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A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

ABSTRACT: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV(1) or FEV(1)/FVC traits using a carefully defined significance threshold of 1.3×10(-5). The most significant loci associated with FEV(1) include SNPs tagging MACROD2 (P?=?6.81×10(-5)), CNTN5 (P?=?4.37×10(-4)), and TRPV4 (P?=?1.58×10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV(1) (P?=?8.41×10(-5)), followed by PDE4D (P?=?1.22×10(-4)). The strongest association with FEV(1)/FVC ratio was observed with ABCC1 (P?=?4.38×10(-4)), and ESR1 (P?=?5.42×10(-4)) among ever-smokers.Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV(1) among smokers in the general population.

SUBMITTER: Obeidat M

PROVIDER: S-EPMC3098839 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

Obeidat Ma'en M Wain Louise V LV Shrine Nick N Kalsheker Noor N Soler Artigas Maria M Repapi Emmanouela E Burton Paul R PR Johnson Toby T Ramasamy Adaikalavan A Zhao Jing Hua JH Zhai Guangju G Huffman Jennifer E JE Vitart Veronique V Albrecht Eva E Igl Wilmar W Hartikainen Anna-Liisa AL Pouta Anneli A Cadby Gemma G Hui Jennie J Palmer Lyle J LJ Hadley David D McArdle Wendy L WL Rudnicka Alicja R AR Barroso Inês I Loos Ruth J F RJ Wareham Nicholas J NJ Mangino Massimo M Soranzo Nicole N Spector Tim D TD Gläser Sven S Homuth Georg G Völzke Henry H Deloukas Panos P Granell Raquel R Henderson John J Grkovic Ivica I Jankovic Stipan S Zgaga Lina L Polašek Ozren O Rudan Igor I Wright Alan F AF Campbell Harry H Wild Sarah H SH Wilson James F JF Heinrich Joachim J Imboden Medea M Probst-Hensch Nicole M NM Gyllensten Ulf U Johansson Åsa Å Zaboli Ghazal G Mustelin Linda L Rantanen Taina T Surakka Ida I Kaprio Jaakko J Jarvelin Marjo-Riitta MR Hayward Caroline C Evans David M DM Koch Beate B Musk Arthur William AW Elliott Paul P Strachan David P DP Tobin Martin D MD Sayers Ian I Hall Ian P IP

PloS one 20110520 5

<h4>Rationale</h4>Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the Spiro ...[more]

PMID: 21625484

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Project description:BACKGROUND:Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES:We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS:For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter <10 µm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)<0.05). Replication was attempted for SNPs with MAF>10% in 3320 SAPALDIA participants without GWAS. RESULTS:On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction)?=?2.5×10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction)?=?9.7×10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction)?=?3.0×10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS:Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.

Project description:Rationale & objectiveClonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.Study designCohort study.Setting & participants12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.ExposureCHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.OutcomeRisk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.Analytical approachCox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.ResultsThe median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.LimitationsSmall number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.ConclusionsWe report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

Project description:The objective of this study was to explore trajectories of lung function decline with age in the general population, and to study the effect of sociodemographic and life style related risk factors, in particular smoking and BMI. For this purpose, we used data from the Doetinchem Cohort Study (DCS) of men and women, selected randomly from the general population and aged 20-59 years at inclusion in 1987-1991, and followed until the present. Participants in the DCS are assessed every five years. Spirometry has been performed as part of this assessment from 1994 onwards. Participants were included in this study if spirometric measurement of FEV1, which in this study was the main parameter of interest, was acceptable and reproducible on at least one measurement round, leading to the inclusion of 5727 individuals (3008 females). Statistical analysis revealed three typical trajectories. The majority of participants followed a trajectory that closely adhered to the Global Lung Initiative Reference values (94.9% of men and 96.4% of women). Two other trajectories showed a more pronounced decline. Smoking and the presence of respiratory complaints were the best predictors of a trajectory with stronger decline. A greater BMI over the follow-up period was associated with a more unfavorable FEV1 course both in men (β = -0.027 (SD = 0.002); P < 0.001) and in women (β = -0.008 (SD = 0.001); P < 0.001). Smokers at baseline who quit the habit during follow-up, showed smaller decline in FEV1 in comparison to persistent smokers, independent of BMI change (In men β = -0.074 (SD = 0.020); P < 0.001. In women β = -0.277 (SD = 0.068); P < 0.001). In conclusion, three typical trajectories of age-related FEV1 decline could be distinguished. Change in the lifestyle related risk factors, BMI and smoking, significantly impact aging-related decline of lung function. Identifying deviant trajectories may help in early recognition of those at risk of a diagnosis of lung disease later in life.

Project description:IntroductionInsufficient vitamin D levels were found to be related to various psychiatric disorders and particularly depression. The functional polymorphisms rs4588 and rs7041 of the vitamin D-binding protein (also group-specific component or Gc) influence vitamin D level and activity. Resilience is considered the individual predisposition to maintain psychological functioning in the face of adversities. We sought to investigate whether associations of vitamin D levels and genotypes of rs4588 and rs7041 were associated with trait resilience and symptoms of depression.MethodsSerum levels of total 25(OH)D were measured in a general population sample (n = 1,908) of the Study of Health in Pomerania (SHIP-1). The Resilience Scale-25 (RS-25) was applied to assess trait resilience. Lifetime depressive symptoms were assessed using the CID-S, while current depressive symptoms were measured using the Beck Depression Inventory II (BDI-II). Study participants were genotyped for rs4588 and rs7041.ResultsParticipants with vitamin D insufficiency had lower adjusted mean RS-25 scores as compared to vitamin D replete subjects (p = .002). Linear regression analyses revealed a positive association between 25(OH)D and RS-25 scores (ß = 2.782, p = .002). Additional adjustment for BDI-II scores slightly attenuated this result (ß = 1.830 and p = .026). Symptoms of depression and the lifetime diagnosis of MDD were not significantly associated with vitamin D concentrations. rs4588 and rs7041 showed strong associations with vitamin D concentrations (both p < .001), but not RS-25 scores.ConclusionsIn contrast with previous studies, our findings do not provide evidence for a strong role of vitamin D in the psychopathology of depression. However, considering the role of trait resilience as a common protective factor to different psychiatric disorders, our results support the concept of low vitamin D as a general risk factor to stress-related psychopathologies.

Project description:ObjectiveThe purpose of this study was to identify prognostic inflammatory markers regulated by enhancers in lung adenocarcinoma (LUAD).MethodsInflammatory indices of 490 LUAD patients in TCGA database were calculated using genomic variation analysis (GSVA). Patients were divided into high- and low-inflammatory index groups. Fraction of 22 infiltrating immune cells was estimated using the Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). Gene set enrichment analysis (GSEA) was used to analyze gene enrichment. Differentially expressed genes were screened based on TCGA database. The H3K27ac ChIP-seq of A549 cells in GEO database (GSE42374) was analyzed to identify super enhancers. Kaplan-Meier method and multivariate Cox proportional hazards models were used for survival analysis. CCK8 and RT-qPCR were used for cellular level verification.ResultsInflammation was associated with better outcome in LUAD patients. Anti-cancer immune cell fractions were upregulated in high-inflammatory index group. Genes enriched in inflammation-related signaling pathways were positively correlated with high-inflammatory index group. A total of 146 upregulated genes regulated by enhancers were screened, of which five genes including GDF10, HPGDS, ABCA8, SLIT3 and ADAMTS8 had significant influence on prognosis. ChIP-seq analysis showed that TGFβ+TNFα treatment promoted the enhancer activation of the five genes. Cellular experiments revealed that there was no significant effect of TGFβ treatment on the five genes expression. TNFα treatment upregulated the five genes expression, while the BET-bromodomain inhibitor JQ1 restored the effect of TNFα. Overexpression of the five genes significantly inhibited the proliferation of A549 and H1299 cells.ConclusionGDF10, HPGDS, ABCA8, SLIT3 and ADAMTS8 were identified as enhancer-regulated prognostic inflammation-related biomarkers, and the expression of these genes inhibited proliferation of LUAD cells.

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A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

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A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.

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