International journal of molecular epidemiology and genetics最新文献

Despite the notion that monozygotic (identical) twins share 100% identical genetic information, genetic differences among monozygotic twin pairs do occur and can be explained by mechanisms occurring during post-zygotic events. Despite such twins being fundamentally "identical", these post-zygotic genetic changes may give rise to phenotypic differences and genetic diseases. Consequently, studies of monozygotic twin pairs discordant for specific genetic diseases represent an important tool for the identification of disease genes. We used array comparative genomic hybridization (aCGH) and methylation arrays to search for genetic and epigenetic differences in blood drawn from four monozygotic twin pairs discordant for testicular germ cell tumors. No consistent differences were identified. A larger twin study would be required to achieve confident discovery of very subtle differences between monozygotic twins discordant for testicular germ cell tumors.

Anti-Mullerian hormone (AMH) regulates ovarian folliculogenesis by signaling via its receptors, and elevated serum AMH levels are associated with an increased risk of breast cancer. No previous studies have examined the effects of genetic variants in AMH-related genes on breast cancer risk. We evaluated the associations of 62 single nucleotide polymorphisms (SNPs) in AMH and its receptor genes, including AMH type 1 receptor (ACVR1) and AMH type 2 receptor (AMHR2), with the risk of breast cancer in the Women's Insights and Shared Experiences (WISE) Study of Caucasians (346 cases and 442 controls), as well as African Americans (149 cases and 246 controls). Of the 62 SNPs evaluated, two showed a nominal significant association (P for trend < 0.05) with breast cancer risk among Caucasians, and another two among African Americans. The age-adjusted additive odds ratios (ORs) (95% confidence interval (95% CI)) of those two SNPs (ACVR1 rs12694937[C] and ACVR1 rs2883605[T]) for the risk of breast cancer among Caucasian women were 2.33 (1.20-4.52) and 0.68 (0.47-0.98), respectively. The age-adjusted additive ORs (95% CI) of those two SNPs (ACVR1 rs1146031[G] and AMHR2 functional SNP rs2002555[G]) for the risk of breast cancer among African American women were 0.63 (0.44-0.92) and 1.67 (1.10-2.53), respectively. However, these SNPs did not show significant associations after correction for multiple testing. Our findings do not provide strong supportive evidence for the contribution of genetic variants in AMH-related genes to the risk of developing breast cancer in either Caucasians or African Americans.

Background: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear.

Goal: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males.

Methods: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction.

Results: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation.

Conclusions: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.

Purpose: Polycyclic aromatic hydrocarbons (PAHs) are byproducts of incomplete combustion of organic materials. Sources include tobacco smoke, charbroiled meat, and air pollution. Indirect evidence suggests that PAHs may be associated with carcinogenesis, but the association with gastric cancer is unclear.

Methods: Using a nested case-control study design, we examined prediagnostic urinary concentrations of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite, in 153 gastric cancer cases and 306 matched controls within the Shanghai Women's Health Study. Conditional logistic regression adjusted for potential risk factors was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: Urinary 1-OHPG concentrations were slightly higher among cases than controls, with medians of 0.29 μmol/mol Cr (interquartile range, 0.16-0.48) and 0.24 μmol/mol Cr (interquartile range, 0.12-0.45), respectively. Increasing concentrations of 1-OHPG appeared to be associated with elevated risk of gastric cancer, but not within the highest category of 1-OHPG (Q4 vs Q1: OR = 1.4; 95% CI = 0.8-2.5).

Conclusions: Our findings suggest that higher concentrations of 1-OHPG are related to gastric cancer risk, but no clear dose-response relationship was observed.

Previous mass spectrometry analysis of cerebrospinal fluid (CSF) has allowed the identification of a panel of molecular markers that are associated with Alzheimer's disease (AD). The panel comprises Amyloid beta, Apolipoprotein E, Fibrinogen alpha chain precursor, Keratin type I cytoskeletal 9, Serum albumin precursor, SPARC-like 1 protein and Tetranectin. Here we report the development and implementation of immunoassays to measure the abundance and diagnostic capacity of these putative biomarkers in matched lumbar CSF and blood plasma samples taken in life from individuals confirmed at post-mortem as suffering from AD (n = 10) and from screened 'cognitively healthy' subjects (n = 18). The inflammatory components of Alzheimer's disease were also investigated. Employment of supervised learning techniques permitted examination of the interrelated expression patterns of the putative biomarkers and identified inflammatory components, resulting in biomarker panels with a diagnostic accuracy of 87.5% and 86.7% for the plasma and CSF datasets respectively. This is extremely important as it offers an ideal high-throughput and relatively inexpensive population screening approach. It appears possible to determine the presence or absence of AD based on our biomarker panel and it seems likely that a cheap and rapid blood test for AD is feasible.

Epidemiological studies suggest sex-specific trends in the prevalence and mortality of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that are distinct for each disease. While the expression of numerous immune and extracellular matrix (ECM) genes in the lung have been well characterized in these diseases, associations elucidating their sex-specific expression patterns by disease type and severity, and the evaluation of hormone-related genes, have not been well studied. Here we performed targeted transcriptional profiling of 48 genes was performed on lung tissue samples from males and females with mild or medium severity IPF or COPD. The genes assessed included those involved in inflammation, ECM remodeling and hormonal processes. Data for 36 lung tissue samples were obtained that were stratified by disease and sex. Expression levels revealed a subset of genes which show differential expression among sexes, disease type, and disease severity. The most significant observations were the increased expression primarily of ECM genes in medium severity IPF (CATHK, COL1A1, COL3, MMP1, MMP7, IL-1RN) compared to mild IPF and COPD. Two genes, CH3L1 and MMP7 showed a tendency of interaction between sex and disease in IPF severity. Surprisingly, there were no significant differences in any of the sex genes measured between the IPF groups; however, ESR1 and AR expression levels were higher and lower, respectively, compared to COPD samples. Overall, this work highlights two genes, CH3L1 and MMP7, that may contribute to gender trends observed for IPF and COPD and are potential targets for future research.

Modifier genes, as the TNF-α gene, can modulate the cystic fibrosis (CF) severity. Thus, -238G>A and -308G>A polymorphisms of TNF-α gene were analyzed as modifiers of CF. In this context, the present study enrolled 49 CF patients (diagnosis performed by sweat test and complete CFTR screening). The -238G>A polymorphism analysis was performed by ARMS-PCR, and -308G>A, by PCR-RFLP. In our data, the -238G>A polymorphism was not associated with clinical variability. The AA genotype for -308G>A polymorphism was a risk factor for early gastrointestinal symptoms (OR=5.98, 95%CI=1.06-49.68) and protection for the first Pseudomonas aeruginosa (OR=0.05, 95%CI=0.0003-0.007). For the first P. aeruginosa, GA genotype was a risk factor (OR=10.2, 95%CI=1.86-84.09); for the same genotype, the diagnosis was made in minor time than the AA genotype (p=0.031). Considering the -308G>A polymorphism alleles, the G allele was a risk factor for early pulmonary symptoms (OR=3.81, 95%CI=1.13-12.97) and P. aeruginosa (OR=66.77, 95%CI=15.18-482.7); however, the same allele showed better transcutaneous oxygen saturation (OR=9.24, 95%CI=1.53-206.1). The A allele was a protective factor for early pulmonary symptoms (OR=12.26, 95%CI=0.08-0.89) and P. aeruginosa (OR=12.15, 95%CI=0002-0007), however, the same allele was a risk factor for worst transcutaneous oxygen saturation (OR=7.01, 95%CI=1.14-157.4). As conclusion, the -308G>A polymorphism of the TNF-α gene was associated with the CF severity.

Insulin-like growth factors are peptide hormones that have an endocrine role in the development, growth and repair of human tissues including the respiratory tract. To date, only one population study exists which found positive cross-sectional associations with IGF-I and higher lung volumes. We hypothesised that higher IGF-I, IGF-II, IGFBP-3 and IGF molar ratio would be associated with better cross-sectional and longitudinal lung function. We examined cross-sectional (n=843) and prospective associations (n=717) between IGF-I, IGF-II, IGFBP-3 and IGF molar ratio with lung function in the Caerphilly Prospective Study (CaPS) from blood samples obtained around 1986, with spirometry (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)) performed in the same year and around 2003. Higher IGF molar ratio was associated with improved FEV1/FEV ratio cross-sectionally in both simple (0.007, 95% CI 0.001-0.013, P=0.02) and fully adjusted (0.001, 95% CI 0.001-0.012, P=0.03) models. With the exception of IGFBP-3 and FEV1/FVC in the simple model (0.009, 95% CI 0.001-0.018, P=0.04) all prospective associations between IGF and spirometric measures were consistent with chance. In this study of men, higher IGF molar ratio was associated with improved cross-sectional lung function, although these findings were not replicated prospectively. Further work is required with repeat IGF sampling during follow up to see if IGF levels play any role in predicting future lung function through the life course.

Background: Candidate pathway approaches in disease association studies often utilize a tagSNP approach to capture genetic variation. In this paper we assess gene expression patterns with SNPs in genes in the CHIEF pathway to help determine their potential functionality.

Methods: Quantitative real-time RT-PCR was run to determine gene expression of 13 genes in normal colon tissue samples from 82 individuals. TagSNP genotype data were obtained from a GoldenGate Illumina multiplex bead array platform. Age, sex, and genetic ancestry adjusted general linear models were used to estimate beta coefficients and p values.

Results: Genetic variation in mTOR (1 SNP), NFKB1 (4 SNPs), PRKAG2 (3 SNPs), and TSC2 (1 SNP) significantly influenced their expression. After adjustment for multiple comparisons several associations between pathway genes and expression of other genes were significant. These included AKT1 rs1130214 associated with expression of PDK1; NFκB1 rs13117745 and rs4648110 with STK11 expression; PRKAG2 rs6965771 with expression of NFκB1, PIK3CA, and RPS6KB2; RPS6KB1 rs80711475 with STK11 expression; STK11 rs741765 with PIK3CA and PRKAG2 expression; and TSC2 rs3087631 with AKT1, IkBκB, NFκB1, PDK1, PIK3CA, PRKAG2, and PTEN expression. The higher levels of differential expression were noted for TSC2 rs3087631 (percent difference ranges from 108% to 198% across genes). Many of these SNPs and genes also were associated with colon and rectal cancer risk.

Conclusions: Our results suggest that pathway genes may regulate expression of other genes in the pathway. The convergence of these genes in several biological pathways involved in cancer further supports their importance to the carcinogenic process.

There is increasing interest in clarifying the role of global DNA methylation levels in colorectal cancer (CRC) etiology. Most commonly, in epidemiologic studies, methylation is measured in DNA derived from blood leukocytes as a proxy measure of methylation changes in colon tissue. However, little is known about the correlations between global methylation levels in DNA derived from colon tissue and more accessible tissues such as blood or buccal cells. This cross-sectional study utilized DNA samples from a screening colonoscopy population to determine to what extent LINE-1 methylation levels (as a proxy for genome-wide methylation) in non-target tissue (e.g., blood, buccal cells) reflected methylation patterns of colon mucosal tissue directly at risk of developing CRC. The strongest Pearson correlation was observed between LINE-1 methylation levels in buccal and blood leukocyte DNA (r = 0.50; N = 67), with weaker correlations for comparisons between blood and colon tissue (r = 0.36; N = 280), and buccal and colon tissue (r = 0.27; N = 72). These findings of weak/moderate correlations have important implications for interpreting and planning future investigations of epigenetic markers and CRC risk.