Browsing by Subject "Gene Frequency"
Now showing 1 - 20 of 26
- Results Per Page
- Sort Options
Item Open Access 29 mammalian genomes reveal novel exaptations of mobile elements for likely regulatory functions in the human genome.(PloS one, 2012-01) Lowe, Craig B; Haussler, DavidRecent research supports the view that changes in gene regulation, as opposed to changes in the genes themselves, play a significant role in morphological evolution. Gene regulation is largely dependent on transcription factor binding sites. Researchers are now able to use the available 29 mammalian genomes to measure selective constraint at the level of binding sites. This detailed map of constraint suggests that mammalian genomes co-opt fragments of mobile elements to act as gene regulatory sequence on a large scale. In the human genome we detect over 280,000 putative regulatory elements, totaling approximately 7 Mb of sequence, that originated as mobile element insertions. These putative regulatory regions are conserved non-exonic elements (CNEEs), which show considerable cross-species constraint and signatures of continued negative selection in humans, yet do not appear in a known mature transcript. These putative regulatory elements were co-opted from SINE, LINE, LTR and DNA transposon insertions. We demonstrate that at least 11%, and an estimated 20%, of gene regulatory sequence in the human genome showing cross-species conservation was co-opted from mobile elements. The location in the genome of CNEEs co-opted from mobile elements closely resembles that of CNEEs in general, except in the centers of the largest gene deserts where recognizable co-option events are relatively rare. We find that regions of certain mobile element insertions are more likely to be held under purifying selection than others. In particular, we show 6 examples where paralogous instances of an often co-opted mobile element region define a sequence motif that closely matches a transcription factor's binding profile.Item Open Access A functional NQO1 609C>T polymorphism and risk of gastrointestinal cancers: a meta-analysis.(PloS one, 2012-01-17) Yu, Hongping; Liu, Hongliang; Wang, Li-E; Wei, QingyiThe functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.We performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 - 1.19, P(heterogeneity) = 0.27, I(2) = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 - 1.20, P(heterogeneity) = 0.14; I(2) = 0.27). Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies.This meta-analysis suggests that the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.Item Open Access A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.(PLoS genetics, 2011-03-17) McKay, James D; Truong, Therese; Gaborieau, Valerie; Chabrier, Amelie; Chuang, Shu-Chun; Byrnes, Graham; Zaridze, David; Shangina, Oxana; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Holcatova, Ivana; Janout, Vladimir; Foretova, Lenka; Lagiou, Pagona; Trichopoulos, Dimitrios; Benhamou, Simone; Bouchardy, Christine; Ahrens, Wolfgang; Merletti, Franco; Richiardi, Lorenzo; Talamini, Renato; Barzan, Luigi; Kjaerheim, Kristina; Macfarlane, Gary J; Macfarlane, Tatiana V; Simonato, Lorenzo; Canova, Cristina; Agudo, Antonio; Castellsagué, Xavier; Lowry, Ray; Conway, David I; McKinney, Patricia A; Healy, Claire M; Toner, Mary E; Znaor, Ariana; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Neto, José Eluf; Garrote, Leticia Fernández; Boccia, Stefania; Cadoni, Gabriella; Arzani, Dario; Olshan, Andrew F; Weissler, Mark C; Funkhouser, William K; Luo, Jingchun; Lubiński, Jan; Trubicka, Joanna; Lener, Marcin; Oszutowska, Dorota; Schwartz, Stephen M; Chen, Chu; Fish, Sherianne; Doody, David R; Muscat, Joshua E; Lazarus, Philip; Gallagher, Carla J; Chang, Shen-Chih; Zhang, Zuo-Feng; Wei, Qingyi; Sturgis, Erich M; Wang, Li-E; Franceschi, Silvia; Herrero, Rolando; Kelsey, Karl T; McClean, Michael D; Marsit, Carmen J; Nelson, Heather H; Romkes, Marjorie; Buch, Shama; Nukui, Tomoko; Zhong, Shilong; Lacko, Martin; Manni, Johannes J; Peters, Wilbert HM; Hung, Rayjean J; McLaughlin, John; Vatten, Lars; Njølstad, Inger; Goodman, Gary E; Field, John K; Liloglou, Triantafillos; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; González, Carlos A; Quirós, J Ramón; Martínez, Carmen; Navarro, Carmen; Ardanaz, Eva; Larrañaga, Nerea; Khaw, Kay-Tee; Key, Timothy; Bueno-de-Mesquita, H Bas; Peeters, Petra HM; Trichopoulou, Antonia; Linseisen, Jakob; Boeing, Heiner; Hallmans, Göran; Overvad, Kim; Tjønneland, Anne; Kumle, Merethe; Riboli, Elio; Välk, Kristjan; Vooder, Tõnu; Metspalu, Andres; Zelenika, Diana; Boland, Anne; Delepine, Marc; Foglio, Mario; Lechner, Doris; Blanché, Hélène; Gut, Ivo G; Galan, Pilar; Heath, Simon; Hashibe, Mia; Hayes, Richard B; Boffetta, Paolo; Lathrop, Mark; Brennan, PaulGenome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.Item Open Access Association between p21 Ser31Arg polymorphism and cancer risk: a meta-analysis.(Chinese journal of cancer, 2011-04) Ma, Hongxia; Zhou, Ziyuan; Wei, Sheng; Wei, QingyiP21 (CDKN1A), a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase, can regulate cell proliferation, growth arrest, and apoptosis. The Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct proteins. Although many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk, the findings remain conflicting. This meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model (homozygote comparison: OR = 1.17, 95% CI = 0.99 to 1.37, P = 0.0002 for the heterogeneity test; recessive model comparison: OR = 1.16, 95% CI = 1.01 to 1.33, P = 0.0001 for the heterogeneity test). Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer, estrogen-related cancer, Caucasians, population-based studies, studies with matching information or a larger sample size. Heterogeneity analysis showed that tumor type contributed to substantial between-study heterogeneity (recessive model comparison: Χ(2) = 21.83, df = 7, P = 0.003). The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.Item Open Access Associations of genotypes and haplotypes of IL-17 with risk of gastric cancer in an eastern Chinese population.(Oncotarget, 2016-12) Zhou, Fei; Qiu, Li-Xin; Cheng, Lei; Wang, Meng-Yun; Li, Jin; Sun, Meng-Hong; Yang, Ya-Jun; Wang, Jiu-Cun; Jin, Li; Wang, Ya-Nong; Wei, Qing-YiInterleukin-17 plays a crucial role in inflammation-related carcinogenesis. We hypothesize that genetic variants in IL-17 are associated with gastric cancer (GCa) risk, and we genotyped five potentially functional single nucleotide polymorphisms (SNPs) (rs1974226 G > A, rs2275913 A > G, rs3819024 A > G, rs4711998 A > G, and rs8193036 C > T) of IL-17 in 1121 GCa patients and 1216 cancer-free controls in an eastern Chinese population. Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Meta-analysis and genotype-mRNA expression correlation were performed to further validate positive associations. We found that an increased GCa risk was independently associated with rs1974226 (adjusted OR = 2.60, 95% CI = 1.27-5.32 for AA vs. GG + GA) and rs2275913 (adjusted OR = 1.33, 95% CI = 1.03-1.72 for GA + AA vs. GG), while a decreased GCa risk was independently associated with rs3819024 (adjusted OR = 0.72, 95% CI = 0.54-0.96 for GG vs. AA + AG). Additional meta-analyses confirmed the observed risk association with rs2275913. We also found that two IL-17 haplotypes (G-G-G-A-C) and (A-G-G-A-C) (in the order of rs1974226, rs2275913, rs3819024, rs4711998 and rs8193036) were associated with a reduced GCa risk (adjusted OR = 0.64, 95% CI = 0.46-0.89 and adjusted OR = 0.38, 95% CI = 0.17-0.81, respectively). However, the expression Quantitative Trait Locus (eQTL) analysis for the genotype-phenotype correlation did not find mRNA expression changes associated with either the genotypes. In conclusions, genetic variants of IL-17 are likely to be associated with risk of GCa, and additional larger studies with functional validation are needed to explore the molecular mechanisms underlying the observed associations.Item Open Access Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.(Journal of visualized experiments : JoVE, 2019-01-16) Jones, Edward G; Landstrom, Andrew PAdvancements in the cost and speed of next generation genetic sequencing have generated an explosion of clinical whole exome and whole genome testing. While this has led to increased identification of likely pathogenic mutations associated with genetic syndromes, it has also dramatically increased the number of incidentally found genetic variants of unknown significance (VUS). Determining the clinical significance of these variants is a major challenge for both scientists and clinicians. An approach to assist in determining the likelihood of pathogenicity is signal-to-noise analysis at the protein sequence level. This protocol describes a method for amino acid-level signal-to-noise analysis that leverages variant frequency at each amino acid position of the protein with known protein topology to identify areas of the primary sequence with elevated likelihood of pathologic variation (relative to population "background" variation). This method can identify amino acid residue location "hotspots" of high pathologic signal, which can be used to refine the diagnostic weight of VUSs such as those identified by next generation genetic testing.Item Open Access Effect of polymorphisms in XPD on clinical outcomes of platinum-based chemotherapy for Chinese non-small cell lung cancer patients.(PloS one, 2012-01) Wu, Wenting; Li, Huan; Wang, Huibo; Zhao, Xueying; Gao, Zhiqiang; Qiao, Rong; Zhang, Wei; Qian, Ji; Wang, Jiucun; Chen, Hongyan; Wei, Qingyi; Han, Baohui; Lu, DaruPURPOSE: Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: 353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg(156)Arg, Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing. RESULTS: Variant genotypes of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10(-4), log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0-1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS. CONCLUSIONS: Our study provides evidence for the predictive role of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.Item Open Access Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity.(Age (Dordr), 2013-04) Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Suchiman, H Eka D; Jacobsen, Rune; McGue, Matt; Stevnsner, Tinna; Bohr, Vilhelm A; de Craen, Anton JM; Westendorp, Rudi GJ; Schreiber, Stefan; Slagboom, P Eline; Nebel, Almut; Vaupel, James W; Christensen, Kaare; Christiansen, LeneIn this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.Item Open Access Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.(PloS one, 2012-01) Yang, Lei; Qiu, Fuman; Lu, Xiaoxiao; Huang, Dongsheng; Ma, Guanpei; Guo, Yuan; Hu, Min; Zhou, Yumin; Pan, Mingan; Tan, Yigang; Zhong, Haibo; Ji, Weidong; Wei, Qingyi; Ran, Pixin; Zhong, Nanshan; Zhou, Yifeng; Lu, JiachunRecently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14-1.54) and lung cancer (OR = 1.57; 95% CI = 1.31-1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13-1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.Item Open Access Genetic variants in IGF-I, IGF-II, IGFBP-3, and adiponectin genes and colon cancer risk in African Americans and Whites.(Cancer Causes Control, 2012-07) Keku, Temitope O; Vidal, Adriana; Oliver, Shannon; Hoyo, Catherine; Hall, Ingrid J; Omofoye, Oluwaseun; McDoom, Maya; Worley, Kendra; Galanko, Joseph; Sandler, Robert S; Millikan, RobertPURPOSE: Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)( n ) repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor-binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. METHODS: Participants were African Americans (231 cases and 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5'-exonuclease (Taqman) assay. The IGF-I (CA)(n) repeat was assayed by PCR and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by logistic regression. RESULTS: The IGF-I (CA)( 19 ) repeat was higher in White controls (50 %) than African American controls (31 %). Whites homozygous for the IGF-I (CA)(19) repeat had a nearly twofold increase in risk of colon cancer (OR = 1.77; 95 % CI = 1.15-2.73), but not African Americans (OR = 0.73, 95 % CI 0.50-1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR = 0.49, 95 % CI 0.28-0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p-trend <0.05). CONCLUSIONS: These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.Item Open Access Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival.(Molecular carcinogenesis, 2018-01) Xu, Yinghui; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Hyslop, Terry; Li, Xin; Han, Jiali; Wei, QingyiMetzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.Item Open Access Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence.(Prostate Cancer Prostatic Dis, 2015-12) Gu, C; Li, Q; Zhu, Y; Qu, Y; Zhang, G; Wang, M; Yang, Y; Wang, J; Jin, L; Wei, Q; Ye, DBACKGROUND: Telomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is not fully understood whether genetic variations in telomere-related genes are associated with development and progression in PCa patients. METHODS: Six potentially functional single-nucleotide polymorphisms (SNPs) of three key telomere-related genes were evaluated in 1015 PCa cases and 1052 cancer-free controls, to test their associations with risk of PCa. Among 426 PCa patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was also assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTLs) were measured in peripheral blood leukocytes using real-time PCR in the RP patients. RESULTS: TEP1 rs1760904 AG/AA genotypes were significantly associated with a decreased risk of PCa (odds ratio (OR): 0.77, 95% confidence interval (CI): 0.64-0.93, P=0.005) compared with the GG genotype. By using median RTL as a cutoff level, RP patients with TEP1 rs1760904 AG/AA genotypes tended to have a longer RTL than those with the GG genotype (OR: 1.55, 95% CI: 1.04-2.30, P=0.031). A significant interaction between TEP1 rs1713418 and age in modifying PCa risk was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR in the RP cohorts (hazard ratio: 0.53, 95% CI: 0.36-0.79, P=0.002 and hazard ratio: 1.67, 95% CI: 1.07-2.48, P=0.017, respectively). CONCLUSIONS: These data suggest that genetic variations in the TEP1 gene may be biomarkers for risk of PCa and BCR after RP.Item Open Access Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences.(Genome biology, 2014-06-30) Colonna, Vincenza; Ayub, Qasim; Chen, Yuan; Pagani, Luca; Luisi, Pierre; Pybus, Marc; Garrison, Erik; Xue, Yali; Tyler-Smith, Chris; 1000 Genomes Project Consortium; Abecasis, Goncalo R; Auton, Adam; Brooks, Lisa D; DePristo, Mark A; Durbin, Richard M; Handsaker, Robert E; Kang, Hyun Min; Marth, Gabor T; McVean, Gil ABACKGROUND:Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes. RESULTS:We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively. CONCLUSIONS:We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.Item Open Access Inductive determination of allele frequency spectrum probabilities in structured populations.(Theoretical population biology, 2019-10) Uyenoyama, Marcy K; Takebayashi, Naoki; Kumagai, SeijiWe present a method for inductively determining exact allele frequency spectrum (AFS) probabilities for samples derived from a population comprising two demes under the infinite-allele model of mutation. This method builds on a labeled coalescent argument to extend the Ewens sampling formula (ESF) to structured populations. A key departure from the panmictic case is that the AFS conditioned on the number of alleles in the sample is no longer independent of the scaled mutation rate (θ). In particular, biallelic site frequency spectra, widely-used in explorations of genome-wide patterns of variation, depend on the mutation rate in structured populations. Variation in the rate of substitution across loci and through time may contribute to apparent distortions of site frequency spectra exhibited by samples derived from structured populations.Item Open Access Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.(Rejuvenation Res, 2016-06) Zeng, Y; Chen, H; Ni, T; Ruan, R; Nie, C; Liu, X; Feng, L; Zhang, F; Lu, J; Li, J; Li, Y; Tao, W; Gregory, SG; Gottschalk, W; Lutz, MW; Land, KC; Yashin, A; Tan, Q; Yang, Z; Bolund, L; Ming, Q; Yang, H; Min, J; Willcox, DC; Willcox, BJ; Gu, J; Hauser, E; Tian, X; Vaupel, JWOn the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are significantly associated with lower risk of mortality at advanced ages. Such a significant association is replicated in two independent Han Chinese CLHLS cohorts (p = 0.028-0.048 in the discovery and replication cohorts, and p = 0.003-0.016 in the combined dataset). We found the associations between tea drinking and reduced mortality are much stronger among carriers of the FOXO1A-209 genotype compared to non-carriers, and drinking tea is associated with a reversal of the negative effects of carrying FOXO1A-209 minor alleles, that is, from a substantially increased mortality risk to substantially reduced mortality risk at advanced ages. The impacts are considerably stronger among those who carry two copies of the FOXO1A minor allele than those who carry one copy. On the basis of previously reported experiments on human cell models concerning FOXO1A-by-tea-compounds interactions, we speculate that results in the present study indicate that tea drinking may inhibit FOXO1A-209 gene expression and its biological functions, which reduces the negative impacts of FOXO1A-209 gene on longevity (as reported in the literature) and offers protection against mortality risk at oldest-old ages. Our empirical findings imply that the health outcomes of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles, and the research on the effects of nutrigenomics interactions could potentially be useful for rejuvenation therapies in the clinic or associated healthy aging intervention programs.Item Open Access Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.(Circulation. Arrhythmia and electrophysiology, 2017-04) Landstrom, AP; Dailey-Schwartz, AL; Rosenfeld, JA; Yang, Y; McLean, MJ; Miyake, CY; Valdes, SO; Fan, Y; Allen, HD; Penny, DJ; Kim, JJBACKGROUND:The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers. METHODS AND RESULTS:CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world's largest collections of clinical WES referral tests (N=6517, Baylor Miraca Genetics Laboratories) and compared with a control cohort of ostensibly healthy individuals (N=60 706) and a case cohort of CPVT cases (N=155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicion for CPVT. CONCLUSIONS:The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.Item Open Access Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality.(Rejuvenation Res, 2012-08) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Ukraintseva, Svetlana VRecently we have shown that the human life span is influenced jointly by many common single-nucleotide polymorphisms (SNPs), each with a small individual effect. Here we investigate further the polygenic influence on life span and discuss its possible biological mechanisms. First we identified six sets of prolongevity SNP alleles in the Framingham Heart Study 550K SNPs data, using six different statistical procedures (normal linear, Cox, and logistic regressions; generalized estimation equation; mixed model; gene frequency method). We then estimated joint effects of these SNPs on human survival. We found that alleles in each set show significant additive influence on life span. Twenty-seven SNPs comprised the overlapping set of SNPs that influenced life span, regardless of the statistical procedure. The majority of these SNPs (74%) were within genes, compared to 40% of SNPs in the original 550K set. We then performed a review of current literature on functions of genes closest to these 27 SNPs. The review showed that the respective genes are largely involved in aging, cancer, and brain disorders. We concluded that polygenic effects can explain a substantial portion of genetic influence on life span. Composition of the set of prolongevity alleles depends on the statistical procedure used for the allele selection. At the same time, there is a core set of longevity alleles that are selected with all statistical procedures. Functional relevance of respective genes to aging and major diseases supports causal relationships between the identified SNPs and life span. The fact that genes found in our and other genetic association studies of aging/longevity have similar functions indicates high chances of true positive associations for corresponding genetic variants.Item Open Access Polymorphisms in the mTOR gene and risk of sporadic prostate cancer in an Eastern Chinese population.(PloS one, 2013-01) Li, Qiaoxin; Gu, Chengyuan; Zhu, Yao; Wang, Mengyun; Yang, Yajun; Wang, Jiucun; Jin, Li; Zhu, Mei-Ling; Shi, Ting-Yan; He, Jing; Zhou, Xiaoyan; Ye, Ding-wei; Wei, QingyiBACKGROUND: The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis. CONCLUSIONS/SIGNIFICANCES: In the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13-1.78), P = 0.003 and 1.29 (1.07-1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64-0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04-1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies.Item Open Access Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis.(BMC cancer, 2006-01) Zhai, Xiangjun; Gao, Jun; Hu, Zhibin; Tang, Jinhai; Qin, Jianwei; Wang, Shui; Wang, Xuechen; Jin, Guangfu; Liu, Jiyong; Chen, Wenshen; Chen, Feng; Wang, Xinru; Wei, Qingyi; Shen, HongbingBACKGROUND: Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR)] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk. METHODS: To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population. RESULTS: We found that the distribution of TS3'-UTR (1494del6) genotype frequencies were significantly different between the cases and controls (P = 0.026). Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35-0.97) but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82-1.46). Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks. CONCLUSION: These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings.Item Open Access Potentially functional polymorphisms in the CASP7 gene contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population.(PloS one, 2013-01) Wang, Meng-Yun; Zhu, Mei-Ling; He, Jing; Shi, Ting-Yan; Li, Qiao-Xin; Wang, Ya-Nong; Li, Jin; Zhou, Xiao-Yan; Sun, Meng-Hong; Wang, Xiao-Feng; Yang, Ya-Jun; Wang, Jiu-Cun; Jin, Li; Wei, Qing-YiBACKGROUND: Caspase 7 (CASP7) is an important regulator and executioner in the apoptosis pathway and plays a crucial role in cancer development and progression. However, few studies have evaluated associations between functional single nucleotide polymorphisms (SNPs) in the 3' untranslational region (UTR) of CASP7 and risk of gastric cancer. METHODS: In a case-control study of 1117 patients with gastric cancer and 1146 cancer-free controls with frequency matching on age and sex, we genotyped four potentially functional SNPs (rs4353229T>C, rs10787498T>G, rs1127687G>A and rs12247479G>A) located in the microRNA binding sites of the CASP7 3' UTR by using Taqman assays and evaluated their associations with risk of gastric cancer by using logistic regression analyses as well as multifactorial dimension reduction (MDR) analysis. RESULTS: In the single-locus analysis, only the CASP7 rs4353229 TT genotype was associated with 0.83-fold decreased risk (95% confidence interval [CI] = 0.70-0.98) of gastric cancer under a recessive model, compared with the CT/CC genotypes. In the combined analysis of all four SNPs, we found that the risk of gastric cancer decreased by 19% in those carrying any of the risk genotypes (adjusted odds ratio = 0.81, 95% CI = 0.68-0.96), compared with those carrying zero risk genotypes, and this risk was more evident in subgroups of younger age (<59 years), females, non-smokers, non-drinkers and patients with non-gastric cardia adenocarcinoma. Further MDR analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer. CONCLUSIONS: Potentially functional CASP7 variants may contribute to risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.