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PubMed2006

Cytogenetic damage and genetic variants in the individuals susceptible to arsenic-induced cancer through drinking water.

In West Bengal, India, more than 300,000 arsenic-exposed people are showing symptoms of arsenic toxicity, which include cancers of skin and different internal organs. Since only 15-20% of the exposed population manifest arsenic-induced skin lesions, it is thought that genetic variation might play an important role in arsenic toxicity and carcinogenicity. A total of 422 unrelated arsenic-exposed subjects (244 skin-symptomatic and 178 asymptomatic) were recruited for this study. Cytogenetic damage, as measured by chromosomal aberrations in lymphocytes and micronuclei formation in oral mucosa cells, urothelial cells and binucleated lymphocytes, was studied in unexposed, skin-symptomatic and asymptomatic individuals with similar socioeconomic status. Identification of null mutations in GSTT1 and GSTM1 genes were carried out by PCR amplification. GSTP1 SNPs, implicated in susceptibility to various cancers, were assessed by PCR-RFLP method. Symptomatic individuals had higher level of cytogenetic damage compared to asymptomatic individuals and asymptomatic individuals had significantly higher genotoxicity than unexposed individuals. No difference in allelic variants in GSTT1 and GSTP1 was observed between these 2 groups. Incidence of GSTM1 null gene frequencies was significantly higher in the asymptomatic group. Individuals with GSTM1-positive (at least one allele) had significantly higher risk of arsenic-induced skin lesions (odds ratio, 1.73; 95% confidence interval, 1.24-2.22). These results show a protective role of GSTM1 null in arsenic toxicity. This study also indicates that asymptomatic individuals are sub clinically affected and are also significantly susceptible to arsenic-induced genotoxicity.

Adolescent↗

PubMed1995

HepG2/erythrocyte glucose transporter (GLUT1) gene in NIDDM: a population association study and molecular scanning in Japanese subjects.

To evaluate the role of mutations in the glucose transporter (GLUT1) gene in Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM), we first conducted a population association study using the XbaI polymorphism of the gene. A polymerase chain reaction (PCR)-based assay was developed and used for the analysis. When analysed in 91 diabetic patients and 87 non-diabetic control subjects, the distribution of the genotype frequency was significantly different between the two groups (p = 0.0025). The (-) allele was significantly associated with NIDDM (odds ratio 2.317, 95% confidence interval 1.425-3.768). To identify possible mutation(s) in the GLUT1 gene, which was in linkage disequilibrium with the (-) allele, all ten exons of the gene were analysed by PCR single-strand conformation polymorphism (SSCP) analysis in 53 diabetic patients with at least one (-) allele. Variant SSCP patterns were detected in exons 2, 4, 5, 7, 9 and 10. Sequence analysis revealed that all the variants represented silent mutations. One of the variants in exon 2, GCT (Ala15)-->GCC(Ala), created a HaeIII restriction site. This polymorphism was common in Japanese subjects with heterozygosity of 0.36 and polymorphism information content 0.29. We conclude that the structural mutation of GLUT1 is rare and not likely to be a major genetic determinant of NIDDM in Japanese subjects. The XbaI (-) allele of the GLUT1 gene appeared to be a genetic marker of NIDDM in Japanese subjects. The possibility of the presence of mutation(s) in the regulatory region of the gene or in another locus nearby could not be excluded.

Alleles↗

PubMed2004

CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori.

OBJECTIVE: Proton pump inhibitors, metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2C19, are essential drugs for Helicobacter pylori eradication. It was reported that patients with CYP2C19 wild type in Asia had lower eradication rates. This study tests the hypothesis that CYP2C19 wild type ( wt/wt ) in white patients is also associated with a higher probability of treatment failure. METHODS: This was a cohort study involving 131 H pylori -positive white (German) patients treated by quadruple therapy including lansoprazole (30 mg twice daily for 5 days). Eradication success, as well as lansoprazole trough steady-state serum concentrations, was determined according to different CYP2C19 genotypes. RESULTS: We found 3 homozygous variant patients (2.3%) ( mt/mt, CYP2C19*2/*2 ), 42 heterozygous patients (32.1%) ( wt/mt, CYP2C19*1/*2 ), and 86 wild-type individuals (65.6%). Significant differences in eradication success could be found between wt/wt patients (80.2%) versus combined mt/mt (100%) and wt/mt patients (97.8%) ( P <.01; odds ratio, 10.8 [confidence interval, 1.4-84]), which were associated with corresponding changes in the serum levels of lansoprazole (median, 753 ng/mL for mt/mt, 59 ng/mL for wt/mt, and 21 ng/mL for wt/wt; P <.001). Apart from antibiotic resistance, CYP2C19 polymorphism was the most important influencing factor for eradication success on multivariate analysis ( P <.0001). CONCLUSION: Eradication rates of H pylori highly depend on CYP2C19 in white patients if standard doses of lansoprazole (30 mg twice daily) are administered within a quadruple regimen. Because wt/wt individuals have lower eradication rates and lower serum concentrations of lansoprazole, these patients might benefit from a higher proton pump inhibitor dosage.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2026

Whole genome sequence data on Ethiopian key sorghum landraces and founder lines.

Sorghum (Sorghum bicolor (L.) Moench) is the fifth most important cereal globally. Its genetic diversity is key to improving yield stability, stress tolerance, and adaptation to different environments. Ethiopia is one of the centers for the crop's origin, diversity, and use in both human food and livestock feed. However, genomic data on Ethiopian sorghum remain limited, especially for landraces preferred by local farmers. This dataset consists of whole-genome sequencing data for 188 Ethiopian sorghum accessions, including founder lines and important landraces from major agroecological zones. Sequencing was performed using the Complete Genomics DNBSEQ-T7 platform, generating high-coverage whole-genome data (20 × coverage). On average, each accession produced 64.7 million reads. Reads were aligned to the Sorghum bicolor NCBIv3 reference genome and variants called using GATK HaplotypeCaller with joint genotyping (GATK v4.6.1.0). Hard-filtering followed GATK best-practice thresholds (QD <2.0, FS> 60.0, MQ <40.0, MQRankSum <-12.5, ReadPosRankSum <-8.0), retaining biallelic SNPs with mean depth 10-50×, missingness ≤20%, and MAF ≥0.05, yielding 6095,752 high-confidence SNPs across 185 accessions. Both the raw FASTQ files and processed VCF files are publicly available to support studies of sorghum genetic diversity, population structure, selection, and the genetic basis of important traits.

Adaptation↗

PubMed2004

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients.

AIM: This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. METHODS: Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. RESULTS: No significant differences were observed between groups. Differences in mean tacrolimus C(0) values between carriers and noncarriers of each haplotype ranged from -0.04 microg/litre (95% confidence interval: -0.53 to 0.60) to -23 microg/litre (-1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. CONCLUSION: MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.

Adolescent↗

PubMed2006

The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients.

Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.-1639G > A polymorphism of the vitamin K-epoxide reductase (VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.-1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low (n = 42), medium (n = 42) or high (n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.-1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 (CYP2C9). A total of 90.5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.-1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9.4; 95% confidence interval (CI) 1.9-46.4; P = 0.006], especially when the homozygous form was present (OR 44.2; 95% CI 5.5-354.6; P < 0.001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0.04; 95% CI 0.01-0.22; P < 0.001). The A allele of the c.-1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy.

Acenocoumarol↗

PubMed1998

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men.

Several studies have examined the relation between factor VII and coronary artery disease by measuring factor VII levels in plasma and some found an association between high levels and disease. This suffers problems of interpretation concerning the causality of high factor VII levels, because factor VII levels may be affected by atherogenic risk factors and may become elevated as a consequence of atherosclerosis. We investigated the association between a genetic variant (353Arg-->Gln), shown to be related to factor VII levels, and myocardial infarction in a large case-control study, including 560 cases and 644 controls. Individuals carrying the 353Arg-Arg genotype seemed to have a lower risk of myocardial infarction (odds ratio 0.80 [95% confidence interval 0.60-1.061). In this study, we confirmed higher factor VII antigen and activity level in 529 men homozygous for the 353Arg allele compared with 115 men carriers of the 353Gln allele (around 20% higher). Our results indicate that a genetic propensity to high factor VII levels is not associated with the risk of myocardial infarction. Since we confirmed the association of the 353Arg-Arg genotype with higher factor VII levels, we conclude that high levels of factor VII are not a causal determinant of myocardial infarction.

Adult↗

PubMed2006

The mannose-binding lectin (MBL2) haplotype and breast cancer: an association study in African-American and Caucasian women.

Common genetic variants in cancer-related genes contribute to breast cancer. The innate immune system plays a crucial role in the immune surveillance against malignancies, thus it is plausible that genetic variations in key genes of the innate immunity such as the mannose-binding lectin (MBL), MBL2, could influence the risk for breast cancer. We investigated the association of MBL2 genotypes with breast cancer and conducted a comprehensive genotype and haplotype analysis of 26 MBL2 single nucleotide polymorphisms (SNPs) in a case-control study of breast cancer [166 African-American (AA) case patients versus 180 controls and 127 Caucasian (CAU) case patients versus 137 controls]. We observed that the A allele of the 3'-UTR SNP Ex4-1067 (NCBI SNP ID: rs10824792) was significantly associated with a decreased disease risk in AA women [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.27-0.81]. Haplotype analysis of MBL2 showed that the frequency of the corresponding 3' haplotype TATAAC (Ex4-1483, Ex4-1067, Ex4-1047, Ex4-901, Ex4-710, 3238bp 3' STP) was lower in cases than controls among AA women (0.15 versus 0.21; P = 0.02) suggesting a protective effect after adjusting for covariates (OR = 0.51, 95% CI = 0.29-0.88, P = 0.018). In conclusion, this study presents preliminary evidence that common genetic variants in the 3'-UTR of MBL2 might influence the risk for breast cancer in AA women, probably in interaction with the 5' secretor haplotypes that are associated with high concentrations of MBL.

3' Untranslated Regions↗

PubMed2005

Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk.

This nested case-control study evaluated the role of polymorphisms in the myeloperoxidase (MPO) and catechol-O-methyltransferase (COMT) genes that modulate oxidative stress in breast cancer risk in a Chinese population. Our results demonstrate that the MPO A/A genotype was associated with a reduced risk of breast cancer (odds ratio (OR) 0.64; 95% confidence interval (CI) 0.11-3.76), whereas there was no overall association of COMT genotype with breast cancer. Of note, an elevated breast cancer risk associated with the increasing numbers of high-risk genotypes of MPO and COMT genes was observed in women with a longer duration between menarche and first full-term pregnancy.

Breast Neoplasms↗

PubMed2006

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk.

Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).

ADP-Ribosylation Factors↗

PubMed1994

Mixed venous O2 saturation: measured by co-oximetry versus calculated from PVO2.

OBJECTIVE: The objectives of our study were (1) to compare mixed venous saturations calculated by a blood gas machine with those measured directly by a co-oximeter; and (2) to compare the sensitivities and specificities of VO2s derived from these values. METHODS: Charts were retrospectively reviewed of all MICU patients [n = 16] between December 1, 1991 and January 31, 1992, who required pulmonary artery catheters for their usual care and who had hemoglobin saturations of mixed venous blood concurrently measured by both a co-oximeter (Co-Ox Model 482, Instrumentation Lab, Lexington, MA) and a blood gas analyzer (Nova Biomedical StatLab5, Waltham, MA) which uses a variant of the Severinghaus equation to calculate SVO2 from PVO2). Data used at the time of each SVO2 measurement to calculate oxygen consumption (VO2) further was collected. RESULTS: Available for analysis were 118 mixed venous blood samples. Although the SVO2 values had a correlation coefficient of 0.807 (95% confidence interval [CI] 0.736 to 0.861, Fisher's z-transform), when VO2s were calculated, the blood gas analyzer calculated saturations had a sensitivity of only 58.3% and a specificity of 89%, when compared with those calculated using the saturations measured by the co-oximeter. Attempts to mathematically improve upon the Severinghaus equation and upon an additional four regression equations used by other blood gas analyzers resulted in universally worse sensitivity. CONCLUSION: If SVO2s calculated by a blood gas machine--rather than those co-oximetrically measured--are used to calculate VO2s, 42% of patients with low O2s will be misclassified as normal and 11% of normals will be misclassified as low. This total error appears to be the result of measurement error by the PO2 electrode of the blood gas analyzer and shifts of the oxyhemoglobin dissociation curve, which are not accounted for in the equation that is used to calculate saturation from measured PO2. We were not able to improve mathematically the sensitivity of any of the available regression equations used by blood gas analyzers to calculate SVO2 from PVO2. Therefore, it remains necessary to use co-oximetrically measured saturations when calculating VO2.

Oximetry↗

PubMed1995

Ornithine decarboxylase: an indicator for growth of NIH 3T3 fibroblasts and their c-Ha-ras transformants.

Growth rates of different clones, all derived from NIH 3T3 mouse fibroblasts, were determined. Four different types of cells were studied: (1) Normal NIH 3T3 fibroblasts; (2) a fast-growing NIH 3T3 clone obtained by repeated passages; (3) transformed clones (obtained by transfecting NIH 3T3 with the oncogene c-Ha-ras); (4) a slow-growing revertant obtained by repeated passages of the transformed line. Growth rates were determined by the following markers of proliferation: thymidine incorporation, protein accumulation and cell number. In parallel experiments growth rates were determined by a new approach based on measuring ornithine decarboxylase (ODC) activity. Transformed cells, which were characterized by phase-contrast microscopy and by electron microscopy grew rapidly and showed high ODC activity. Similarly, a high-passage NIH 3T3 variant, which grew rapidly, also possessed high ODC activity. On the other hand, high-passage of a transformed clone revealed phenotypic changes confirmed by electron microscopy. These cells exhibited reduced growth rates and their ODC activities were similar to those of the normal NIH 3T3 cells. A confident correlation was found among each of the three conventional parameters of growth and between them and ODC activity. However, in all the cases studied ODC activity appeared early in the cell cycle before the expression of the other markers of proliferation. It has been suggested that ODC is a reliable early marker of cell proliferation and might also serve as an important tool for determining the arrest of growth.

3T3 Cells↗

PubMed2005

Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility.

Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that is likely to be influenced by multiple genes some of which may be capable of causing vascular changes leading to disease onset. This study was conducted to determine whether the ACE I/D gene variant is involved in migraine risk and whether this variant might act in combination with the previously implicated MTHFR C677T genetic variant in 270 migraine cases and 270 matched controls. Statistical analysis of the ACE I/D variant indicated no significant difference in allele or genotype frequencies (P > 0.05). However, grouping of genotypes showed a modest, yet significant, over-representation of the DD/ID genotype in the migraine group (88%) compared to controls (81%) (OR of 1.64, 95% CI: 1.00-2.69, P = 0.048). Multivariate analysis, including genotype data for the MTHFR C677T, provided evidence that the MTHFR (TT) and ACE (ID/DD) genotypes act in combination to increase migraine susceptibility (OR = 2.18, 95% CI: 1.15-4.16, P = 0.018). This effect was greatest for the MA subtype where the genotype combination corresponded to an OR of 2.89 (95% CI:1.47-5.72, P = 0.002). In Caucasians, the ACE D allele confers a weak independent risk to migraine susceptibility and also appears to act in combination with the C677T variant in the MTHFR gene to confer a stronger influence on the disease.

Adult↗

PubMed2004

Association between dependent smoking and a polymorphism in the tyrosine hydroxylase gene in a prospective population-based study of adolescent health.

This study reports pilot data on an association between tobacco dependence and a five-allele tetranucleotide repeat polymorphism in the first intron of the tyrosine hydroxylase (TH) gene. One hundred and twenty-six Australian adolescents who had participated in the Health in Transition Study (1993-1997), and who showed patterns of either dependent or nondependent smoking across four waves of data collection, consented to participation in the pilot study. The smoking status of those recruited was confirmed using a telephone-administered drug use questionnaire during 2000. Tobacco dependence was defined as smoking more than 6 days per week and more than 10 cigarettes per day during wave 5 (year 2000) and at least one prior wave ( n = 58). A second, more stringent phenotype included smoking within an hour of waking ( n = 37). The control group comprised adolescents who had used tobacco but had remained low-level social smokers across each wave of data ( n = 56). DNA was collected using a mouthwash procedure. Using the more strictly defined tobacco dependence phenotype, and after adjusting for sex, a significant protective association was found between the K4 allele and tobacco dependence (OR 0.27, 95% confidence interval [CI] 0.09, 0.82). No association was found using the liberal criteria of tobacco dependence (OR 0.51, 95% confidence interval [CI] 0.23, 1.2). These preliminary results replicate a previous association between tobacco use and the K4 allele of the TH gene (Lerman et al., 1997). The potential significance of including time to first cigarette in definitions of tobacco dependence and the possible role that these TH variants might play in tobacco dependence are discussed.

Adolescent↗

PubMed2005

Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk.

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4). Thus, genetic alterations within the candidate tumour suppressor gene DR4 would be expected to provoke a deficient apoptotic signalling thereby facilitating the development of cancer. The DR4 variants Thr209Arg and Glu228Ala were genotyped in a series of 521 breast cancer cases and 1100 control subjects from Germany, determining their impact on breast cancer risk. Neither Thr209Arg (626C>G) nor Glu228Ala (683A>C) alone were significantly associated with breast cancer risk [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.65-1.08, P = 0.18 and OR = 0.89, 95% CI = 0.72-1.12, P = 0.30]. However, haplotype analysis revealed a 3.5-fold risk for carriers of the 626C-683C haplotype (OR = 3.52, 95% CI = 1.45-8.52, P = 0.003).

Adult↗

PubMed2006

Polymorphisms in the two helicases ERCC2/XPD and ERCC3/XPB of the transcription factor IIH complex and risk of lung cancer: a case-control analysis in a Chinese population.

The transcription factor IIH (TFIIH) helicases ERCC2/XPD and ERCC3/XPB are responsible for opening the DNA strand around the lesion site during nucleotide excision repair process. Genetic variants in these two genes may be markers for interindividual variability in DNA repair capacity and thus predisposition to cancer risk. In this case-control study of 1,010 incident lung cancer cases and 1,011 age and sex frequency-matched cancer-free controls in a Chinese population, we genotyped eight tagging polymorphisms of ERCC2 and ERCC3 using the high-throughput Taqman platform to determine their associations with risk of lung cancer. Although none of the eight polymorphisms was individually associated with lung cancer risk, we found that genetic variants in ERCC2 and ERCC3 jointly contributed to lung cancer risk in a dose-response manner. Compared with those with 0 to 1 "at-risk" locus, subjects carrying >1 at-risk loci were at increased risk for lung cancer [adjusted odds ratio (OR), 1.29; 95% confidence interval (95% CI), 0.98-1.70 for 2 at-risk loci; adjusted OR, 1.38; 95% CI, 1.02-1.85 for 3 at-risk loci; and adjusted OR, 1.51; 95% CI, 1.09-2.10 for > or =4 at-risk loci, respectively; P(trend) = 0.015]. This combined effect was slightly more evident in young subjects (<60 years), males, current smokers, and those with family history of cancer, particularly for histologic type of adenocarcinomas. No evidence for interaction was found. These findings indicate that these tagSNPs of the ERCC2 and ERCC3 along with their surrounding regions may serve as biomarkers of susceptibility to lung cancer, which warrant further validation by other population-based and phenotypic studies to determine the biological relevance of these tagSNPs.

Adenocarcinoma↗

PubMed2004

The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration.

PURPOSE: To date, of all the genes studied in relation to age-related macular degeneration (AMD), the alleles of the apolipoprotein (apoE) gene have been the most consistently associated with disease. However, not all apoE studies have found an association, and among these the associations differ. The current study was conducted to investigate further the association of this gene in AMD. METHODS: Three hundred twenty-two unrelated individuals with diagnosed AMD and 123 unrelated but ethnically matched control subjects were analyzed. All subjects completed a standard questionnaire and were given a fundus examination. A blood sample was collected for DNA extraction. The common allelic variants of apoE were screened through the use of polymerase chain reaction (PCR) and restriction enzyme digestion followed by statistical analysis. RESULTS: Individuals with the epsilon3 epsilon4 genotype of apoE had an approximate halving of disease risk for late (end-stage) AMD (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.34-0.98) relative to the epsilon3 epsilon3 genotype at age of ascertainment. Stratification of late AMD into atrophic and neovascular disease revealed that the greatest protective effect for the epsilon3 epsilon4 genotype was in individuals with atrophic disease (OR 0.35, 95% CI 0.13-0.92). Men with the epsilon3 epsilon4 genotype also showed almost a threefold reduction in risk of disease in late AMD (OR 0.36, 95% CI 0.16-0.82). However, individuals with late AMD and the epsilon2 epsilon3 genotype had a significantly earlier mean age of diagnosis of disease (3.4 years, P = 0.015) compared with those with the epsilon3 epsilon3 genotype, and this was most evident in women (3.9 years, P = 0.011) and in individuals with neovascular disease (4.7 years, P = 0.003). CONCLUSIONS: The alleles of apoE appear to have a role in the etiology of AMD, with the epsilon4 allele being protective, or at the very least, delaying the age of diagnosis of disease, whereas the epsilon2 allele appears to have a modifier effect by bringing forward the mean age of disease diagnosis.

Aged↗

PubMed2006

The Val279Phe variant of the lipoprotein-associated phospholipase A2 gene is associated with catalytic activities and cardiovascular disease in Korean men.

CONTEXT AND OBJECTIVE: It is unclear whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) exerts a pro- or antiatherogenic effect on cardiovascular disease (CVD). We investigated the association between Lp-PLA(2) variant (V279F and A379V) and CVD in Korean men. DESIGN: CVD patients (n = 532) and healthy controls (n = 670) were genotyped for the Lp-PLA(2) polymorphism (V279F and A379V). MAIN OUTCOME MEASURES: We calculated odds ratio (OR) on CVD risk and measured anthropometries, lipid profiles, low-density lipoprotein (LDL) particle size, oxidized LDL, lipid peroxides, and Lp-PLA(2) activity. RESULTS: The presence of the 279F allele was associated with a lower risk of CVD [OR 0.646 (95% confidence interval 0.490-0.850), P = 0.002], and the association still remained after adjustments for age, body mass index, waist circumference, waist to hip ratio, cigarette smoking, and alcohol consumption [OR 0.683 (95% confidence interval 0.512-0.911), P = 0.009]. Lp-PLA(2) activity was lower in CVD patients taking a lipid-lowering drug (31%), those not taking a lipid-lowering drug (26%), and control subjects (23%) with the V/F genotype, compared with those with the V/V genotype. Subjects with the F/F genotype in controls and two CVD patients groups showed no appreciable enzymatic activity. Control subjects with the V/F genotype had larger LDL particle size than those with the V/V genotype. In addition, control subjects carrying the F allele showed lower malondialdehyde concentrations. On the other hand, we found no significant relationship between A379V genotype and CVD risk. CONCLUSIONS: The association of the F279 loss of function variant with the reduced risk of CVD supports the concept that Lp-PLA(2) plays a proatherogenic and causative role in CVD.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗