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PubMed2003

Manganese superoxide dismutase and cytochrome P450 1A1 genes polymorphisms in rheumatoid arthritis in Taiwan.

To investigate the role of manganese superoxide dismutase (MnSOD) and cytochrome P450 1A1 (CYP1A1) gene polymorphisms in the pathogenesis of rheumatoid arthritis (RA) in Taiwan, MnSOD and CYP1A1 genes polymorphisms were determined by he polymerase chain reaction/restriction fragment length polymorphism method in 112 patients with RA and 96 controls. There were no significant differences in the genotype, allele, and phenotype frequencies of MnSOD Ala-9Val (C1183T) polymorphisms between patients with RA and controls. The polymorphism of MnSOD 5777T, threonine at the 58th amino acid, cannot be found in RA patients and controls in Taiwan. The allele and phenotype frequencies of CYP1A1 4887A and genotype frequency of CYP1A1 4887C/A were lower in RA patients than in controls, whereas the significant difference was lost after correction. MnSOD C1183T polymorphisms were not associated with the clinical manifestations of RA. However, RA patients with CYP1A1 4889G/G have significantly higher frequency of Sjögren's syndrome, especially in the presence of MnSOD 1183T/T. Patients with CYP1A1 4887C/A also have a trend to develop Sjögren's syndrome in the presence of MnSOD 1183T/T. The linkage disequilibrium between CYP1A1 4889G and CYP1A1 6235C can be found in this study. MnSOD gene polymorphisms are not related to susceptibility to RA in Taiwan, whereas individuals with CYP1A1 4887A tend to avoid the development of RA. Moreover, CYP1A1 4889G/G and 4887C/A may play a role in the development of Sjögren's syndrome, especially in the presence of MnSOD 1183T/T. These findings are preliminary. A further confirmation study is necessary.

Arthritis, Rheumatoid↗

PubMed2002

Polymorphisms in the DNA repair gene XRCC1 and susceptibility to alcoholic liver cirrhosis in older Southeastern Brazilians.

The population of Southeastern Brazil has a very high mortality rate from liver cirrhosis, a disease that is considered an irreversible pre-malignant condition. This is largely due to the high prevalence of alcohol abuse in the region. Chronic alcohol consumption is associated with the production of free radical intermediates that can cause several DNA lesions. Reduced repair of these DNA lesions would, therefore, constitute a significant risk factor for liver cirrhosis and subsequent cancer. Recently, a number of polymorphisms in several DNA repair genes have been discovered, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate susceptibility to the disease. In this study, we tested the hypothesis that polymorphisms in the DNA repair gene XRCC1 are associated with increased risk of liver cirrhosis in Southeastern Brazilians. We conducted a pilot case-control study of 97 liver cirrhosis cases and 96 controls (matched for age, sex, and ethnicity) to investigate the role of two allelic variants coding for amino acid changes in the XRCC1 gene (the Arg194Trp and the Arg399Gln polymorphisms). Overall, we observed a 1.8-fold increase in the relative risk of liver cirrhosis associated with the 399Gln allele (either the heterozygous Arg/Gln or the homozygous Gln/Gln genotypes). The adjusted odds ratio (OR) was 1.82 (95% confidence limit (CL) 1.10-3.30). The relative risk appears to be highest among the Mestiso ethnic group (OR 2.60, 95% CL 0.92-7.34). There was a significant association between the 399Gln polymorphism and the risk of liver cirrhosis in older individuals over the age of 45 years (OR 2.70 (95% CL 1.14-6.48) compared to an OR of 1.24 (95% CL 0.55-2.78) for those under 45 years of age. No association was observed between the XRCC1 194Trp polymorphism and risk of liver cirrhosis. These preliminary results suggest that the XRCC1 399Gln polymorphism may be a significant risk modifier for alcoholic liver cirrhosis and justifies additional studies in that direction.

Adult↗

PubMed1998

Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor-related protein gene.

The E*4 allele of apolipoprotein E (APOE) is a major risk factor for Alzheimer's disease (AD) but the underlying mechanism is unknown. The low density lipoprotein receptor-related protein (LRP) is directly involved in APOE metabolism and therefore may alter the risk of AD associated with APOE. Two common polymorphisms, a tetranucleotide repeat in the 5'-region and a same-sense mutation in exon 3, are present in the LRP gene. Three studies have reported conflicting association of the tetranucleotide polymorphism with AD. The only study of the exon 3 polymorphism found a significant association with AD. In this study we examined the association of these two LRP polymorphisms with sporadic late-onset AD. No significant association was observed between the tetranucleotide polymorphism and AD. While the overall genotype and allele frequencies for the LRP exon 3 polymorphism were comparable between AD cases and controls, the frequency of the TT genotype was significantly higher in controls than AD (5.7% vs. 2.5%; P < 0.01). Stratification of the data by APOE genotypes indicated that the protective effect associated with the TT genotype was confined to APOE*4 carriers. Although the effect of the exon 3 polymorphism in our sample is small compared to the previous study, this warrants additional studies to confirm this putative association.

Age of Onset↗

PubMed1999

Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease.

Several studies have demonstrated genetic associations between Alzheimer's disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (-219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-epsilon4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the -219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the -219G allele and APOE-epsilon2 and between the -219 T allele and APOE-epsilon4. Controlling for these linkages, we found no independent association between the -219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the -219 polymorphisms.

Alleles↗

PubMed2001

Interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in non-ST-elevation acute coronary syndromes.

OBJECTIVES: The goal of this study was to determine the interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in patients admitted with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: An increased incidence of the P1(A2) polymorphism in smokers presenting with ST-elevation acute myocardial infarction (AMI) has recently been reported. We, therefore, postulated that, as a consequence of this interaction, fewer smokers with the P1(A2) polymorphism would present with non-ST-elevation ACS. METHODS: We performed a prospective cohort analysis of 220 white Caucasoid patients admitted with non-ST-elevation ACS fulfilling Braunwald class IIIb criteria for unstable angina who were stratified by smoking status. RESULTS: There were twice as many nonsmokers as smokers. Nonsmokers compared with smokers were older (mean [SD]; 63.9 [11.2] vs. 57.6 [10.3]; p < 0.0001), more likely to have had a previous admission with unstable angina (24.3% vs. 13.2%; p = 0.051) and AMI (45.8% vs. 30.3%; p < 0.026), more likely to have undergone revascularization (24.3% vs. 1.8%; p = 0.028) and were more likely to be on aspirin on admission (60.4% vs. 44.7%; p = 0.026). The proportion of nonsmokers positive for the P1(A2) polymorphism was equivalent to that expected for this population but was significantly reduced in smokers (28.7% vs. 10%; Pearson chi-square = 9.09, p = 0.0026). In a logistic regression model, the odds ratio (OR) for being positive for the P1(A2) polymorphism was significantly reduced by smoking (OR [interquartile range]: 0.26 [0.11 to 0.62]; p = 0.0026). CONCLUSIONS: There is a significant reduction in the P1(A2) polymorphism in smokers admitted with non-ST-elevation ACS compared with nonsmokers, which suggests an interaction between smoking and this polymorphism.

Acute Disease↗

PubMed2003

The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients.

OBJECTIVES: We sought to investigate whether two polymorphisms located in the promoter (T(-786)C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release. BACKGROUND: Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release. METHODS: We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 +/- 9 years, 151 +/- 11/99 +/- 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 +/- 16 years, 123 +/- 10/78 +/- 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 microg/100 ml/min) and sodium nitroprusside (1, 2, 4 microg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5' end-labeled with LCRed 640) and donor probes (3' end-labeled with fluorescein) specific for each polymorphism. The genotype distribution of T(-786)C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p < 0.001). A significant effect of the T(-786)C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T(-786)C and Glu298Asp polymorphism (p < 0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen. CONCLUSIONS: The T(-786)C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.

Adult↗

PubMed2003

Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors.

OBJECTIVES: The aim of the study was to identify genes that confer susceptibility to coronary artery disease (CAD) in low- or high-risk men or women separately and thereby to assess the genetic risk of CAD in such individuals. BACKGROUND: The prevention of CAD would be facilitated by the identification of genes that confer susceptibility to this condition independently in low- or high-risk individuals, as defined by conventional risk factors. METHODS: The study population comprised 1661 unrelated Japanese individuals, including 1011 patients with CAD and 650 control subjects. Among all study subjects, 601 individuals (high-risk subjects) had hypertension, diabetes mellitus, and hypercholesterolemia, and 1060 individuals (low-risk subjects) had none of these risk factors for CAD. The genotypes for 37 polymorphisms of 31 candidate genes were determined by a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. RESULTS: Multivariate logistic regression analysis, with adjustment for age, body mass index, and the prevalence of smoking and hyperuricemia, revealed that the -219G-->T polymorphism of the apolipoprotein E gene in low-risk men, the -1171/5A-->6A polymorphism of the stromelysin-1 gene in low-risk women, the 1019C-->T polymorphism of the connexin 37 gene in high-risk men, and the 3932T-->C polymorphism of the apolipoprotein E gene in high-risk women were significantly associated with CAD. A stepwise forward selection procedure revealed that the effects of these polymorphisms on CAD were statistically independent of age or conventional risk factors. CONCLUSIONS: Genotyping of these polymorphisms may prove informative for assessment of the genetic risk of CAD in low- or high-risk men or women.

Apolipoproteins E↗

PubMed1999

Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes.

OBJECTIVES: We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND: Adaptive left ventricular hypertrophy is a feature of the athlete's heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS: We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS: The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS: Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.

Adaptation, Physiological↗

PubMed2003

Relation among alcohol dehydrogenase 2 polymorphism, alcohol consumption, and levels of gamma-glutamyltransferase.

In human beings, alcohol is metabolized primarily by alcohol dehydrogenase 2 (ADH2) and acetaldehyde dehydrogenase 2 (ALDH2). Whereas polymorphisms of the ALDH2 are common in Asian persons, polymorphisms of the ADH2 seem to be more important in Caucasian individuals. The aim of this study was to assess the relation among ADH2 polymorphism, alcohol consumption, and levels of gamma-glutamyltransferase (GGT). The question was examined among 1,663 subjects (736 men and 927 women) participating in a national representative health and nutrition survey (VERA substudy of the German National Nutrition Survey). Alcohol consumption was assessed through responses to a semiquantitative food frequency questionnaire (FFQ), and the ADH2 restriction fragment length polymorphism (RFLP) Mae III and GGT levels were analyzed from frozen serum samples. The relations between the polymorphism and alcohol consumption and between alcohol consumption and GGT levels according to the polymorphism were assessed with the use of descriptive statistics and contingency table analysis. Of the subjects studied, 2.8% were homozygous or heterozygous for the ADH2*2 allele, and high levels of alcohol consumption (>20 g/day) were less common among these subjects (8.5%) than among subjects with the ADH2*1 allele (19.9%). Median levels of GGT increased with increasing levels of alcohol consumption. This increase tended to be stronger among subjects with the ADH2*2 allele than among other subjects, although differences were not statistically significant (P value for interaction=.1) given the small number of subjects with the polymorphism. These results are consistent with the hypothesis that subjects with the ADH2*2 allele, on the one hand, might tend to drink less alcohol but, on the other hand, might be at increased risk of alcohol-related effects on the liver with consumption of larger amounts of alcohol. However, this hypothesis needs to be evaluated among larger population samples.

Adult↗

PubMed1999

Polymorphisms of the endothelin-A and -B receptor genes in relation to blood pressure and myocardial infarction: the Etude Cas-Témoins sur l'Infarctus du Myocarde (ECTIM) Study.

Endothelin-1 is a potent vasoconstrictor that has also mitogenic properties, stimulating the synthesis and secretion of several vasoactive molecules. There is much evidence to suggest that endothelin-1 might be involved in the pathogenesis of hypertension, atherosclerosis, and ischemic heart disease. Endothelin-1 exerts its effects through at least two receptors, ET(A) and ET(B), which are encoded by different genes and have separate tissue distributions and biologic properties. The objective of this study was to identify polymorphisms of the ET(A) and ET(B) receptor genes and to study their association with myocardial infarction (MI) and blood pressure. The coding regions and 1.3 kb upstream of the ET(A) and ET(B) receptor genes were explored by polymerase chain reaction/single strand conformation polymorphism. Six polymorphisms were found in the ET(A) receptor gene and three in the ET(B) receptor gene. Most of these polymorphisms were frequent. Associations between the detected polymorphisms, blood pressure, and MI were examined in the ECTIM study, a multicenter study comparing 652 patients having survived an MI and 773 controls from Belfast (Northern Ireland) and France. Alleles at the different polymorphic sites were similarly distributed in patients with MI and controls. Allele frequencies were similar in both countries, except for the ET(A)/-231 G allele, which appeared more frequently in France than in Belfast (P < .01). The mean systolic and diastolic blood pressure levels did not significantly differ between genotypes. However, a C/T substitution located in the nontranslated part of exon 8 of the ET(A) receptor gene (ET(A)/EX8nt1363) was associated with pulse pressure (P < .005). These results do not support an involvement of the endothelin receptor genes in a predisposition to MI or the determination of blood pressure levels, but suggest that a polymorphism of the ET(A) receptor gene might influence the pulse pressure. This result will have to be confirmed in other studies.

Adult↗

PubMed2003

T102C and -1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive-compulsive disorder.

OBJECTIVE: This study aimed to investigate the possible association between T102C and -1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive-compulsive disorder (OCD). METHOD: Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive-Compulsive Scale. T102C and -1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes. RESULTS: OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for -1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate-severe OCD. CONCLUSION: The -1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of -1438 G/A polymorphism might be a factor in clinical severity of OCD.

Adolescent↗

PubMed1997

Polymorphisms of coagulation/fibrinolysis genes: gene environment interactions and vascular risk.

Circulating concentrations of plasminogen activator inhibitor-1 (PAI-1), factor VII and fibrinogen have all been related to vascular risk in large prospective studies. Evidence indicates that all three proteins are increased in the presence of insulin resistance and factor VII and PAI-1 correlate strongly with circulating levels of insulin and lipids. Polymorphisms of the genes coding for PAI-1, factor VII and fibrinogen have been investigated in relation to gene environment interactions and vascular risk. Three polymorphisms have been described in the PAI-1 gene, a 3' Hind III RFLP, an intronic CA repeat and a 4G/5G insertion deletion 675 bp 5' of the start site of transcription. The 4G/5G site has been shown to be triglyceride responsive and higher levels of PAI-1 have been reported in subjects homozygous for the 4G allele. Three out of four case control studies have related possession of the 4G/4G genotype to an increased risk of coronary artery disease and our studies in patients undergoing coronary angiography indicate that this is due to increased myocardial infarction rather than atheroma. We have investigated 600 subjects with cerebrovascular disease and found no relationship to the 4G/5G polymorphism. Two major polymorphisms have been identified in the factor VII gene, a promoter decanucleotide repeat and a G-A substitution at codon 353. Evidence indicates that the latter mutation affects factor VII levels by interfering with intracellular processing of the molecule and subjects homozygous for the adenine genotype (M2/M2) have levels of factor VII 20-30% lower than M1/M2 or M1/M1 carriers. Two studies have, however, failed to show a relationship between genotype and cardiovascular disease and we have found no association with cerebrovascular disease. A number of mutations have been described in the genes coding for the alpha, beta and gamma chains of fibrinogen. These polymorphisms are reported to be responsible for from 3% to 50% of circulating levels in various studies and there is evidence that the effect of smoking is genotype specific. In the ECTIM study the beta Bcl I polymorphism has been related to cardiovascular disease and work from our unit has related the Bbeta448 polymorphism to the presence of cerebrovascular disease in women. Further prospective studies are warranted to evaluate the role of these genes in disease.

Blood Coagulation↗

PubMed1996

Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative Western analysis and gene sequence polymorphisms.

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfation of DHEA and other hydroxysteroids. DHEA ST enzymatic activity in individual human liver biopsy samples has been shown to vary over a five-fold range, and frequency distribution histograms are bimodal, with approximately 25% of subjects included in a high activity subgroup. We set out to characterize the molecular basis for variation in human liver DHEA ST activity. The first step involved performing quantitative Western analysis of cytosol preparations from 92 human liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. There was a highly significant correlation (r(s) = 0.635, P < 0.0001) between levels of DHEA ST activity and immunoreactive protein. We next attempted to determine whether the expression of DHEA ST might be controlled, in part, by a genetic polymorphism. DNA was isolated from three "low" and three "high" DHEA ST activity liver samples. Exons and the 5'-flanking region of the DHEA ST gene (STD) were amplified for each of these samples with the polymerase chain reaction (PCR). When compared with "wild type" STD sequence, some of the samples contained a T --> C transition at DHEA ST cDNA nucleotide 170, located within exon 2, resulting in a Met 57 --> Thr change in amino acid. Other samples contained an A --> T transversion at nucleotide 557 within STD exon 4 that resulted in a Glu 186 --> Val change. STD exons 2 and 4 were then sequenced for DNA isolated from an additional 87 liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. The allele frequency for the exon 2 polymorphism in these samples was 0.027, whereas that for the exon 4 polymorphism was 0.038, but neither polymorphism was systematically related to the level of enzyme activity in these samples. Transient expression in COS-1 cells of cDNA that contained the nucleotide 170 and 557 polymorphisms, either separately or together, resulted in decreased expression of both DHEA ST enzymatic activity and level of immunoreactive protein, but only when the nucleotide 557 variant was present. Identification of common genetic polymorphisms within STD will now make it possible to test the hypothesis that those polymorphisms might alter in vivo expression and/or function of this important human steroid-metabolizing enzyme.

Amino Acid Sequence↗

PubMedDate not supplied

Recipient gene polymorphisms in the Th-1 cytokines IL-2 and IFN-gamma in relation to acute rejection and graft vascular disease after clinical heart transplantation.

IL-2 and IFN-gamma are associated with acute rejection (AR) and graft vascular disease (GVD) after clinical heart transplantation. Polymorphisms in the genes of IL-2 (T-330G in the promoter) and IFN-gamma (CA repeat in the first intron) influence the production levels of these cytokines. Therefore, these polymorphisms might have an effect on the outcome after transplantation. To investigate possible effects of genetic variations in IL-2 and IFN-gamma genes on AR and GVD, we analyzed the IL-2 T-330G and the IFN-gamma CA repeat polymorphism in DNA of 301 heart transplant recipients. No associations were found for allele or genotype distributions between patients with or without AR (IL-2 allele frequency: P=0.44, genotype distribution: P=0.46; IFN-gamma allele frequency P=0.10, genotype distribution 12 repeats allele: P=0.21). Also, no associations were found analyzing the number (0 vs. 1 vs. >or=1) of AR (IL-2 allele frequency: P=0.59; genotype distribution: P=0.37; IFN-gamma allele frequency: P=0.27, genotype distribution 12 repeats allele: P=0.41) or analyzing the polymorphisms in patients with AR within the first month or thereafter (IL-2 allele frequency: P=0.45, genotype distribution: P=0.38; IFN-gamma allele frequency: P=0.21, genotype distribution 12 repeats allele: P=0.41). Analyzing both polymorphisms in relation to GVD, resulted in comparable allele and genotype distributions (IL-2 allele frequency: P=0.75; genotype distribution: P=0.77; IFN-gamma allele frequency: P=0.70, genotype distribution 12 repeats allele: P=0.63). In conclusion, we did not detect an association between the IL-2 T-330G promoter polymorphism and CA repeat polymorphism in the first intron of the IFN-gamma gene and AR or GVD after heart transplantation.

Adult↗

PubMed2002

Chromosomal inversion polymorphism in Afrotropical populations of Drosophila melanogaster.

When 41 populations from Africa (south of the Sahara) and Indian Ocean islands were analysed for their chromosomal inversion polymorphism, 34 rearrangements were found, including the four common cosmopolitans (In(2L)t, In(2R)NS, In(3L)P and In(3R)P), four rare cosmopolitans (In(2L)NS, In(3R)C, In(3R)Mo and In(3R)K) and six African polymorphic ('recurrent') endemics. Mean inversion frequencies per major autosome arm were positively and, generally, highly correlated to each other. There was no altitudinal nor latitudinal cline of inversion frequency, except for one African polymorphic endemic. Significant longitudinal clines were detected for In(2L)t, In(3L)P and In(3R)K; in all cases, inversion frequencies decreased eastward. Principal components analysis and ANOVA made it possible to distinguish three groups of populations. A high level of polymorphism was found in populations from west tropical Africa. The other low altitude populations from the mainland were moderately polymorphic, whereas the lowest levels of polymorphism were those of high altitude populations and of Indian Ocean islands. Moreover, some regional and local differentiation was also found. The frequency of unique autosomal inversions was not different from those found in Asia, Australia and America, but was significantly higher than that in Europe and North Africa. A West-East differentiation was also observed for the African polymorphic endemics. The present geographic pattern suggests a long, patchy evolution with restricted gene flow, followed by the modern period with numerous recent migrations linked to human transportation.

Africa South of the Sahara↗

PubMed2005

Polymorphisms in the goat beta-lactoglobulin gene.

Beta-lactoglobulin polymorphisms have been reported in the milk of different goat breeds, although no genetic variants affecting the protein have been characterized. In the present study, we amplified and sequenced the proximal promoter and the first six exons containing the entire coding region for the beta-lactoglobulin gene in eleven goat breeds from Spain, France, Italy, Switzerland, Senegal and Asia to identify genetic variants. Fifteen polymorphisms were detected, nine in the promoter region and six in the exons of the beta-lactoglobulin gene. All polymorphisms were single nucleotide substitutions with the exception of one deletion/insertion in the promoter region. The polymorphisms in the coding region did not produce any amino acid change. In addition, pyrosequencing technology was used to genotype four polymorphisms in the promoter region in 200 goats belonging to eleven breeds. Differences in allelic frequencies for these polymorphisms between breeds are described and a specific polymorphism for the Italian populations was identified. Finally, the analysis of association between these four promoter point mutations was investigated resulting in five haplotypes, GCGC being the most frequent haplotype in all breeds analysed.

Alleles↗

PubMed2002

Association of vitamin D receptor gene polymorphism with sporadic breast cancer in Taiwanese patients.

PURPOSE: Previous reports have suggested that polymorphism in the vitamin D receptor (VDR) gene is associated with sporadic breast cancer, but there is controversy among different authors and ethnic groups. The purpose of this study was to determine whether polymorphism in the VDR gene might also influence breast cancer risk in Taiwan, a country with a low incidence of breast cancer. METHODS: Polymorphisms in the end of the VDR gene were genotyped for 34 Taiwanese women with sporadic breast cancer, 46 with benign breast tumors and 169 cancer-free female cohort controls. RESULTS: The ApaI, TaqI, and BsmI polymorphisms in the 3' end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increased numbers of BsmI B alleles and ApaI AA genotypes. When the allele frequencies of BsmI polymorphism were compared among the three populations, a significant difference was observed (chi2 = 13.684, df = 4, p = 0.0084). The OR of the Aa genotype was 0.333 (95% CI = 0.1 14-0.978) and that of the aa genotype was 0.515 (95% CI = 0.190-1.398). These data indicate that the AA genotype may be associated with an increased risk of breast cancer, while the Aa genotype tends to be associated with decreased risk. The TaqI polymorphism was not associated with breast cancer risk in this study. CONCLUSION: These results suggest that polymorphic variation in or near the 3' end of the VDR gene may influence breast cancer risk in Taiwanese women and justifies further investigation of the role of VDR for sporadic breast cancer in low-incidence areas. These findings also should help when designing targeted therapy.

Aged↗

PubMed2002

Polymorphisms in the DNA repair enzyme XPD are associated with increased levels of PAH-DNA adducts in a case-control study of breast cancer.

We present findings on the associations between DNA adduct levels in breast tissue, risk of breast cancer, and polymorphisms in the DNA repair enzyme XPD. Breast cancer cases, benign breast disease (BBD) controls, and healthy controls were enrolled. Polycyclic aromatic hydrocarbons (PAH)-DNA adduct levels were measured by immunohistochemistry in breast tissue samples from cases and BBD controls. XPD polymorphisms at codons 312 and 751 was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis using white blood cell DNA. Neither of the polymorphisms were associated with case-control status, both in comparisons of cases and BBD controls, and cases and healthy controls. XPD polymorphisms at codons 312 and 751 were associated with higher levels of PAH-DNA in tumor tissue from breast cancer cases. Subjects with an Asp/Asn or Asn/Asn polymorphic genotype in codon 312 of XPD had elevated levels of PAH-DNA adducts compared to subjects with the Asp/Asp genotype (0.55 optical density (OD) v.s. 0.33 OD, p < 0.01). PAH-DNA adducts were associated with increasing copy number of the Gln allele for the codon 751 polymorphism (p for trend <0.01). Among subjects with the Asp/Asn or Asn/Asn genotype at codon 312, adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.55 OD v.s. 0.36 OD, p = 0.003). Among subjects with the Gln/Gln genotype at codon 751 adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.68 OD v.s. 0.40 OD, p = 0.01). The trend of increasing PAH-DNA adduct levels with either the Asn/Asn or Gln/Gln genotype was greater in tumor tissue than the trend in BBD control tissue.

Analysis of Variance↗