δ-Aminolevulinic Acid Dehydratase Polymorphism and Risk of Brain Tumors in Adults

The enzyme δ -aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme synthesis, can be inhibited by several chemicals, including lead, a potential risk factor for brain tumors, particularly meningioma. In this study we examined whether the ALAD G177C polymorphism in the gene coding for ALAD is associated with risk of intracranial tumors of the brain and nervous system. We use data from a case–control study with 782 incident brain tumor cases and 799 controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to the hospital. Blood samples were drawn and DNA subsequently sent for genotyping for 73% of subjects. ALAD genotype was determined for 94% of these samples (355 glioma, 151 meningioma, 67 acoustic neuroma, and 505 controls). Having one or more copy of the ALAD2 allele was associated with increased risk for meningioma [odds ratio (OR) = 1.6; 95% confidence interval (CI), 1.0–2.6], with the association appearing stronger in males (OR = 3.5; 95% CI, 1.3–9.2) than in females (OR = 1.2; 95% CI, 0.7–2.2). No increased risk associated with the ALAD2 variant was observed for glioma or acoustic neuroma. These findings suggest that the ALAD2 allele may increase genetic susceptibility to meningioma

Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer

Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (P(SNP-trend)) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (P(Region) and P(Pathway)) were assessed by combining individual P(SNP-trend) values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (P(SNP-FDR)/P(SNP-trend) = 0.02/6×10(−6) and P(SNP-FDR)/P(SNP-trend) = 0.04/2×10(−5), respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (P(Region-FDR)/P(Region = )0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (P(Pathway) = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC

Improved Imputation of Common and Uncommon Single Nucleotide Polymorphisms (SNPs) with a New Reference Set

Statistical imputation of genotype data is an important technique for analysis of genome-wide association studies (GWAS). We have built a reference dataset to improve imputation accuracy for studies of individuals of primarily European descent using genotype data from the Hap1, Omni1, and Omni2.5 human SNP arrays (Illumina). Our dataset contains 2.5-3.1 million variants for 930 European, 157 Asian, and 162 African/African-American individuals. Imputation accuracy of European data from Hap660 or OmniExpress array content, measured by the proportion of variants imputed with R^2^>0.8, improved by 34%, 23% and 12% for variants with MAF of 3%, 5% and 10%, respectively, compared to imputation using publicly available data from 1,000 Genomes and International HapMap projects. The improved accuracy with the use of the new dataset could increase the power for GWAS by as much as 8% relative to genotyping all variants. This reference dataset is available to the scientific community through the NCBI dbGaP portal. Future versions will include additional genotype data as well as non-European populations

Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. Materials and Methods We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. Discussion Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, Disinfection By-products, and Risk of Bladder Cancer in Spain

Background: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.Objectives: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case–control study in Spain. Methods: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms. Results: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8–1.8), 1.8 (1.1–2.9), and 1.8 (0.9–3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/– versus GSTT1 null (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7–3.5), 3.4 (1.4–8.2), and 5.9 (1.8–19.0), respectively. Conclusions: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (N02-CP-11015), the Fondo de Investigación Sanitaria (00/0745, G03/174, G03/160, C03/09, and C03/90), and the Instituto de Salud Carlos III, Spanish Health Ministry (CP06/00341

Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB

Genetics and geography of leukocyte telomere length in sub-Saharan Africans

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases

Polymorphisms of an Innate Immune Gene, Toll-Like Receptor 4, and Aggressive Prostate Cancer Risk: A Systematic Review and Meta-Analysis

Background: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews. Methods: We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls. Results: Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity. Conclusions: TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa

Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk

Background: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage