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Tagging Single Nucleotide Polymorphisms in the IRF1 and IRF8 Genes and Tuberculosis Susceptibility  [PDF]
Shiping Ding, Tao Jiang, Jianqin He, Beibei Qin, Shuangyan Lin, Lanjuan Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042104
Abstract: Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35~2.27, P = 0.002), 4.75 (95% CI 2.16~10.43, P = 0.002) and 3.39 (95% CI 1.60~7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.
Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs
Patrick R Benusiglio, Fabienne Lesueur, Craig Luccarini, Joan McIntosh, Robert N Luben, Paula Smith, Alison Dunning, Douglas F Easton, Bruce AJ Ponder, Paul D Pharoah
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-81
Abstract: We used a genetic association study design to determine if common genetic variation (frequency ≥ 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman? in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional.HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t>g), rs4245443 (IVS7 g>a), rs2513511 (IVS16 a>g), rs2155220 (3'down c>t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a>g) and rs11600501 (IVS10 c>t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population.We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.Breast and ovarian cancer are two of the most common causes of cancer in women in the United Kingdom (Office for National Statistics). Together, they account for about a third of all new cancer cases and a quarter of cancer deaths.
Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma  [PDF]
Linda E. Kelemen,Qinggang Wang,Robert A. Vierkant,Julie M. Cunningham,Ernest K. Amankwah,Thomas A. Sellers
Frontiers in Genetics , 2012, DOI: 10.3389/fgene.2012.00033
Abstract: ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case–control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6–0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1–2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a null distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the null hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.
Characterization of Single Nucleotide Polymorphisms in 13 Members of the ABC Drug Transporter Genes in Three Different Populations
Zihua Wang, Samuel S. Chong and Caroline G.L. Lee
The Open Pharmacology Journal , 2007, DOI: 10.2174/1874143600701010001]
Abstract: To evaluate the usefulness of the two public databases, HapMap and Perlegen, in facilitating studies associating polymorphisms in these genes with drug response, we examined 111 single-nucleotide-polymorphisms from 13 ABCtransporter genes in Singaporean-Chinese, European-Americans and African-Americans. We found that genotype data from the HapMap/Perlegen databases are generally transferable to different sampling of the same population and to similar populations residing elsewhere. However, not all ABC-transporter family genes are amenable to SNP-tagging due to the low tagging-efficiency of low-LD genes resulting in negligible cost-savings. Hence, alternative approaches may have to be explored for low-LD ABC genes.
Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer
Kristin L White, Robert A Vierkant, Catherine M Phelan, Brooke L Fridley, Stephanie Anderson, Keith L Knutson, Joellen M Schildkraut, Julie M Cunningham, Linda E Kelemen, V Shane Pankratz, David N Rider, Mark Liebow, Lynn C Hartmann, Thomas A Sellers, Ellen L Goode
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-170
Abstract: We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in NFKBIA and NFKBIB (the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.The minor allele for one synonymous SNP in NFKBIA, rs1957106, was associated with decreased risk (p = 0.03).Considering the number of single-SNP tests performed and null gene-level results, we conclude that NFKBIA and NFKBIB are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.Despite estimates of more than 21,000 newly diagnosed cases of ovarian cancer and 15,000 related deaths each year in the United States [1], the etiology of ovarian cancer remains poorly understood. Known risk factors include increased risk with family history and use of fertility drugs, and decreased risk with oral contraceptive use, parity, and long duration of breast feeding [2]. Rare, high-penetrant mutations in BRCA1 and BRCA2 account for approximately 40% of familial risk, leaving most inherited risk unexplained [3,4]. The search for additional loci includes thoughtful selection of candidate genes in key biological pathways, an approach which has been successful in identifying new risk alleles for a variety of cancers [5].Inflammation has been implicated in ovarian carcinogenesis because of its role in ovulation and post-ovulatory repair. During ovulation the ovarian epithelial surface is damaged, requiring a repair process involving the recruitment of leukocytes and inflammatory cytokines, release of nitrous oxide, DNA repair, and tissue restructuring [6-9]. Over time, this continuous repair of the ovarian epithelial tissue increases the likelihood of errors during replicatio
Inherited Variants in Regulatory T Cell Genes and Outcome of Ovarian Cancer  [PDF]
Ellen L. Goode, Melissa DeRycke, Kimberly R. Kalli, Ann L. Oberg, Julie M. Cunningham, Matthew J. Maurer, Brooke L. Fridley, Sebastian M. Armasu, Daniel J. Serie, Priya Ramar, Krista Goergen, Robert A. Vierkant, David N. Rider, Hugues Sicotte, Chen Wang, Boris Winterhoff, Catherine M. Phelan, Joellen M. Schildkraut, Rachel P. Weber, Ed Iversen, Andrew Berchuck, Rebecca Sutphen, Michael J. Birrer, Shalaka Hampras, Leah Preus, Simon A. Gayther, Susan J. Ramus, Nicolas Wentzensen, Hannah P. Yang, Montserrat Garcia-Closas, Honglin Song, Jonathan Tyrer, Paul P. D. Pharoah, Gottfried Konecny, Thomas A. Sellers, Roberta B. Ness, Lara E. Sucheston, Kunle Odunsi, Lynn C. Hartmann, Kirsten B. Moysich, Keith L. Knutson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053903
Abstract: Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10?5), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10?4, and rs3753348, p = 9.0×10?4, respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10?4). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10?4) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.
Polymorphisms in the Vitamin D Receptor (VDR) and the Risk of Ovarian Cancer: A Meta-Analysis  [PDF]
Yanling Liu, Chenglin Li, Peizhan Chen, Xiaoguang Li, Mian Li, He Guo, Jingquan Li, Ruiai Chu, Hui Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066716
Abstract: The vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Various epidemiological studies have investigated the associations of VDR gene polymorphisms with ovarian cancer; however, the results have been inconclusive. In the current study, we evaluated, in a meta-analysis, the association of five common single nucleotide polymorphisms (SNPs) in the VDR gene (ApaI, BsmI, Cdx-2, FokI, and TaqI) with the risk of ovarian cancer. Six eligible studies, with a total of 4,107 cases and 6,661 controls, which evaluated the association of these variants and ovarian cancer risk, were identified from the MEDLINE and PubMed databases. The meta-analysis indicated that FokI was associated with an increased ovarian cancer risk, with a pooled odds ratio (OR) of 1.10 [95% confidence intervals (95% CI) = 1.00–1.20] for CT heterozygotes and 1.16 (95% CI = 1.02–1.30) for TT homozygotes relative to common CC carriers. Carriers of the T allele (also known as the f allele) showed an 11% (pooled OR = 1.11, 95% CI = 1.02–1.21; TT/CT vs. CC) increased risk of ovarian cancer relative to CC carriers. For FokI, no significant heterogeneity between the studies was found (I2 = 0%, P = 0.62 for the Q test). There was no statistically significant association between the other four variants (ApaI, BsmI, Cdx-2 and TaqI) and risk of ovarian cancer. These data indicate that the polymorphism FokI on the VDR is a susceptibility factor for ovarian cancer. Nevertheless, more studies are warranted to elucidate the underlying mechanisms of the VDR in development of ovarian cancer.
Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)
Federico Canzian, Rudolf Kaaks, David G Cox, Katherine D Henderson, Brian E Henderson, Christine Berg, Sheila Bingham, Heiner Boeing, Julie Buring, Eugenia E Calle, Stephen Chanock, Francoise Clavel-Chapelon, Laure Dossus, Heather Feigelson, Christopher A Haiman, Susan E Hankinson, Robert Hoover, David J Hunter, Claudine Isaacs, Per Lenner, Eiliv Lund, Kim Overvad, Domenico Palli, Celeste Pearce, Jose R Quiros, Elio Riboli, Daniel O Stram, Gilles Thomas, Michael J Thun, Dimitrios Trichopoulos, Carla H van Gils, Regina G Ziegler
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-257
Abstract: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects.Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels.Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.Exposure to steroid hormones (estrogens and androgens) is a risk factor for breast cancer. Increased exposure to estrogens, for instance by early menarche, late menopause, low parity and post-menopausal obesity, contributes to increased breast cancer risk (reviewed in ref. [1]). High circulating levels of estrogens are associated with elevated breast cancer risk [2,3].The primary stimulus for production of estrogen and other ovarian steroid hormones is the release of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the anterior pituitary. These are released when gonadotropin-releasing hormone 1 (GNRH1), from the hypothalamus, binds to the gonadotropin-releasing hormone receptor (GNRHR) in the anterior pituitary. The resultant G-protein activation of a phosphatidylinositol-calcium second messenger system ultimately triggers the release of FSH and LH.GNRH1 activity is low during childhood but increases
DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk
Dominique Bernard-Gallon, Rémy Bosviel, Laetitia Delort, Luc Fontana, Alain Chamoux, Nadège Rabiau, Fabrice Kwiatkowski, Nasséra Chalabi, Samir Satih, Yves-Jean Bignon
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-36
Abstract: High levels of DNA damage, caused by excessive exposure to carcinogens, might be responsible for increased breast cancer susceptibility in women known to have significantly reduced DNA repair proficiencies [1]. In particular, dysfunctions of the nucleotide excision repair (NER) pathway are known or suspected to be involved in cancer. The DNA helicase encoded by the excision repair cross-complementing group 2 gene ERCC2 (formely XPD) is one of seven nucleotide excision repair enzymes that cause Xeroderma Pigmentosum when mutated in germ line [2]. Several polymorphisms have been identified in this gene and particularly the Asp312Asn ERCC2 polymorphism which consists of the substitution of a G to A resulting in an amino acid change in the coding region, and the Lys751Gln which consists in a A to C substitution in the coding region [3]. A change of amino acid is able to modify the effect of protein more or less, which can translate by an effect on the systems of repair and consequently on the carcinogenesis. Conflicting data on the roles of these polymorphisms on cancer risk including breast and ovarian cancers have been described [4-6].The objective of this study was to establish the role of two functional polymorphisms of a DNA repair gene ERCC2 in the risk of breast or ovarian cancer. We investigated the possible interactions between these polymorphisms and specific environmental factors (reproductive factors, body mass index, tobacco smoking...) which could influence the risk of cancer.In this breast cancer population (Table 1), no significant differences were found between breast cancer cases and controls. A trend to the increase in breast cancer risk could be observed with heterozygous women for the SNP at position 312 of ERCC2 protein (OR = 1.06; 95% CI = 0.93–1.21) after adjustment for age. For ovarian cancer (Table 2), there was no significant modification in the risk for the two studied SNP.Results concerning interactions between environmental factors and risk
Polymorphisms in the p63 and p73 genes are associated with ovarian cancer risk and clinicopathological variables  [cached]
Guan Xiao,Zhang Ning,Yin Yongshuo,Kong Beihua
Journal of Experimental & Clinical Cancer Research , 2012, DOI: 10.1186/1756-9966-31-89
Abstract: Objective p73 and p63 are two structural and functional homologs of p53, and their biological functions in cancer progression have attracted attention due to the presence of variants generated by genetic polymorphisms. Recently, three single nucleotide polymorphisms (SNPs) in the p63 and p73 genes have been associated with female reproduction. In the present study, we aimed to evaluate the relationship between these SNPs and ovarian cancer susceptibility and clinical pathology. Methods We genotyped the p63 (rs873330 [Genbank, refSNP ID] T > C [T: original base, C: mutant base]) and p73 (rs4648551 G > A and rs6695978 G > A) SNPs in ovarian cancers and healthy controls and analyzed the distributions of genotype frequencies to evaluate the association of the genotypes with the risk of ovarian cancer and the clinicopathological characteristics. Logistic regression models were applied in statistical analyses. Results Our research revealed that p73 rs6695978 G > A was significantly associated with ovarian cancer patients. Women with the A allele were at increased risk of ovarian cancer compared to carriers of the G allele (OR = 1.55; 95% CI:1.07–2.19; P = 0.003). Meanwhile, the at-risk A allele was positively related with the occurrence of mucinous ovarian cancer (OR = 3.48; 95% CI:1.15-6.83; P = 0.001), low degree of differentiation (OR = 1.87; 95% CI:1.03-3.47; P = 0.003), lymph node metastasis (OR = 1.69; 95% CI: 1.14-2.75; P = 0.010) and estrogen receptor positive (OR = 2.72; 95% CI: 1.38-4.81; P = 0.002). However, we were unable to find any associations of the polymorphisms in another two SNPs (rs4648551 G > A, rs873330 T > C) with ovarian cancer risk and clinicopathological parameters. Conclusions The p73 rs6695978 G > A polymorphism will serve as a modifier of ovarian cancer susceptibility and prognosis. Further investigations with large sample sizes and of the mechanistic relevance of p73 polymorphism will be warranted
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