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PubMed2006

CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China.

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile duct and ampulla of Vater, are rare but highly fatal malignancies. Other than gallstones, little is known about the risk factors for biliary tract cancers. Endogenous estrogens are thought to play a role in the etiology of gallstones and gallbladder cancer, since both conditions predominate in females and are associated with parity and obesity. In view of reports linking the CYP17 MspA1 polymorphism to high circulating levels of estrogens and a predisposition to other hormonally related cancers, we examined the relationship between CYP17 MspA1 variants and risk of biliary disease in a population-based case-control study in Shanghai. The study included 446 cancer cases (254 gallbladder, 139 extrahepatic bile duct, 53 ampullary cancers), 929 biliary stone cases (691 gallbladder, 238 bile duct) and 818 population controls. Genomic DNA from peripheral blood lymphocytes was used for genotyping. Relative to those with the A2/A2 genotype, A1 carriers (A1/A1 and A1/A2 genotypes) had an increased risk of gallbladder cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.1). In addition, women with the A1 allele and high parity (> or =3) had a 3-fold risk of gallbladder cancer (OR = 3.3, 95% CI = 1.6-6.9), compared to those with the A2/A2 genotype and lower parity, with the highest risk seen for those also having biliary stones (OR = 4.6, 95% CI = 1.8-11.7, P(interaction) = 0.04). The A1 allele was not associated with a higher risk of gallstones except among those with body mass index (BMI) greater than 25 kg/m2 (OR = 3.1, 95% CI = 2.0-4.8, P(interaction) = 0.02) and among those with a history of diabetes (OR = 2.5, 95% CI = 1.4-4.3, P interaction = 0.09). No clear relation was seen between the CYP17 polymorphism and cancers of the bile duct or ampulla of Vater. The association of the CYP17 MspA1 polymorphism with an increased risk of gallbladder cancer, as well as biliary stones among overweight and diabetic individuals, suggests an interplay between genetic and hormonal risk factors in gallbladder disease.

Adult↗
PubMed2001

Human immunodeficiency virus-related lymphoma: relation between clinical features and histologic subtypes.

PURPOSE: Non-Hodgkin's lymphoma occurs frequently in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). We determined the association between the clinical and histologic features of HIV-related lymphoma. SUBJECTS AND METHODS: We reviewed the medical records of 291 patients with noncerebral HIV-related lymphoma who had been treated in multicenter trials coordinated by the Groupe d'Etude des Lymphomes de l'Adulte between 1988 and 1997. This study was performed mainly before the availability of combination antiretroviral therapy. RESULTS: The main histologic subtypes were centroblastic lymphoma in 131 patients (45%), immunoblastic lymphoma in 39 patients (13%), and Burkitt's lymphoma (including the classical form and the variant with plasmacytic differentiation) in 115 patients (40%). Burkitt's lymphoma was the most aggressive form, whereas immunoblastic lymphoma occurred in severely immunodeficient patients. Two-year survival after enrollment was 15% in immunoblastic lymphoma, 32% in Burkitt's lymphoma, and 31% in centroblastic lymphoma (P = 0.006), but multivariate analysis did not confirm the independent prognostic value of histologic subtype. Instead, five independent pretreatment factors increased the risk of mortality: age 40 years or older [relative risk (RR) = 1.5; 95% confidence interval (CI), 1.1 to 2.1; P = 0.005], elevated serum lactate dehydrogenase level (RR = 1.5; 95% CI, 1.1 to 2.1; P = 0.02), having a diagnosis of AIDS before lymphoma (RR = 1.8; 95% CI, 1.2 to 2.6; P = 0.006), CD4(+) cell count less than 100 x 10(6)/L (RR = 1.8; 95% CI, 1.3 to 2.6; P = 0.0004), and impaired performance status (RR = 2.4; 95% CI, 1.7 to 3.4; P <0.0001). CONCLUSION: Several pretreatment characteristics of HIV-related lymphoma were linked to the histologic form, but HIV disease parameters other than those of lymphoma were the main determinants of outcome, so the histologic features of the lymphoma were not associated with prognosis.

Adult↗
PubMed2003

Reduced prevalence of Plasmodium falciparum infection and of concomitant anaemia in pregnant women with heterozygous G6PD deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency confers protection against malaria in children, yet its role in malaria in pregnancy is unknown. In a cross-sectional study among 529 pregnant Ghanaian women, Plasmodium falciparum infection, anaemia and G6PD genotypes were assessed. Of these, 30.4% were heterozygous and 2.6% were homozygous for G6PD deficiency. The prevalence of P. falciparum infection decreased from 66% in G6PD-normal women to 58% in heterozygotes, and to 50% in individuals with homozygous G6PD deficiency (Chi2(trend) = 4.4, P = 0.04). Multivariate analysis revealed that in multigravid women but not in primigravidae, heterozygous G6PD deficiency was associated with a reduced risk of P. falciparum infection (Odds ratio (OR), 0.6; 95% confidence interval (95% CI), [0.4-0.9]). This protection against infection was limited to the third trimenon of pregnancy. In addition, heterozygous G6PD deficiency was associated with a reduced risk of anaemia among infected multigravidae (OR, 0.5 [0.3-1.0]). Pregnancy is a period of high vulnerability to malaria. The results of this study provide evidence for protection against malaria in pregnancy caused by heterozygous G6PD deficiency. This advantage, even if confined to multigravid women, may contribute to the selection of G6PD variants in malaria-endemic regions.

Adolescent↗
PubMed2001

Ethnic differences in fibrinogen levels: the role of environmental factors and the beta-fibrinogen gene.

Fibrinogen is a cardiovascular risk factor, but little is known about levels in ethnic groups that differ in their cardiovascular risk. Fibrinogen was measured in 479 Black individuals, 459 South Asian Indians, and 453 Whites aged 40-59 years living in south London, England, from March 1994 to July 1996. Genotype was determined at two sites in the promoter of the beta-fibrinogen gene (G-455-->A and C-148-->T). Plasma fibrinogen levels were lower in Blacks than in Whites by 0.22 g/liter (95% confidence interval (CI): 0.08, 0.36) in men and 0.11 g/liter (95% CI: -0.01, 0.23) in women. These differences were not explained by measured environmental variables, including smoking, or by genotypes. The fibrinogen levels of South Asians were not consistently different from those of WHITES: The A-455 and T-148 alleles were less common in Blacks than in either Whites or South ASIANS: In Whites and South Asians, but not in Blacks, there was complete allelic association between the two variants. In Blacks, the T allele rather than the A allele was associated with higher fibrinogen levels. The average fibrinogen-raising effect of the T-148 allele across all ethnic groups was 0.14 g/liter (95% CI: 0.02, 0.26 g/liter) in women and 0.15 g/liter (95% CI: 0.03, 0.27 g/liter) in men. Low fibrinogen levels in Blacks may partly explain their lower risk of ischemic heart disease in the United KINGDOM:

Adult↗
PubMed1999

Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in never-smoking women.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is considered to be a major lung cancer risk factor for never smokers. We investigated the hypothesis that never-smoking women who are exposed to ETS and develop lung cancer are a genetically susceptible population. METHODS: Archival tumor tissues were analyzed from 106 never-smoking women enrolled in a case-control study of ETS (and other personal and environmental factors) and lung cancer risk. We analyzed germline polymorphisms in genes that have been associated with cancer susceptibility and whose products activate (cytochrome P450 1A1 [CYP1A1]) and detoxify (glutathione S-transferases M1 [GSTM1] and T1 [GSTT1]) chemical carcinogens found in tobacco smoke. RESULTS: When compared with never smokers who had no ETS exposure and developed lung cancer (n = 55), never smokers with exposure to ETS who developed lung cancer (n = 51) were more likely to be deficient in GSTM1 activity (i.e., were GSTM1 null) because of a genetic polymorphism in the GSTM1 gene (odds ratio = 2.6; 95% confidence interval = 1.1-6.1). A statistically significant rising trend in risk occurred with increasing ETS exposure (two-sided P =. 02), reaching a more than sixfold excess risk in those exposed to 55 pack-years of ETS (ETS pack-year = ETS produced by an active smoker, within a confined space such as a room, who smokes one pack of cigarettes a day for a year). No evidence was found of associations between GSTT1 deficiency or the CYP1A1 valine variant and lung cancer risk due to ETS exposure. CONCLUSIONS: A common genetic polymorphism divides the population of never smokers into two groups of approximately equal size, one (homozygous carriers of the GSTM1 null allele) that has a statistically significant greater risk of lung cancer from ETS than the other (heterozygous or homozygous carriers of the wild-type GSTM1 allele).

Adult↗
PubMed2001

Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom.

The size of the variant Creutzfeldt-Jakob Disease (vCJD) epidemic in the United Kingdom is a major public health concern and a subject of speculation. The cases are young (mean age = 28). Assuming that the risk of developing the disease in susceptible exposed subjects decreases exponentially with age after age 15, that all infections occurred between 1980 and 1989, and that the distribution of the incubation period is lognormal, we estimate that the mean duration of the incubation period is 16.7 years [95% confidence interval (CI): 12.4 to 23.2] and that the total number of cases will be 205 (upper limit of the 95% CI: 403).

Adolescent↗
PubMed1995

Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension.

BACKGROUND: The basal release of nitric oxide by the endothelium plays an important role in regulating blood flow and pressure and mediates most of the endothelium-dependent vasodilation. Impairment of nitric oxide production by specific inhibitors increases blood pressure in humans, and several reports suggest that hypertensive subjects have a blunted endothelium-dependent vasodilatation that might be secondary to decreased nitric oxide production from the vessel wall. METHODS AND RESULTS: To determine whether the endothelial nitric oxide synthase gene is involved in human essential hypertension, we identified informative biallelic and multiallelic markers of this locus and performed case-control and linkage studies in hypertensive subjects and normotensive control subjects. We used the affected sib pair method to test for potential linkage in 145 hypertensive pedigrees (269 sib pairs, 346 subjects) with a highly polymorphic marker of the nitric oxide synthase gene (polymorphism information content of 92%). There was no evidence for linkage among affected siblings. The 95% upper confidence limit of this value suggests that at most 1% of alleles in excess of expected are shared. We also identified two informative biallelic markers of this gene to perform a case-control study on white hypertensive and normotensive subjects. Similar genotype distributions between the two groups were noted for both markers. Estimated haplotype frequencies by maximum likelihood methods combining the two biallelic markers were also similar in both groups. CONCLUSIONS: These findings do not suggest that common molecular variants of the endothelial nitric oxide synthase gene are involved in essential hypertension.

Adult↗
PubMed2006

Transforming-growth factor beta1 Leu10Pro polymorphism and breast cancer morbidity.

TGF-beta1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-beta1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1-2.0) against non-carriers. Our data suggest that the TGF-beta1 Leu10Pro polymorphism might play a role in breast cancer risk.

Aged↗
PubMed1997

Global analysis of the acid-induced and urea-induced unfolding of staphylococcal nuclease and two of its variants.

We have studied the equilibrium unfolding staphylococcal nuclease and two of its variants, V66W and V66W', over two perturbation axes (acid-induced unfolding as a function of urea concentration and urea-induced unfolding as a function of pH). The transitions were monitored by simultaneous measurements of circular dichroism and fluorescence. With this multidimensional array of data (2 perturbation axes and 2 signals), we present a strategy of performing a global analysis, over as many as 12 individual data sets, to test various models for the unfolding process, to determine with greater confidence the pertinent thermodynamic parameters, and to characterize unfolding intermediates. For example, wildtype nuclease shows a cooperative two-state transition with either urea or pH as denaturant, but the global fits are improved when the model is expanded to include a pH dependence of the urea m value or when two distinct classes of protonic groups are considered. The best fit for wild-type nuclease is with delta G degree 0,UN = 6.4 kcal/mol at pH 7, with the acid-induced unfolding being triggered by protonation of three to five carboxylate groups (with possible contribution from His121), and with the urea m = 2.5 kcal mol-1 M-1. V66W' lacks the last 13 amino acids on the C-terminus, has a tryptophan at position 66, has a predominantly beta-sheet structure, and is less stable than the wild type. For V66W', delta G degree 0,UN = 1.6 kcal/mol, m = 1.2 kcal mol-1 M-1, and there are two or three groups responsible for acid unfolding. V66W, a full-length mutant with two tryptophan residues, unfolds via a three-state mechanism: native reversible intermediate reversible unfolded. It appears that its beta-barrel subdomain retains structure in the intermediate state. Assuming that the unfolding of V66W' and the beta-barrel subdomain of V66W can be described by the same thermodynamic parameters, a global analysis enabled a description of the alpha subdomain of V66W with delta G degree 0,IN = 2.7 kcal/mol, mIN = 1.1 kcal mol-1 M-1, and with the acid unfolding being triggered by protonation of a single group. This group has a pKa around 6 in the unfolded state, suggesting that the state of protonation of a histidine residue may contribute significantly to the stability of V66W.

Circular Dichroism↗
PubMed2004

Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis.

Hyperhomocysteinemia is an independent and graded risk factor for arterial vascular disease and venous thrombosis. It is still debated via which mechanism homocysteine (Hcy) causes vascular disease. S-adenosylhomocysteine hydrolase (AHCY) catalyses the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to Hcy. As an increase in AdoHcy, a strong inhibitor of many methyltransferases, is observed in hyperhomocysteinemic individuals, AdoHcy may play a role in the development of cardiovascular diseases by inhibiting transmethylation reactions. We sequenced the entire coding region and parts of the untranslated regions (UTRs) of the AHCY gene of 20 patients with recurrent venous thrombosis in order to identify genetic variation within this gene. We identified three sequence variants in the AHCY gene: a C > T transition in the 5' UTR (-34 bp C > T), a missense mutation in exon 2, which mandates an amino-acid conversion at codon 38 (112 C > T; Arg38Trp) and a silent mutation in exon 4 (390 C > T; Asp130Asp). We studied the effect of the first two variants on total plasma Hcy and venous thrombosis risk in a case-control study on recurrent venous thrombosis. The two polymorphisms under study seem to have no evident effect on tHcy. The adjusted relative risk of venous thrombosis associated with the 112CT genotype compared with 112CC individuals was 1.27 (95% CI 0.55-2.94), whereas the -34CT genotype confers a risk of 1.25 (95% CI 0.44-3.52) compared with the wild-type genotype at this locus. However, the wide confidence intervals do not allow firm conclusions to be drawn.

Adenosylhomocysteinase↗
PubMed1999

Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-DR4/DRB1*0407.

Actinic prurigo (AP) and polymorphic light eruption (PLE) both belong to the group of idiopathic photodermatoses, but it remains controversial whether AP is a distinct photodermatosis or a variant of PLE. The aim of this study, by collecting data from 119 patients with features of these disorders, was to establish whether specific criteria could be used to distinguish AP from PLE prospectively. We found that presence of the eruption on both exposed and covered sites, its occurrence in winter, persistence of lesions beyond 4 weeks, mucosal and conjunctival involvement, excoriation and scarring of the skin were important features of AP which were not typical of PLE. On this basis, confident clinical diagnoses could be reached in 103 of 119 patients (87%), 57 with AP and 46 with PLE, supported by phototesting and negative lupus serology. HLA typing subsequently confirmed the strong association (90%) between AP and the DR4 allele, in particular with the rare subtype DRB1*0407 which was present in 60% of these patients. No HLA association was found in PLE. In the 16 remaining cases, however, clinical overlap meant that no definite diagnosis could be made; these patients were notionally described as having persistent PLE (PPLE). Demographic and HLA data in this group suggested that PPLE was perhaps most appropriately grouped with PLE. In addition to those patients who were difficult to classify, 35% of our typical AP patients also described clinical progression from PLE to AP, AP to PLE or coexistence of both AP and PLE. In conclusion, our study suggests that while AP and PLE are clinically distinct conditions in most cases, they may perhaps share a common pathophysiological basis. The AP phenotype may be determined by HLA and perhaps other factors in patients otherwise predisposed to PLE.

Adolescent↗
PubMed2004

Differential effects of the C1431T and Pro12Ala PPARgamma gene variants on plasma lipids and diabetes risk in an Asian population.

We investigated the association of C1431T and Pro12Ala polymorphisms at the peroxisome proliferator-activated receptor gamma (PPARgamma) locus with plasma lipids and insulin resistance-related variables, according to diabetes status, in a large and representative Asian population from Singapore consisting of 2,730 Chinese, 740 Malays, and 568 Indians. Moreover, we estimated the diabetes risk and examined gene-nutrient interactions between these variants and the ratio of polyunsaturated fatty acid to saturated fat (SFA) in determining body mass index (BMI) and fasting insulin. We found differential effects of these gene variants. The Pro12Ala polymorphism was more associated with plasma lipids and fasting glucose concentrations, whereas the C1431T polymorphism was related to the risk of diabetes. Carriers of the 12Ala allele had higher HDL-cholesterol than did Pro12Pro homozygotes (P < 0.05), and the effect of the 12Ala allele on fasting glucose was modified by diabetes status (P < 0.001). After controlling for confounders, carriers of the T allele had decreased risk of diabetes compared with CC homozygotes [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58-0.93; P = 0.011]; this effect was stronger in Indians (OR 0.38, 95% CI 0.15-0.92; P = 0.032). For both polymorphisms, normal subjects carrying the less prevalent allele had higher BMI (P < 0.05). The PUFA/SFA did not modify the effect of these polymorphisms on BMI or insulin.

Adult↗
PubMed1999

Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility.

In a population-based case-control study, 182 human immunodeficiency virus (HIV)-positive persons and 135 healthy control subjects were enrolled from the metropolitan area of Medellin, Colombia. Four genotypes of the natural resistance-associated macrophage protein l (NRAMP1) gene (5' GT repeat, 274C/T, 469+14G/T, and 823C/T) were associated with altered risk of HIV infection (P=.013,.015,.020, and. 035, respectively). Three of these markers (5' [GT]n, 274C/T, 469+14G/T) are in strong linkage disequilibrium, and genotypes of these markers are associated with reduced risk of HIV infection with relative risks (RRs) of 0.35 (95% confidence interval [CI], 0.14-0.91), 0.31 (CI, 0.10-0.93), and 0.24 (CI, 0.08-0.72), respectively. Conversely, heterozygosity at the fourth independent marker (823C/T) was associated with increased risk of HIV infection (RR, 2.29; CI, 1.06-4.92). These findings suggest that NRAMP1 modifies risk of HIV infection.

Alleles↗
PubMed2003

The effect of methylenetetrahydrofolate reductase C677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values.

The C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene causes a moderate increase in total plasma homocysteine (tHcy). We studied the effect of MTHFR TT homozygosity and mild hyperhomocysteinemia on arterial hypertension. Normotensive controls (n = 223) and hypertensive subjects (n = 235) were matched for age, gender, and history of cardiovascular disease. Homocysteine levels were measured by a polarization immunoassay method. Methylenetetrahydrofolate reductase we determined by polymerase chain reaction and restriction fragment analysis. Hypertensives showed elevated tHcy compared to normotensive group in men (P = 0.039). Homocysteine values higher than 15 micromol/L were associated with increased hypertensive risk in the male population [odds ratios (OR) = 1.63; 95% confidence interval (CI) = 1.06-2.52; P = 0.027]. In multivariate analysis, TT genotype was associated with an increased risk of hypertension in males (OR = 2.27; 95% CI = 1.12-4.60; P = 0.022) An increased hypertensive risk was observed in those TT males with tHcy levels higher than 15 micromol/L (OR = 2.78; 95% CI = 1.05-7.3; P = 0.032) but not in those non-TT males with tHcy levels higher than 15 micromol/L (P = 0.33). Our findings do not support the possibility that mild hyperhomocysteinemia my solely account for the hypertensive risk associated to the TT genotype.

Aged↗
PubMed2005

A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample.

BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.

Adult↗
PubMed2006

Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.

CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). CONCLUSION: This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

Adult↗
PubMed2005

Genetic polymorphisms of GSTs and their association with primary brain tumor incidence.

Glutathione S-transferases GSTM1, GSTT1, and GSTP1 are phase II biotransformation enzymes that function on detoxification of a wide range of exogenous agents including carcinogens. It has been shown that genetic variations in these genes play an important role in determining the response of an individual to environmental carcinogens. Some studies revealed a statistically significant association between the polymorphisms in the genes encoding GST enzymes and some cancers, although contrary reports exist. In this study, the association between polymorphisms in these genes and primary brain tumor incidence was investigated in 228 Turkish individuals (75 patients with primary brain tumor and 153 controls). The prevalence of GSTM1 null genotype in the case group was 43%, compared to 24% in the control group, giving an odds ratio (OR) of 2.33 (95% confidence interval CI=1.24-4.39). No association was observed between the GSTT1 or GSTP1 Ile105Val polymorphism and brain tumor incidence. Polymorphisms in GSTM1, GSTT1, and GSTP1 did not show association with histopathologic type of brain tumor (glioma or meningioma). Analysis of the polymorphisms in the studied genes and smoking status of the brain tumor patients revealed no statistically significant association. The presented data clearly suggest a relation between brain tumor incidence with GSTM1 null genotype but not with GSTT1 or GSTP1 gene variants.

Adult↗
PubMed2005

ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy.

PURPOSE: To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene. METHODS AND MATERIALS: DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED50). RESULTS: A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED50 of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED50 values) of 1.13 (1.05-1.22), which was significantly greater than unity. CONCLUSION: The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy.

Ataxia Telangiectasia Mutated Proteins↗