Browsing by Subject "Polymorphism, Single Nucleotide"

Now showing 1 - 20 of 156
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    ItemOpen Access
    A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death.
    (Mol Biol Cell, 2014-01) Salinas, Raul E; Ogohara, Cassandra; Thomas, Monica I; Shukla, Kajal P; Miller, Samuel I; Ko, Dennis C
    Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) using Salmonella typhimurium infection of human lymphoblastoid cell lines as a means of dissecting the genetic architecture of susceptibility to pyroptosis and identifying unknown regulatory mechanisms. Cellular GWAS revealed that a common human genetic difference that regulates pyroptosis also alters microtubule stability. An intergenic single-nucleotide polymorphism on chromosome 18 is associated with decreased pyroptosis and increased expression of TUBB6 (tubulin, β 6 class V). TUBB6 is unique among tubulin isoforms in that its overexpression can completely disrupt the microtubule network. Cells from individuals with higher levels of TUBB6 expression have lower microtubule stability and less pyroptosis. Reducing TUBB6 expression or stabilizing microtubules pharmacologically with paclitaxel (Taxol) increases pyroptosis without affecting the other major readout of caspase-1 activation, interleukin-1β secretion. The results reveal a new role for microtubules and possibly specific tubulin isoforms in the execution of pyroptosis. Furthermore, the finding that there is common diversity in TUBB6 expression and microtubule stability could have broad consequences for other microtubule-dependent phenotypes, diseases, and pharmacological responses.
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    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, Qingyi
    The 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.
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    A Functional Polymorphism (rs2494752) in the AKT1 Promoter Region and Gastric Adenocarcinoma Risk in an Eastern Chinese Population.
    (Scientific reports, 2016-01-28) Wang, Meng-Yun; He, Jing; Zhu, Mei-Ling; Teng, Xiao-Yan; Li, Qiao-Xin; Sun, Meng-Hong; Wang, Xiao-Feng; Yang, Ya-Jun; Wang, Jiu-Cun; Jin, Li; Wang, Ya-Nong; Wei, Qing-Yi
    AKT is an important signal transduction protein that plays a crucial role in cancer development. Therefore, we evaluated associations between single nucleotide polymorphisms (SNPs) in the AKT promoter region and gastric cancer (GCa) risk in a case-control study of 1,110 GCa patients and 1,114 matched cancer-free controls. We genotyped five SNPs (AKT1 rs2494750G >C, AKT1 rs2494752A >G, AKT1 rs10138227C >T, AKT2 rs7254617G>A and AKT2 rs2304186G >T) located in the 5' upstream regulatory, first intron or promoter regions. In the logistic regression analysis, a significantly elevated GCa risk was associated with the rs2494752 AG/GG variant genotypes (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42) under a dominant genetic model, and this risk was more evident in subgroups of ever drinkers. The luciferase reporter assay showed that the rs2494752 G allele significantly increased luciferase activity. Our results suggest that the potentially functional AKT1 rs2494752 SNP may affect GCa susceptibility, likely by modulating the AKT1 promoter transcriptional activity. Larger, independent studies are warranted to validate our findings.
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    A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population.
    (BMC cancer, 2011-01) Zhou, Keke; Hu, Dezhi; Lu, Juan; Fan, Weiwei; Liu, Hongliang; Chen, Hongyan; Chen, Gong; Wei, Qingyi; Du, Guhong; Mao, Ying; Lu, Daru; Zhou, Liangfu
    BACKGROUND: The human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes. METHODS: The APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations. RESULTS: The significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014. CONCLUSIONS: Our results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.
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    A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.
    (PLoS Genet, 2010-02-19) Tsai, Fuu-Jen; Yang, Chi-Fan; Chen, Ching-Chu; Chuang, Lee-Ming; Lu, Chieh-Hsiang; Chang, Chwen-Tzuei; Wang, Tzu-Yuan; Chen, Rong-Hsing; Shiu, Chiung-Fang; Liu, Yi-Min; Chang, Chih-Chun; Chen, Pei; Chen, Chien-Hsiun; Fann, Cathy SJ; Chen, Yuan-Tsong; Wu, Jer-Yuarn
    To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54x10(-10); odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36-1.82), and serine racemase (SRR) (P = 3.06x10(-9); OR = 1.28; 95% CI = 1.18-1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65x10(-10); OR = 1.29, 95% CI = 1.19-1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.
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    A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.
    (J Gerontol A Biol Sci Med Sci, 2010-05) Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L; Garcia, Melissa E; Slagboom, P Eline; Christensen, Kaare; Arnold, Alice M; Aspelund, Thor; Aulchenko, Yurii S; Benjamin, Emelia J; Christiansen, Lene; D'Agostino, Ralph B; Fitzpatrick, Annette L; Franceschini, Nora; Glazer, Nicole L; Gudnason, Vilmundur; Hofman, Albert; Kaplan, Robert; Karasik, David; Kelly-Hayes, Margaret; Kiel, Douglas P; Launer, Lenore J; Marciante, Kristin D; Massaro, Joseph M; Miljkovic, Iva; Nalls, Michael A; Hernandez, Dena; Psaty, Bruce M; Rivadeneira, Fernando; Rotter, Jerome; Seshadri, Sudha; Smith, Albert V; Taylor, Kent D; Tiemeier, Henning; Uh, Hae-Won; Uitterlinden, André G; Vaupel, James W; Walston, Jeremy; Westendorp, Rudi GJ; Harris, Tamara B; Lumley, Thomas; van Duijn, Cornelia M; Murabito, Joanne M
    BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
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    A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer.
    (Scientific reports, 2016-10-07) Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Owzar, Kouros; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J; McLaughlin, John; Brhane, Yonathan; Brennan, Paul; Bickeboeller, Heike; Rosenberger, Albert; Houlston, Richard S; Caporaso, Neil; Landi, Maria Teresa; Heinrich, Joachim; Risch, Angela; Christiani, David C; Gümüş, Zeynep H; Klein, Robert J; Amos, Christopher I; Wei, Qingyi
    Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10-7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 × 10-9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.
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    A pri-miR-218 variant and risk of cervical carcinoma in Chinese women.
    (BMC cancer, 2013-01-15) Shi, Ting-Yan; Chen, Xiao-Jun; Zhu, Mei-Ling; Wang, Meng-Yun; He, Jing; Yu, Ke-Da; Shao, Zhi-Ming; Sun, Meng-Hong; Zhou, Xiao-Yan; Cheng, Xi; Wu, Xiaohua; Wei, Qingyi
    BACKGROUND: MicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma. METHODS: In this case-control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women. RESULTS: We found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95, P=0.015). However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3. Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma. CONCLUSIONS: The pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.
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    A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting significant life stress.
    (PloS one, 2014-01) Brummett, Beverly H; Babyak, Michael A; Williams, Redford B; Harris, Kathleen Mullan; Jiang, Rong; Kraus, William E; Singh, Abanish; Costa, Paul T; Georgiades, Anastasia; Siegler, Ilene C
    Psychosocial stress is well known to be positively associated with subsequent depressive symptoms. Cortisol response to stress may be one of a number of biological mechanisms that links psychological stress to depressive symptoms, although the precise causal pathway remains unclear. Activity of the x-linked serotonin 5-HTR2C receptor has also been shown to be associated with depression and with clinical response to antidepressant medications. We recently demonstrated that variation in a single nucleotide polymorphism on the HTR2C gene, rs6318 (Ser23Cys), is associated with different cortisol release and short-term changes in affect in response to a series of stress tasks in the laboratory. Based on this observation, we decided to examine whether rs6318 might moderate the association between psychosocial stress and subsequent depressive symptoms. In the present study we use cross-sectional data from a large population-based sample of young adult White men (N = 2,366) and White women (N = 2,712) in the United States to test this moderation hypothesis. Specifically, we hypothesized that the association between self-reported stressful life events and depressive symptoms would be stronger among homozygous Ser23 C females and hemizygous Ser23 C males than among Cys23 G carriers. In separate within-sex analyses a genotype-by-life stress interaction was observed for women (p = .022) but not for men (p = .471). Homozygous Ser23 C women who reported high levels of life stress had depressive symptom scores that were about 0.3 standard deviations higher than female Cys23 G carriers with similarly high stress levels. In contrast, no appreciable difference in depressive symptoms was observed between genotypes at lower levels of stress. Our findings support prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress.
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    A TGF-β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16-associated oropharyngeal cancer.
    (International journal of cancer, 2018-09) Tao, Ye; Sturgis, Erich M; Huang, Zhigang; Sun, Yan; Dahlstrom, Kristina R; Wei, Qingyi; Li, Guojun
    TGF-β1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF-β1rs1982073 polymorphism at the miRNA-187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF-β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer-free controls in the non-Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF-β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6-960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2-1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3-87.0 vs. OR, 6.0; 95% CI, 1.7-17.9, respectively). The significant associations between this polymorphism and HPV16-associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF-β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16-associated oral cancer, particularly in OPSCC subjects who are never-smokers, never-drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.
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    An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.
    (Genome medicine, 2021-05) Wang, Liuyang; Balmat, Thomas J; Antonia, Alejandro L; Constantine, Florica J; Henao, Ricardo; Burke, Thomas W; Ingham, Andy; McClain, Micah T; Tsalik, Ephraim L; Ko, Emily R; Ginsburg, Geoffrey S; DeLong, Mark R; Shen, Xiling; Woods, Christopher W; Hauser, Elizabeth R; Ko, Dennis C

    Background

    While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility.

    Results

    Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity.

    Conclusions

    Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .
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    An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy.
    (International journal of cancer, 2018-03) Zhang, Ruoxin; Jia, Ming; Xu, Yuan; Qian, Danwen; Wang, Mengyun; Zhu, Meiling; Sun, Menghong; Chang, Jianhua; Wei, Qingyi
    Platinum-based chemotherapy (PBC) in combination with the 3rd generation drugs is the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3-4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum-induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)adj =1.61 and 2.35, 95% confidence interval (CI)=1.11-2.33 and 1.25-4.41, and Padj =0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57-0.65 vs. 0.55-0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.
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    An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men.
    (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021-05) Vann, Christopher G; Morton, Robert W; Mobley, Christopher B; Vechetti, Ivan J; Ferguson, Brian K; Haun, Cody T; Osburn, Shelby C; Sexton, Casey L; Fox, Carlton D; Romero, Matthew A; Roberson, Paul A; Oikawa, Sara Y; McGlory, Chris; Young, Kaelin C; McCarthy, John J; Phillips, Stuart M; Roberts, Michael D
    We examined the association between genotype and resistance training-induced changes (12 wk) in dual x-ray energy absorptiometry (DXA)-derived lean soft tissue mass (LSTM) as well as muscle fiber cross-sectional area (fCSA; vastus lateralis; n = 109; age = 22 ± 2 y, BMI = 24.7 ± 3.1 kg/m2 ). Over 315 000 genetic polymorphisms were interrogated from muscle using DNA microarrays. First, a targeted investigation was performed where single nucleotide polymorphisms (SNP) identified from a systematic literature review were related to changes in LSTM and fCSA. Next, genome-wide association (GWA) studies were performed to reveal associations between novel SNP targets with pre- to post-training change scores in mean fCSA and LSTM. Our targeted investigation revealed no genotype-by-time interactions for 12 common polymorphisms regarding the change in mean fCSA or change in LSTM. Our first GWA study indicated no SNP were associated with the change in LSTM. However, the second GWA study indicated two SNP exceeded the significance level with the change in mean fCSA (P = 6.9 × 10-7 for rs4675569, 1.7 × 10-6 for rs10263647). While the former target is not annotated (chr2:205936846 (GRCh38.p12)), the latter target (chr7:41971865 (GRCh38.p12)) is an intron variant of the GLI Family Zinc Finger 3 (GLI3) gene. Follow-up analyses indicated fCSA increases were greater in the T/C and C/C GLI3 genotypes than the T/T GLI3 genotype (P < .05). Data from the Auburn cohort also revealed participants with the T/C and C/C genotypes exhibited increases in satellite cell number with training (P < .05), whereas T/T participants did not. Additionally, those with the T/C and C/C genotypes achieved myonuclear addition in response to training (P < .05), whereas the T/T participants did not. In summary, this is the first GWA study to examine how polymorphisms associate with the change in hypertrophy measures following resistance training. Future studies are needed to determine if the GLI3 variant differentiates hypertrophic responses to resistance training given the potential link between this gene and satellite cell physiology.
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    Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.
    (Int J Cancer, 2015-11-15) Zhang, Fenghua; Sturgis, Erich M; Sun, Yan; Zhang, Yang; Wei, Qingyi; Zhang, Caiyun; Zheng, Hongliang; Li, Guojun
    Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.
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    Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites.
    (Journal of cellular and molecular medicine, 2013-07) Guan, Xiaoxiang; Wang, Li-E; Liu, Zhensheng; Sturgis, Erich M; Wei, Qingyi
    Recently, several studies have investigated the association between a newly reported rare functional single nucleotide polymorphism (SNP) in TP53 (rs78378222) and cancer risk, but generated inconsistent findings. The present study further investigated this association with risk of melanoma, squamous cell carcinoma of head and neck (SCCHN) and lung cancer. Using volunteers of non-Hispanic Whites recruited for three large case-control studies, we genotyped the TP53 rs78378222 SNP in 1329 patients with melanoma, 1096 with SCCHN, 1013 with lung cancer and 3000 cancer-free controls. Overall, we did not observe any variant homozygotes in this study population, nor significant associations between the TP53 rs78378222AC genotype or C allele and risk for melanoma (P = 0.680 and 0.682 respectively) and lung cancer (P = 0.379 and 0.382 respectively), but a protection against SCCHN (P = 0.008 and 0.008 respectively), compared with the AA genotype or A allele. An additional meta-analysis including 19,423 cancer patients and 54,050 controls did not support such a risk association either. Our studies did not provide statistical evidence of an association between this rare TP53 variant and increased risk of melanoma, nor of lung cancer, but a possible protection against SCCHN.
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    Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.
    (PLoS One, 2010-04-08) Schildkraut, Joellen M; Iversen, Edwin S; Wilson, Melanie A; Clyde, Merlise A; Moorman, Patricia G; Palmieri, Rachel T; Whitaker, Regina; Bentley, Rex C; Marks, Jeffrey R; Berchuck, Andrew
    BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.
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    Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.
    (BMC cancer, 2011-06-20) Ma, Hongxia; Wang, Li-E; Liu, Zhensheng; Sturgis, Erich M; Wei, Qingyi
    Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95).Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers.
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    Association between single nucleotide polymorphisms in ERCC4 and risk of squamous cell carcinoma of the head and neck.
    (PloS one, 2012-01) Yu, Hongping; Liu, Zhensheng; Huang, Yu-Jing; Yin, Ming; Wang, Li-E; Wei, Qingyi
    Excision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.In this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50-0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58-1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40-0.92 for rs2276466; OR = 0.69, 95% CI: 0.48-0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.These results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.
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    Association between the ERCC5 Asp1104His polymorphism and cancer risk: a meta-analysis.
    (PloS one, 2012-01) Zhu, Mei-Ling; Wang, Mengyun; Cao, Zhi-Gang; He, Jing; Shi, Ting-Yan; Xia, Kai-Qin; Qiu, Li-Xin; Wei, Qing-Yi
    BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92-1.06, P = 0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93-1.03, P = 0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.
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    Association between XPF polymorphisms and cancer risk: a meta-analysis.
    (PloS one, 2012-01) Shi, Ting-Yan; He, Jing; Qiu, Li-Xin; Zhu, Mei-Ling; Wang, Meng-Yun; Zhou, Xiao-Yan; Han, Jiali; Yu, Hongpin; Zang, Rong-Yu; Wei, Qingyi
    BACKGROUND: Xeroderma pigmentosum complementation group F (XPF or ERCC4) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. A series of epidemiological studies have examined associations between XPF polymorphisms and cancer risk, but the findings remain inconclusive. METHODOLOGY/PRINCIPAL FINDINGS: In this meta-analysis of 47,639 cancer cases and 51,915 controls, by searching three electronic databases (i.e., MEDLINE, EMBASE and CNKI), we summarized 43 case-control studies from 29 publications on four commonly studied polymorphisms of XPF (i.e., rs1800067, rs1799801, rs2020955 and rs744154), and we did not find statistical evidence of any significant association with overall cancer risk. However, in stratification analyses, we found a significant association of XPF-rs1799801 with a reduced cancer risk in Caucasian populations (4,845 cases and 5,556 controls; recessive model: OR=0.87, 95% CI=0.76-1.00, P=0.049, P=0.723 for heterogeneity test, I(2) =0). Further genotype-phenotype correlation analysis showed that the homozygous variant CC genotype carriers had higher XPF expression levels than that of the TT genotype carriers (Student's t test for a recessive model: P=0.046). No publication bias was found by using the funnel plot and Egger's test. CONCLUSION: This meta-analysis suggests a lack of statistical evidence for the association between the four XPF SNPs and overall risk of cancers. However, XPF-rs1799801 may be associated with cancer risk in Caucasian populations, which needs to be further validated in single large, well-designed prospective studies.