TY - JOUR
T1 - Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function
AU - Reardon, Brian J.
AU - Hansen, Joyanna G.
AU - Crystal, Ronald G.
AU - Houston, Denise K.
AU - Kritchevsky, Stephen B.
AU - Harris, Tamara
AU - Lohman, Kurt
AU - Liu, Yongmei
AU - O'Connor, George T.
AU - Wilk, Jemma B.
AU - Mezey, Jason
AU - Gao, Chuan
AU - Cassano, Patricia A.
N1 - Funding Information:
This research was supported by National Institutes of Health, National Heart Lung and Blood Institute R03 HL095414 (PAC) and P50 HL084936 (RGC), by RC1-AG035835 (SK, PI; PAC, PI subcontract), and by NRSA Institutional Research Training Grant T32-DK-7158-36 (JGH). This research also was supported by R01‐ AG029364, by NIA contracts N01AG62101, N01AG62103, and N01AG62106, and by the Ashken Foundation (RGC). The genome-wide association study was funded by NIA grant R01-AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Research was conducted in part using data and resources from the Framingham Heart Study of the NHLBI of the NIH and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the NHLBI's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyp-ing services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.
PY - 2013/11/25
Y1 - 2013/11/25
N2 - 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.
AB - 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.
KW - Airflow obstruction
KW - FEV1
KW - FEV1/FVC
KW - SGPP2
KW - Vitamin D
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U2 - 10.1186/1471-2350-14-122
DO - 10.1186/1471-2350-14-122
M3 - Article
C2 - 24274704
AN - SCOPUS:84888103206
SN - 1755-8794
VL - 14
JO - BMC Medical Genetics
JF - BMC Medical Genetics
IS - 1
M1 - 122
ER -