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1.  Molecular detection of virulence genes as markers in Pseudomonas aeruginosa isolated from urinary tract infections 
Catheter associated urinary tract infections by P. aeruginosa are related to variety of complications. Quorum sensing and related circuitry guard its virulence potential. Though P. aeruginosa accounts for an appreciable amount of virulence factors, this organism is highly unstable phenotypically. Thus, genotyping of clinical isolates of P. aeruginosa is of utmost importance for understanding the epidemiology of infection. This may contribute towards development of immunotherapeutic approaches against this multi drug resistant pathogen. Moreover, no epidemiological study has been reported yet on uroisolates of P. aeruginosa. Thus this study was planned to obtain information regarding presence, distribution and rate of occurrence of quorum sensing and some associated virulence genes at genetic level. The profiling of quorum sensing genes lasI, lasR, rhlI, rhlR and virulence genes like toxA, aprA, rhlAB, plcH, lasB and fliC of twelve strains of P. aeruginosa isolated from patients with UTIs was done by direct PCR. The results showed variable distribution of quorum sensing genes and virulence genes. Their percentage occurrence may be specifically associated with different levels of intrinsic virulence and pathogenicity in urinary tract. Such information can help in identifying these virulence genes as useful diagnostic markers for clinical P. aeruginosa strains isolated from UTIs.
PMCID: PMC4214259  PMID: 25379131
Epidemiology; PCR; Pseudomonas aeruginosa; urinary tract infections; quorum sensing
2.  Genetic and epigenetic analysis of monozygotic twins discordant for testicular cancer 
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.
PMCID: PMC4214260  PMID: 25379132
Testicular germ cell tumor; twin study; epigenetics; familial cancer; array CGH; methylation
3.  Polycyclic aromatic hydrocarbons and risk of gastric cancer in the Shanghai Women’s Health Study 
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.
PMCID: PMC4214261  PMID: 25379133
1-hydroxypyrene glucuronide; polycyclic aromatic hydrocarbons; gastric cancer; China
4.  Genetic variants in anti-Mullerian hormone and anti-Mullerian hormone receptor genes and breast cancer risk in Caucasians and African Americans 
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.
PMCID: PMC4214262  PMID: 25379134
Single nucleotide polymorphism; anti-Mullerian hormone; anti-Mullerian hormone receptors; breast cancer
5.  Determinants of concentrations of Nε-carboxymethyl-lysine and soluble receptor for advanced glycation end products and their associations with risk of pancreatic cancer 
The soluble receptor for advanced glycation end-products (sRAGE) is shown to mitigate pro-inflammatory effects triggered by ligation of RAGE with Nε-carboxymethyl-lysine (CML)-AGE or other ligands. We examined the associations among host, lifestyle, and genetic determinants of CML-AGE or sRAGE and risk of pancreatic cancer in the prospective ATBC Study. We obtained baseline exposure information, data on serological and genetic biomarkers from 141 patients with pancreatic cancer and 141 subcohort controls. Stepwise linear and logistic regression models were used for data analysis. Multiple linear regression analyses showed that CML-AGE concentrations were independently inversely correlated with the minor allele of rs640742 of DDOST, physical activity, alcohol consumption, diastolic blood pressure (BP), and positively correlated with heart rate, serum sRAGE and HDL concentrations (P < 0.05). sRAGE concentrations were independently inversely correlated with the 82Ser allele of rs2070600 of RAGE, age, body mass index, heart rate, and serum HDL; and positively correlated with serum CML-AGE, sucrose consumption, and diastolic BP (P < 0.05). The minor allele of rs1035786 of RAGE was associated with reduced risk of pancreatic cancer (any T compared with CC: multivariate OR = 0.61, 95% CI: 0.38-0.98). We identified host metabolic profile, lifestyle and genetic factors that explained approximately 50% of variability of CML-AGE or sRAGE in Finnish men smokers. The association between RAGE SNPs and pancreatic cancer risk warrants further investigation.
PMCID: PMC4214263  PMID: 25379135
Advanced glycation end-products; metabolic syndrome; inflammation; sRAGE; single nucleotide polymorphism; pancreatic cancer
6.  Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males 
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.
PMCID: PMC4214264  PMID: 25379136
Epidemiology; hepatology; endocrinology; infectious diseases; digestive system; carcinogenesis; genetics
7.  Practical detection of a definitive biomarker panel for Alzheimer’s disease; comparisons between matched plasma and cerebrospinal fluid 
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.
PMCID: PMC4065395  PMID: 24959311
Alzheimer’s disease; biomarker; blood plasma; cerebrospinal fluid
8.  Influence of sex and disease severity on gene expression profiles in individuals with idiopathic pulmonary fibrosis 
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.
PMCID: PMC4065396  PMID: 24959312
Idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; inflammation; steroids; extracellular matrix; gene profiles; chitinase 3-like 1; matrix metalloproteinase 7
9.  TNF-alpha polymorphisms as a potential modifier gene in the cystic fibrosis 
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.
PMCID: PMC4065397  PMID: 24959313
Cystic fibrosis; genotype; phenotype; polymorphism; TNF-α; TNF-alpha; CFTR; lung disease; inflammation; modifier gene
10.  Influence of CHIEF pathway genes on gene expression: a pathway approach to functionality 
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.
PMCID: PMC4065398  PMID: 24959314
Gene expression; colorectal cancer; mTOR; AKT1; STK11; PRKAG2; TSC2; PTEN
11.  Role of IGF-I, IGF-II and IGFBP-3 in lung function of males: the Caerphilly Prospective Study 
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.
PMCID: PMC4065399  PMID: 24959315
Insulin-like growth factors; cohort study; spirometry; lung function
12.  Biomarkers measured in buccal and blood leukocyte DNA as proxies for colon tissue global methylation 
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.
PMCID: PMC4065400  PMID: 24959316
LINE-1 DNA methylation; global DNA methylation; colorectal adenoma; colorectal cancer; correlation
13.  Ethnic characterization of a population of children exposed to high doses of arsenic via drinking water and a possible correlation with metabolic processes 
Because the ratio between the two major arsenic metabolites is related to the adverse health effects of arsenic, numerous studies have been performed to establish a relationship between the ability to metabolically detoxify arsenic and other variables, including exposure level, gender, age and ethnicity. Because ethnicity may play a key role and provide relevant information for heterogeneous populations, we characterized a group of 70 children from rural schools in the Argentinean provinces of Chaco and Santiago del Estero who were exposed to high levels of arsenic. We used genetic markers for maternal, paternal and bi-parental ancestry to achieve this goal. Our results demonstrate that the Amerindian maternal linages are present in 100% of the samples, whereas the Amerindian component transmitted through the paternal line is less than 10%. Informative markers for autosomal ancestry show a predominantly European ancestry, in which 37% of the samples contained between 90 and 99% European ancestry. The native American component ranged from 50 to 80% in 15.7% of the samples, and in all but four samples, the African component was less than 10%. Correlation analysis demonstrated that the ethnicity and the ratio of the excreted arsenic metabolites monomethyl arsenic and dimethyl arsenic are not associated, dismissing a relationship between ethnic origin and differential metabolism.
PMCID: PMC3939002  PMID: 24596592
Arsenic; children; ethnic characterization; ancestral informative markers
14.  Strategies for genetic study of hearing loss in the Brazilian northeastern region 
The overall aim of this study was to estimate the contribution of genetic factors to the etiology of hearing loss (HL) in two counties in the Brazilian northeastern region. A cross-sectional study, based on the key informant approach (KI) was conducted in Queimadas and Gado Bravo counties (Paraíba, Northeast Brazil). The sample consisted of 182 patients with HL. Genetic screening of the most frequent mutations associated with HL was performed for all samples. DFNB1 mutations were the most frequently found in both counties. The c.35delG mutation was detected in homozygosis in seven non-syndromic probands in Queimadas (7/76, 9.2%) and only a single homozygote with this mutation was found in Gado Bravo (1/44, 2.3%). We also detected the del(GJB6-D13S1854) mutation in non-syndromic probands from Gado Bravo (2/44, 4.5%). The c.189C>A (p.TyrY63*) mutation in the CLRN1 gene was detected in homozygosis in 21/23 Usher syndrome patients from Gado Bravo and it was not found in Queimadas. Cases with probable genetic etiology contributed approximately to half of HL probands in each county (54.6% in Gado Bravo and 45.7% in Queimadas). We confirm the importance of DFNB1 locus to non-syndromic HL but we show that the frequency of mutations in the northeastern region differs somewhat from those reported in southeastern Brazil and other populations. In addition, the extremely high frequency of individuals with Usher syndrome with c.189C>A variation in CLRN1 indicates the need for a specific screening of this mutation.
PMCID: PMC3939003  PMID: 24596593
Epidemiology; hearing loss; DFNB1; GB2; Usher syndrome; CLRN1
15.  Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes 
Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.
PMCID: PMC3939004  PMID: 24596594
Type 2 diabetes; statins; thiazide diuretics; whole blood; gene expression; microarray; supervised normalization; surrogate variable analysis; chemokine ligand 14; zinc finger proteins
16.  Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study 
Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.
PMCID: PMC3939005  PMID: 24596595
Circulating levels; Hispanics; genetic polymorphisms; SNPs; genotype-phenotype correlation; vitamin D
17.  Genetic screening for AZF Y chromosome microdeletions in Jordanian azoospermic infertile men 
The azoospermia factor (AZF) region of the human Y chromosome contains essential genes for spermatogenesis. Microdeletions in AZF region has been shown to cause male infertility. The aim of this investigation was to determine the frequency of AZF microdeletions in Jordanian infertile males. A sample of 100 infertile males (36 with azoospermia and 64 with oligozoospermia) was screened for microdeletions using 16 AZF markers and polymerase chain reaction (PCR) technique. Two subjects were found to have microdeletions in AZFc region and one subject has microdeletion that includes AZFb and part of AZFc and AZFa. The three deletions were found in azoospermic subjects (8.3%). No microdeletions were found in oligozoospermic group. The frequency of AZF microdeletions in Jordanian azoospermic infertile males is comparable to that observed in other populations (1%-15%). The results suggest the importance of AZF microdeletion analysis for genetic counseling prior to providing assisted reproduction technique.
PMCID: PMC3939006  PMID: 24596596
AZF; microdeletion; Jordan; infertility; male
19.  Evaluation of the effect of genetic variation on the relationship between statins, cardiovascular disease and cancer 
Statins are a class of medications that are competitive inhibitors of Hydroxy Methyl Glutaryl Co-enzyme A (HMG-CoA) reductase which is the rate-limiting enzyme in the cholesterol bio-synthesis pathway. As a result, statins lower total cholesterol and low density lipoprotein (LDL) cholesterol thus impacting cardiovascular mortality. The downstream effects of statins are not limited to inhibition of cholesterol synthesis alone. Statins have anti-inflammatory effects thought to be important in the setting of acute myocardial infarction which also may be a mechanism involved in anti-carcinogenic properties of statins. Furthermore, statin inhibition of the mevalonate pathway may impact Ras and RhoGTPases that are important in cell proliferation, migration and apoptosis. These alterations may also play a role in the anti-cancer effect of statins. In this article we will review the literature on how genetic variation modifies the effect of statins on the risk of cardiovascular disease and how genetic variation may impact the relationship between statins and the risk of a number of different cancers.
PMCID: PMC3852638  PMID: 24319534
Statins; blood lipids; cancer risk; cardiovascular disease; genetic variation
20.  Fine mapping of variants associated with endometriosis in the WNT4 region on chromosome 1p36 
Genome-wide association studies show strong evidence of association with endometriosis for markers on chromosome 1p36 spanning the potential candidate genes WNT4, CDC42 and LINC00339. WNT4 is involved in development of the uterus, and the expression of CDC42 and LINC00339 are altered in women with endometriosis. We conducted fine mapping to examine the role of coding variants in WNT4 and CDC42 and determine the key SNPs with strongest evidence of association in this region. We identified rare coding variants in WNT4 and CDC42 present only in endometriosis cases. The frequencies were low and cannot account for the common signal associated with increased risk of endometriosis. Genotypes for five common SNPs in the region of chromosome 1p36 show stronger association signals when compared with rs7521902 reported in published genome scans. Of these, three SNPs rs12404660, rs3820282, and rs55938609 were located in DNA sequences with potential functional roles including overlap with transcription factor binding sites for FOXA1, FOXA2, ESR1, and ESR2. Functional studies will be required to identify the gene or genes implicated in endometriosis risk.
PMCID: PMC3852639  PMID: 24319535
Endometriosis; WNT4; CDC42; chromosome 1p36; rare variants; common variants
21.  CYP2E1 and NQO1 genotypes and bladder cancer risk in a Lebanese population 
Urinary bladder cancer incidence in Lebanon ranks among the highest in the world. Cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase1 (NQO1), and N-Acetyltransferase1 (NAT1), are drug-metabolizing enzymes (DMEs) involved in the metabolism of carcinogens, such as arylamines and heterocyclic amines, implicated in bladder cancer. The present study attempts to investigate the role of these DMEs genetic polymorphism in bladder cancer risk among Lebanese men. 54 cases and 106 controls were recruited from two hospitals in Beirut. An interview-based questionnaire was administered to assess suspected environmental and occupational risk factors. PCR-RFLP was performed on blood-based DNA samples to determine DMEs genotypes. Associations between bladder cancer and putative risk factors were measured using adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Results showed CYP2E1 c1/c1, NAT1*14A, and smoking, to be risk factors for bladder cancer. No significant differences in frequency distribution of the NQO1 genotypes were found in cases versus controls. The odds of carrying the CYP2E1 c1/c1 genotype were 4 times higher in cases compared to controls (OR=3.97, 95% CI: 0.48-32.7). The odds of carrying at least one NAT1*14A allele were 14 times higher in cases versus controls (OR=14.4, 95% CI: 1.016-204.9). Our study suggests CYP2E1 c1/c1, NAT1*14A, and smoking, as potential risk factors for bladder cancer in Lebanese. Further studies with larger samples must be conducted to confirm these findings.
PMCID: PMC3852640  PMID: 24319536
Cytochrome P450 CYP2E1; NQO1; N-Acetyltransferase NAT1; bladder cancer; Lebanese
22.  Common sequence variants in chemokine-related genes and risk of breast cancer in post-menopausal women 
Chemokines are small molecules that when secreted by tissues under pathological conditions such as inflammation are believed to be involved in carcinogenesis. Recent reports have found that the genetic variation in chemokine encoding genes are associated with risk of breast cancer. Methods: Using data from a population-based case-control study of 845 invasive breast cases and 807 controls, we genotyped 34 single nucleotide polymorphisms (SNPs) in 8 chemokine candidate genes (CCL3, CCL4, CCL5, CCL20, CCR5, CCR6, CXCL12 and CXCR4). Associations with breast cancer were computed for individual SNPs, groups of SNPs within genes, and in a gene-set analysis. We also performed a meta-analysis of CXCL12 rs1801157 and a haplotype analysis for two SNPs: CXCR4 rs2228014 and CXCL12 rs1801157. Results: We found no significant associations between the risk of breast cancer and any individual SNPs, single genes, or combined gene sets. Some individual variants were marginally associated with some histologic subtypes, but these associations were not significant after adjustment for multiple comparisons. In the meta-analysis of five studies of European ancestry, CXCL12 rs1801157 was marginally associated with breast cancer risk (OR=1.14, 95% CI: 1.00, 1.30). Conclusions: Our findings suggest that genetic variants in the 8 candidate genes coding for chemotactic cytokines have little influence in the risk of breast cancer in postmenopausal women. Additional examination of the relationship between CXCL12 rs1801157 and breast cancer risk is warranted.
PMCID: PMC3852641  PMID: 24319537
Breast cancer; chemokines; genetic variation; epidemiology
23.  LHRH and LHR genotypes and prostate cancer incidence and survival 
Despite their crucial role in initiating steroid-hormone synthesis, the hypothalamic and pituitary hormones (LH, LHRH) and their receptors have received scant attention in genetic studies of hormone-related diseases. This study included 1,170 men diagnosed with prostate cancer (PC) in Los Angeles County between 1999 and 2003. LHRH and LH receptor genotypes were examined for association with PC survival. Additionally, associations with PC incidence were examined by comparing PC cases to control men of similar age and race/ethnicity. The LHR 312 G allele was found to be associated with increased PC mortality (p=0.01). Ten years after diagnosis, 16% of men carrying two copies of the G allele (genotype GG) had died of PC, compared to 11% of those with genotype AG and 9% of those with AA. In a case-control comparison, this same allele was significantly associated with decreased PC risk: OR=0.68 (95% CI: 0.49, 0.93) for genotype GG vs. AA. These results suggest that androgens may play opposing roles in PC initiation and progression, and highlight the need to include these important but overlooked genes in future studies of PC etiology, prognosis, and treatment.
PMCID: PMC3852642  PMID: 24319538
Prostate cancer; LHRH; LHR; genetic polymorphism; survival; association study
24.  Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study 
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR’s contribution to ethnic disparities in breast cancer.
PMCID: PMC3852643  PMID: 24319539
Breast cancer; Hispanic; epidermal growth factor receptor; polymorphisms; tumor phenotype
25.  Intrafamilial spread of hepatitis B virus in Guilan Province-North of Iran 
The aim of the present study was to determine the intrafamilial spread of HBV in the family members of patients with Hepatitis B in Guilan Province, North of Iran. In a descriptive-comparative study, 156 patients with Hepatitis B, 415 family members of the index cases and 599 age and gender matched people as a control group were enrolled. Blood samples were taken from the participants and were checked for HBs Ag, HBC Ab, HBs Ab, and HBV DNA. Totally 44 (10.6%) of family members and only 1 (0.2%) of control group were HBs Ag positive (P=0.0001, OR=70.92). The overall prevalence in members of the original family was 5.3% (1.2% of the mothers, 2.2% of the brothers, 1.9% of the sisters), in sexual partners it was 1.4%, in offsprings it was 2.4% and in other households it was 1.4%. The mean age of HBs Ag positive family members was 35.3 ± 12.9 years old. Among them 27 (61.4%) were female. Only 8 (18.2%) of all HBsAg-positive reported previous HBV vaccination but just one person had the vaccine titer checked. The present survey indicates that there is a significant difference in the prevalence of Hepatitis B in the general population and family members of Hepatitis B patients and this is an evidence for horizontal transmission of HBV in household contacts.
PMCID: PMC3852644  PMID: 24319540
Hepatitis B virus; familial

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