Abstract: BACKGROUND: Blood donors exhibiting a weak D or DEL phenotypical expression may be mistyped D- by standard serology hence permitting incompatible transfusion to D- recipients. Molecular methods may overcome these technical limits. Our aim was to estimate the frequency of RHD alleles among the apparently D- Polish donor population and to characterize its molecular background. STUDY DESIGN AND METHODS: Plasma pools collected from 31,200 consecutive Polish donors typed as D- were tested by real-time polymerase chain reaction (PCR) for the presence of RHD-specific markers located in Intron 4 and Exons 7 and 10. RHD+ individuals were characterized by PCR or cDNA sequencing and serology. RESULTS: Plasma cross-pool strategy revealed 63 RHD+ donors harboring RHD*01N.03 (n = 17), RHD*15 (n = 12), RHD*11 (n = 7), RHD*DEL8 (n = 3), RHD*01W.2 (n = 3), RHD-CE(10) (n = 3), RHD*01W.3, RHD*01W.9, RHD*01N.05, RHD*01N.07, RHD*01N.23, and RHD(IVS1-29G>C) and two novel alleles, RHD*(767C>G) (n = 3) and RHD*(1029C>A). Among 47 cases available for serology, 27 were shown to express the D antigen CONCLUSION: 1) Plasma cross-pool strategy is a reliable and cost-effective tool for RHD screening. 2) Only 0.2% of D- Polish donors carry some fragments of the RHD gene; all of them were C or E+. 3) Almost 60% of the detected RHD alleles may be potentially immunogenic when transfused to a D- recipient.
Abstract: Carcinoma of the gallbladder (GBC) is the most common biliary tree cancer in the world. Beside gallstones, no specific risk factors for GBC are currently established. Several published studies have identified various prognostic gene expression markers in GBC.
Abstract: Holoprosencephaly (HPE) is the most common structural anomaly of the human forebrain. Various genetic and teratogenic causes have been implicated in its pathogenesis. A recent report in mice described Noggin (NOG) as a candidate gene involved in the etiogenesis of microform HPE. Here, we present for the first time genetic analysis of a large HPE cohort for sequence variations in NOG. On the basis of our study, we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human HPE.
Abstract: MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444) and cancer risk by using a two-sided meta-analytic approach.
Abstract: Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.
Abstract: Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes.
Abstract: Holprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by varying degrees of abnormal union of the cerebral hemispheres. These defects are typically co-associated with midline craniofacial anomalies. The combination of forebrain and craniofacial defects that comprise HPE can present along a broad and variable phenotypic spectrum. Both the SHH and NODAL signaling pathways play important roles in the pathogenesis of this disorder. Disruption of these pathways by chromosomal rearrangements, mutations in pathway-related genes and/or biochemical alterations are proposed to contribute to HPE in a large number of patients. Additional factors that are not yet fully delineated are also very likely to be involved in the pathogenesis and phenotypic heterogeneity of the disorder. Genetic loss of GAS1, a cell membrane receptor and positive regulator of SHH, has been demonstrated to contribute to the HPE phenotypic spectrum in animal models. We have evaluated the coding and flanking sequence of GAS1 in 394 patients who have clinical findings within the HPE phenotypic spectrum, and now report five novel missense sequence variants among five unrelated HPE probands. Finally, we tested the effect of these variants (as well as previously reported GAS1 variants) on the ability of GAS1 to bind to SHH. Here, we demonstrate that sequence variants in GAS1 can impair its physical interaction with SHH, suggesting a decrease in the SHH downstream signaling cascade as a pathogenic mechanism of disease.
Abstract: This study aimed to perform a meta-analysis to assess the association of survivin -31 G/C promoter polymorphism and cancer risk. Thirteen case-control studies identified through PubMed and published between 2007 and 2011 with a total of 3329 cancer cases and 3979 controls were included in this meta-analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the pooled analysis showed that survivin -31C allele was associated with 1.27 fold increased risk of cancer compared with the -31G allele (95% CIÂ =Â 1.091-1.479; random model). Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that survivin -31G/C polymorphism was not associated with risk of gastric cancer [ORÂ =Â 2.879; 95% CIÂ =Â 0.553-15.004) for CC vs.GG] and esophageal cancer [ORÂ =Â 1.352; 95% CIÂ =Â 0.494-3.699) for CC vs.GG]. Stratification on the basis of ethnicity showed that the risk due to -31C allele was significant only in Asian population [ORÂ =Â 1.894; 95% CIÂ =Â 1.206-2.974 for CC vs.GG]. The present meta-analysis suggests an important role of survivin -31 G/C polymorphism with cancer risk especially in Asian population. However, further studies with larger sample size are required to draw more comprehensive conclusions and provide more precise evidence in individual cancers.
Abstract: Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population.
Abstract: Caspase-8 (CASP8) is a key controller of apoptosis, and its deregulation plays an important role in carcinogenesis. To evaluate the role of CASP8 polymorphisms in gallbladder cancer (GBC), we examined the risk associated with three single-nucleotide polymorphisms (SNPs) in a case-control study in North Indian population. Genotypes and haplotypes of the CASP8 polymorphisms (-652 6N ins/del; rs3834129, Ex13 + 51G > C; rs1045485 and IVS12-19 G > A; rs3769818) were determined for 230 GBC patients and 230 cancer-free controls randomly selected from the population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in multivariate logistic regression analysis for the association of individual SNPs and haplotypes with GBC. Carriers for the "del" allele of rs3834129 SNP were associated with a 0.60-fold decreased risk for GBC (95% CI = 0.42-0.88; P(trend) = 0.005). In the combined analysis of the three CASP8 variants, we found that the individuals with the diplotypes carrying two copies of the common CASP8 del-G-G haplotype had 0.35-fold reduced risk (95% CI = 0.14-0.85) when compared with the diplotype containing 0-1 copy. The false-positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP < 0.5). The molecular modeling results of rs1045485 polymorphism indicated that the overall configuration of both wild-type and polymorphic CASP8 protein were similar, with negligible deviation at the site of the polymorphism itself. In summary, low penetrance variants in CASP8 gene may alter the susceptibility toward GBC.
Abstract: ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms in ABCG8 gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role of ABCG8 D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response.
Abstract: Carcinoma of gallbladder (GBC) is a relatively rare but highly fatal disease. The DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) -579 G>T promoter polymorphism (rs1569686) influences gene function and has been associated with various malignancies. Present population-based case-control study was undertaken to examine the potential association of DNMT3B -579 G>T variation with GBC in North Indian population.
Abstract: Gall bladder cancer (GBC) is a relatively rare but highly fatal disease, particularly in North India. The angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism influences serum angiotensin II action, which has been associated with various malignancies. This population-based case-control study was undertaken to examine the potential association of ACE I/D variation with GBC in a North Indian population. Genotypes and allelic frequencies of the ACE I/D polymorphism (rs4646994) were determined for 233 GBC patients and 260 cancer-free controls randomly selected from the population using polymerase chain reaction. Odds ratio (OR) and 95% confidence interval were calculated in multivariate logistic regression analysis for the association of ACE polymorphism with GBC. The ACE I/D polymorphism was found to be nonsignificantly associated with an overall increased risk of GBC (OR = 1.04 and 1.38 for I/D and D/D genotypes, respectively; p(trend) = 0.375). The increased risk was predominant significantly in female cohort and nonsignificantly in GBC patients with gallstone status (OR = 1.63; p = 0.039 and OR = 1.37; p = 0.187, respectively). In summary, ACE I/D polymorphism may alter the susceptibility to GBC, especially in women.
Abstract: Toll-like receptors (TLRs) are evolutionarily conserved cell surface receptors of innate immune system. Various polymorphisms in TLR genes have been identified and associated with susceptibility toward various malignancies such as prostate cancer, gastric cancer and colorectal cancer. The present study was undertaken to examine the potential association of two polymorphisms in TLR2 and TLR4 genes with gallbladder cancer (GBC) susceptibility.
Abstract: MicroRNAs (miRNAs) are small, non-coding RNA molecules that function as negative regulators of gene expression. Common genetic variants (single nucleotide polymorphisms, SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences. Present case-control study evaluated the potential association of three SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs with gallbladder cancer (GBC) risk in 230 GBC cases and 230 controls in a North Indian population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of individual SNPs and their interactions with GBC. A non-significant increased risk was observed between carriers of variant genotypes of rs2910164, rs11614913 and rs3746444 (ORs=1.3, 1.3 and 1.1, respectively). This increased risk was more profound in GBC patients with gallstones (ORs=1.4, 1.6 and 1.1, respectively). To further evaluate the cumulative effects of the variant allele, we did a combined unfavorable genotype analysis, which showed a borderline statistical significance. In comparison with the low-risk group (0-2 variant alleles), the high-risk group (>2 variant alleles) had a 1.7-fold (95% CI=1.0-2.8) increased risk for GBC (P(trend)=0.056). These findings suggest, for the first time, that common miRNA variants may not contribute to GBC susceptibility in North Indian population.
Abstract: The excretion of cholesterol from the liver is regulated by the ATP-binding cassette transporter ABCG8. A common genetic polymorphism D19H of ABCG8 might be related to the genetic predisposition of gallstone disease, which is causatively related to supersaturation of cholesterol in bile. We aimed to examine the role of the ABCG8 D19H (rs11887534) polymorphism in susceptibility to gallstone disease in the northern Indian population.
Abstract: DNA damage by endogenous or exogenous source of reactive oxygen species (ROS) plays an important role in induction and progression of various cancers. Physiologically, gallbladder is likely to be exposed to various ROS which leads to extensive DNA damage. Cells overcome the DNA damage by repair mechanisms. Genetic variants of OGG1 and XRCC1, important enzymes participating in base excision repair pathway, may confer interindividual variations in susceptibility to gallbladder cancer (GBC). This study was aimed to examine the role of OGG1 Ser326Cys (rs1052133) and XRCC1 Arg194Trp (C > T) (rs25487) and Arg399Gln (G > A) (rs1799782) polymorphisms in GBC susceptibility.
Abstract: Cyclooxygenase-2 (PTGS2) overexpression has been implicated in various cancers. We aimed to evaluate the role of PTGS2 -1195G>A [reference sequence (rs) 689466], -765G>C (rs20417) and +8473T>C (rs5275) polymorphisms in conferring interindividual susceptibility to gallbladder cancer.
