Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function

Background: Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Methods: Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). Results: 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. Conclusions: SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Baseline characteristics of cohort studies included in the meta-analysis^*.

<p><i>Definition of abbreviations</i>: ARIC  =  Atherosclerosis Risk in Communities; B58C  =  British 1958 Birth Cohort; BHS  =  Busselton Health Study; CARDIA  =  Coronary Artery Risk Development in Young Adults; CHS  =  Cardiovascular Health Study  =  FHS, Framingham Heart Study; Health ABC  =  Health, Aging, and Body Composition; KORA  =  Cooperative Health Research in the Region of Augsburg; LBC1921  =  Lothian Birth Cohort 1921; LBC1936  =  Lothian Birth Cohort 1936; PIVUS  =  Prospective Investigation of the Vasculature in Uppsala Seniors; RS  =  Rotterdam Study; SAPALDIA  =  Swiss Study on Air Pollution and Lung Diseases in Adults; SD  =  standard deviation; SHIP  =  Study of Health in Pomerania.</p><p>^*Data are presented as mean (SD) unless otherwise indicated; total no. participants  =  27,249, total no. FEV₁ measurements  =  62,130.</p>†<p>Pack-years are calculated among current and former smokers at study baseline.</p

Association of the chromosome 15 locus with the rate of change in FEV₁ in the meta-analysis of 14 cohort studies.

<p><b>A</b>) Regional association plot, where the X-axis is Megabase (Mb) position and Y-axes are the negative log of the <i>P</i> value on the left and recombination rate on the right. The sentinel SNP is colored in purple and linkage disequilibrium to the sentinel SNP is depicted by degree of color according to the legend. <b>B</b>) Forest plot for rs4077833, where the size of the square for each study represents its contributing weight to the meta-analysis.</p

Association of the most statistically significant SNPs with the rate of change in FEV₁ (mL/year) in the meta-analysis of 14 cohort studies (n = 27,249)^*.

<p><i>Definition of abbreviations</i>: Chr  =  chromosome; SE  =  standard error; SNP  =  single-nucleotide polymorphism.</p><p>^*Data reported are the meta-analysis results of the SNP-by-time interaction term from the GWAS mixed effects model. A positive β-coefficient indicates an attenuation of FEV₁ decline and a negative β-coefficient an acceleration of FEV₁ decline.</p

Association of the most statistically significant SNPs with the rate of change in FEV₁ (mL/year) in the meta-analysis of the five cohort studies with ≥3 FEV₁ measurements per participant (n = 10,476).

<p><i>Definition of abbreviations</i>: Chr  =  chromosome; SE  =  standard error; SNP  =  single-nucleotide polymorphism.</p><p>^*Data reported are the meta-analysis results of the SNP-by-time interaction term from the GWAS mixed effects model. A positive β-coefficient indicates an attenuation of FEV₁ decline and a negative β-coefficient an acceleration of FEV₁ decline.</p