278; P(M) = 8.3 &#xd7; 10(-8), P(J) = 1.9 &#xd7; 10(-8)), BIN1 (rs7561528; P(M) = 4.0 &#xd7; 10(-14), P(J) = 5.2 &#xd7; 10(-14)) and PICALM (rs561655; P(M) = 7.0 &#xd7; 10(-11), P(J) = 1.0 &#xd7; 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P &#x2264; 1 &#xd7; 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 &#xd7; 10(-17); including ADGC data, meta P = 5.0 &#xd7; 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 &#xd7; 10(-14); including ADGC data, meta P = 1.2 &#xd7; 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 &#xd7; 10(-4); including ADGC data, meta P = 8.6 &#xd7; 10(-9)), CD33 (GERAD+, P = 2.2 &#xd7; 10(-4); including ADGC data, meta P = 1.6 &#xd7; 10(-9)) and EPHA1 (GERAD+, P = 3.4 &#xd7; 10(-4); including ADGC data, meta P = 6.0 &#xd7; 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2005

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes.

We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (-29.6+/-13.4 vs -22.1+/-13.8%, P=0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DeltaTC -27.8%), whereas only 29% of 2386A homozygous reached this reduction (P=0.009). Our data suggest that the SCAP 2386A>G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.

Adult↗