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The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, this study was comprised of all 3619 cancer cases ascertained through 2007 compared with a sample of 2296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O(6)-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk [per minor allele odds ratio (OR) 1.30, 95% confidence interval (CI) 1.19-1.43 and P-value: 4.1 × 10(-8)]. The association between rs2296675 and cancer risk was stronger among those aged ≤54 years old than those who were ≥55 years at baseline (P-for-(interaction) = 0.021). OR were in the direction of increased risk for all 15 categories of malignancies studied (P < 0.0001), ranging from 1.22 (P = 0.42) for ovarian cancer to 2.01 (P = 0.008) for urinary tract cancers; the smallest P-value was for breast cancer (OR 1.45, P = 0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association.
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Reparo do DNA/genética , Neoplasias/genética , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Maryland/epidemiologia , Neoplasias/epidemiologia , Vigilância da População , Fatores de RiscoRESUMO
INTRODUCTION: A personal history of basal cell carcinoma (BCC) is associated with increased risk of other malignancies, but the reason is unknown. The hedgehog pathway is critical to the etiology of BCC, and is also believed to contribute to susceptibility to other cancers. This study tested the hypothesis that hedgehog pathway and pathway-related gene variants contribute to the increased risk of subsequent cancers among those with a history of BCC. METHODS: The study was nested within the ongoing CLUE II cohort study, established in 1989 in Washington County, Maryland, USA. The study consisted of a cancer-free control group (n=2296) compared to three different groups of cancer cases ascertained through 2007, those diagnosed with: (1) Other (non-BCC) cancer only (n=2349); (2) BCC only (n=534); and (3) BCC plus other cancer (n=446). The frequencies of variant alleles were compared among these four groups for 20 single nucleotide polymorphisms (SNPs) in 6 hedgehog pathway genes (SHH, IHH, PTCH2, SMO, GLI1, SUFU), and also 22 SNPs in VDR and 8 SNPs in FAS, which have cross-talk with the hedgehog pathway. RESULTS: Comparing those with both BCC and other cancer versus those with no cancer, no significant associations were observed for any of the hedgehog pathway SNPs, or for the FAS SNPs. One VDR SNP was nominally significantly associated with the BCC cancer-prone phenotype, rs11574085 [per minor allele odds ratio (OR) 1.38, 95% confidence interval (CI) 1.05-1.82; p-value=0.02]. CONCLUSION: The hedgehog pathway gene SNPs studied, along with the VDR and FAS SNPs studied, are not strongly associated with the BCC cancer-prone phenotype.
Assuntos
Carcinoma Basocelular/genética , Proteínas Hedgehog/genética , Mutação/genética , Segunda Neoplasia Primária/genética , Receptores de Calcitriol/genética , Neoplasias Cutâneas/genética , Receptor fas/genética , Adulto , Carcinoma Basocelular/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Maryland/epidemiologia , Registro Médico Coordenado , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Fumar/epidemiologiaRESUMO
For unknown reasons, non-melanoma skin cancer (NMSC) is associated with increased risk of other malignancies. Focusing solely on DNA repair or DNA repair-related genes, this study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. From the parent CLUE II cohort study, established in 1989 in Washington County, MD, the study consisted of a cancer-free control group (n 5 2296) compared with three mutually exclusive groups of cancer cases ascertained through 2007: (i) Other (non-NMSC) cancer only (n 5 2349); (ii) NMSC only (n 5 694) and (iii) NMSC plus other cancer (n 5 577). The frequency of minor alleles in 759 DNA repair gene single nucleotide polymorphisms (SNPs) was compared in these four groups. Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had allelic trend P-values <0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a non-synonymous coding SNP (rs2888805) [per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16-1.70; P-value 5 0.0006] and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). None of the associations had a P-value <6.6310(-5), the threshold for statistical significance after correcting for multiple comparisons. The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.
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Reparo do DNA/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Timina DNA Glicosilase/genética , Adulto , Idoso , Biomarcadores Tumorais , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Nucleotide excision repair (NER) is responsible for protecting DNA in skin cells against UVR-induced damage. Using a candidate pathway approach, a matched case-control study nested within a prospective, community-based cohort was carried out to test the hypothesis that single-nucleotide polymorphisms (SNPs) in NER genes are associated with susceptibility to non-melanoma skin cancer (NMSC). Histologically confirmed cases of NMSC (n=900) were matched to controls (n=900) on the basis of age, gender, and skin type. Associations were measured between NMSC and 221 SNPs in 26 NER genes. Using the additive model, two tightly linked functional SNPs in ERCC6 were significantly associated with increased risk of NMSC: rs2228527 (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.20-2.05) and rs2228529 (OR 1.57, 95% CI 1.20-2.05). These associations were confined to basal cell carcinoma (BCC) of the skin (rs2228529, OR 1.78, 95% CI 1.30-2.44; rs2228527, OR 1.78, 95% CI 1.31-2.43). These hypothesis-generating findings suggest that functional variants in ERCC6 may be associated with an increased risk of NMSC that may be specific to BCC.
Assuntos
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Reparo do DNA , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Adulto , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteínas de Ligação a Poli-ADP-Ribose , Estudos ProspectivosRESUMO
OBJECTIVE: The Grenada Heart Project aims to study the clinical, biological, and psychosocial determinants of the cardiovascular health in Grenada in order to develop and implement a nationwide cardiovascular health promotion program. METHODS: We recruited 2,827 adults randomly selected from the national electronic voter list. The main outcome measures were self-reported cardiovascular disease and behavioral risk factors, anthropometric measures, blood pressure, point-of-care testing for glucose and lipids, and ankle-brachial index. Risk factors were also compared with the U.S. National Health and Nutritional Survey data. RESULTS: Prevalence of cardiovascular disease risk factors were: overweight and obesity-57.7% of the population, physical inactivity-23.4%, diabetes-13.3%, hypertension-29.7%, hypercholesterolemia-8.6%, and smoking-7%. Subjects who were physically active had a significantly lower 10-year Framingham risk score (p<0.001). Compared with the U.S. National Health and Nutrition Survey data, Grenadian women had higher rates of adiposity, diabetes, hypertension, and elevated low-density lipoprotein cholesterol, whereas Grenadian men had a higher rate of diabetes, a similar rate of hypertension, and lower rates of the other risk factors. Prevalence of peripheral arterial disease was 7.6%; stroke and coronary heart disease were equally prevalent at â¼2%. CONCLUSIONS: This randomly selected adult sample in Grenada reveals prevalence rates of obesity, hypertension, and diabetes significantly exceeding those seen in the United States. The contrasting, paradoxically low levels of prevalent cardiovascular disease support the concept that Grenada is experiencing an obesity-related "risk transition." These data form the basis for the implementation of a pilot intervention program based on the Institute of Medicine recommendations and may serve as a model for other low- and middle-income countries.
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OBJECTIVE: To compare the associations of nontraditional (fructosamine, glycated albumin, 1,5-anhydroglucitol [1,5-AG]) and standard (fasting glucose, HbA(1c)) glycemic markers with common microvascular conditions associated with diabetes mellitus. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study of 1,600 participants (227 with a history of diabetes and 1,323 without) from the Atherosclerosis Risk in Communities (ARIC) Study, a community-based population. We conducted logistic regression analyses of the associations of diabetes-specific tertiles of fructosamine, glycated albumin, 1/(1,5-AG), fasting glucose, and HbA(1c) with prevalence of chronic kidney disease, albuminuria, and retinopathy after adjustment for demographic, clinical, and lifestyle variables. RESULTS: We observed significant positive trends in the associations of each marker with albuminuria and retinopathy, even after accounting for demographic, clinical, and lifestyle factors (all P trends <0.05). The associations with chronic kidney disease were similar in direction but were only significant for higher glycated albumin (P trend = 0.005), fructosamine (P trend = 0.003), and HbA(1c) (P trend = 0.005) values. After further adjustment for HbA(1c), glycated albumin and fructosamine remained significantly or borderline significantly associated with the microvascular outcomes. CONCLUSIONS: In cross-sectional analyses, two serum markers of glycemia-glycated albumin and fructosamine-are as, or more strongly, associated with microvascular conditions as HbA(1c). These markers may be useful in settings where whole blood is not available. Whether they might complement or outperform HbA(1c) in terms of long-term predictive value requires further investigation.
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Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Estudos Transversais , Feminino , Frutosamina/sangue , Hemoglobinas Glicadas/metabolismo , Produtos Finais de Glicação Avançada , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Albumina Sérica/metabolismo , Albumina Sérica GlicadaRESUMO
The cholesterol-lowering effects of plant sterols in a format suitable for use in China have not previously been investigated. We conducted the study to quantify in adult Chinese the effects on blood lipid concentrations of a plant sterol-enriched milk tea powder. The study was a double-blind, randomised trial in which 309 participants were randomised to receive daily 2.3 or 1.5 g plant sterol supplementation or placebo for 5 weeks. The milk tea was consumed with the two fattiest meals of the day with half the assigned daily dose taken on each occasion. Fasting venous blood samples were collected before commencement and upon completion of randomised treatment. The mean age of study participants was 44 years, 62% were female and 62% had a history of hypercholesterolaemia. Baseline mean total cholesterol was 5.5 mmol/l and LDL-cholesterol was 3.2 mmol/l. Compared with placebo, the 2.3 g/d plant sterol dose reduced total cholesterol by 0.25 (95% CI 0.07, 0.43) mmol/l (P = 0.01) and the 1.5 g/d dose by 0.23 (95% CI 0.06, 0.41) mmol/l (P = 0.01). For LDL-cholesterol the corresponding reductions were 0.17 (95% CI 0.00, 0.35) mmol/l (P = 0.06) and 0.15 (95% CI -0.02, 0.32) mmol/l (P = 0.08). For neither outcome was there evidence of differences between the effects of the two doses (both P values >0.4). In conclusion, the consumption of plant sterol-enriched milk tea decreased cholesterol concentrations although to a lesser extent than was anticipated. The reason for reduced efficacy is unclear but may be attributable to the novel food format used or the Chinese population studied.