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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.

ABSTRACT: Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.

SUBMITTER: Timofeeva MN

PROVIDER: S-EPMC3607485 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.

Timofeeva Maria N MN Hung Rayjean J RJ Rafnar Thorunn T Christiani David C DC Field John K JK Bickeböller Heike H Risch Angela A McKay James D JD Wang Yufei Y Dai Juncheng J Gaborieau Valerie V McLaughlin John J Brenner Darren D Narod Steven A SA Caporaso Neil E NE Albanes Demetrius D Thun Michael M Eisen Timothy T Wichmann H-Erich HE Rosenberger Albert A Han Younghun Y Chen Wei W Zhu Dakai D Spitz Margaret M Wu Xifeng X Pande Mala M Zhao Yang Y Zaridze David D Szeszenia-Dabrowska Neonilia N Lissowska Jolanta J Rudnai Peter P Fabianova Eleonora E Mates Dana D Bencko Vladimir V Foretova Lenka L Janout Vladimir V Krokan Hans E HE Gabrielsen Maiken Elvestad ME Skorpen Frank F Vatten Lars L Njølstad Inger I Chen Chu C Goodman Gary G Lathrop Mark M Benhamou Simone S Vooder Tõnu T Välk Kristjan K Nelis Mari M Metspalu Andres A Raji Olaide O Chen Ying Y Gosney John J Liloglou Triantafillos T Muley Thomas T Dienemann Hendrik H Thorleifsson Gudmar G Shen Hongbing H Stefansson Kari K Brennan Paul P Amos Christopher I CI Houlston Richard R Landi Maria Teresa MT

Human molecular genetics 20120816 22

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European desce ...[more]

PMID: 22899653

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Project description:BackgroundEvidence suggests that MDM2 T309G polymorphism may be a risk factor for several cancers. Increasing investigations have been conducted on the association of MDM2 T309G polymorphisms with lung cancer risk and have yielded conflicting results. Previous meta-analyses on this issue have reported inconclusive data. The aim of the present study was to derive a more precise estimation of the relationship.Methods and findingsUpdated meta-analyses examining the association between MDM2 T309G polymorphism and lung cancer risk were performed. Separate analyses on ethnicity, smoking status, histological types and gender as well as source of controls were also implemented. Eligible studies were identified for the period up to Feb 2012. Lastly, ten publications including eleven case-control studies were selected for analysis. The overall data failed to indicate a significant association between MDM2 T309G polymorphism and lung cancer risk (GG vs TT OR = 1.14; 95%CI = 0.95-1.37; dominant model: OR = 1.05; 95%CI = 0.92-1.19; recessive model: OR = 1.12; 95%CI = 0.99-1.27). In a subgroup analysis by smoking status, increased lung cancer risk was shown among never-smokers (GG vs TT: OR = 1.76; 95%CI = 1.36-2.29; dominant model: OR = 1.48; 95%CI = 1.22-1.81; recessive model: OR = 1.37; 95%CI = 1.11-1.69). In subgroup analysis by gender, elevated risk was presented among women under a recessive model (OR = 1.29; 95%CI = 1.04-1.59). In the subgroup analysis by ethnicity, histological types and source of controls, no marked associations were observed.ConclusionsCompared to the previous meta-analyses, the results of this study confirmed that MDM2 T309G polymorphism might be a risk factor for lung cancer among never-smokers. However, the data failed to suggest a marked association between the G allele of MDM2 T309G and lung cancer risk among Asians. More interestingly, subgroup analysis by gender indicated that homozygous GG alleles might raise lung cancer risk among females.

Project description:There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

Project description:BackgroundAggressive management of heart and lung transplant (HLTx) requires a team of specialists with dedicated expert to improve long-term outcomes. This study aimed to summarize practical experiences of anesthetic management in HLTx operations.MethodsThis study retrospectively analyzed the anesthesia-related clinical records of 14 cases of HLTx performed from September 2015 to October 2019. Preoperative diagnoses included congenital heart disease with pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension with right heart failure, end-stage cor pulmonale, dilated cardiomyopathy, end-stage heart failure with pulmonary arterial hypertension, congenital heart disease, and lung transplant failure. All recipients received intravenous-inhalation general anesthesia with single-lumen endotracheal intubation, Swan-Ganz catheterization, and transesophageal echocardiography (TEE).ResultsAll 14 cases of HLTx were completed successfully and the patients were transferred to the intensive care units (ICUs). The postoperative data of the 14 patients were collected from 1 month to 4 years: seven cases survived the first year, four cases died in the short term (within 30 days), and one case died within 24 h. As at the end of November 2019, eight cases were reported dead (the longest survival was 2 years 1 month and 22 days). Four cases used extracorporeal membrane oxygenation (ECMO) for cardiopulmonary support.ConclusionsThe success of the HLTx was attributed to the joint efforts of the entire transplantation team. The anesthesiology team was required for experiences in anesthesia for HLTx. The key to anesthesia management was the in-depth participation in preoperative discussions and assessments. Preventing the exacerbation of right heart failure and pulmonary arterial hypertension is critical during the induction of anesthesia. Regulation and support are crucial from the withdrawal of cardiopulmonary bypass (CPB) to within 1 h of the circulation and respiratory functions undertaken independently by the donor heart and lungs.

Project description:Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.

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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.

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