Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Autor: Sun, Wei, Kechris, Katerina, Jacobson, Sean, Drummond, M Bradley, Hawkins, Gregory A, Yang, Jenny, Chen, Ting-Huei, Quibrera, Pedro Miguel, Anderson, Wayne, Barr, R Graham, Basta, Patricia V, Bleecker, Eugene R, Beaty, Terri, Casaburi, Richard, Castaldi, Peter, Cho, Michael H, Comellas, Alejandro, Crapo, James D, Criner, Gerard, Demeo, Dawn, Christenson, Stephanie A, Couper, David J, Curtis, Jeffrey L, Doerschuk, Claire M, Freeman, Christine M, Gouskova, Natalia A, Han, MeiLan K, Hanania, Nicola A, Hansel, Nadia N, Hersh, Craig P, Hoffman, Eric A, Kaner, Robert J, Kanner, Richard E, Kleerup, Eric C, Lutz, Sharon, Martinez, Fernando J, Meyers, Deborah A, Peters, Stephen P, Regan, Elizabeth A, Rennard, Stephen I, Scholand, Mary Beth, Silverman, Edwin K, Woodruff, Prescott G, O'Neal, Wanda K, Bowler, Russell P, SPIROMICS Research Group, COPDGene Investigators
Přispěvatelé: Gibson, Greg
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Chronic bronchitis
Pulmonology
Physiology
Gene Expression
Genome-wide association study
QH426-470
Bioinformatics
Biochemistry
Pulmonary Disease
Chronic Obstructive
Mathematical and Statistical Techniques
0302 clinical medicine
Medicine and Health Sciences
2.1 Biological and endogenous factors
Aetiology
Lung
Genetics (clinical)
Genetics
Genomics
Hematology
Blood Proteins
Single Nucleotide
Obstructive lung disease
Body Fluids
3. Good health
Phenotypes
Blood
Physical Sciences
Respiratory
Biomarker (medicine)
Anatomy
Statistics (Mathematics)
Research Article
Chronic Obstructive
Genotype
Chronic Obstructive Pulmonary Disease
Quantitative Trait Loci
Single-nucleotide polymorphism
Biology
Quantitative trait locus
Research and Analysis Methods
Polymorphism
Single Nucleotide
ABO Blood-Group System
Pulmonary Disease
03 medical and health sciences
ABO blood group system
Genome-Wide Association Studies
medicine
Humans
Genetic Predisposition to Disease
Statistical Methods
Polymorphism
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Genetic association
Emphysema
COPDGene Investigators
Prevention
Human Genome
Biology and Life Sciences
Computational Biology
Human Genetics
SPIROMICS Research Group
Genome Analysis
medicine.disease
Good Health and Well Being
030104 developmental biology
030228 respiratory system
Mathematics
Biomarkers
Meta-Analysis
Genome-Wide Association Study
Developmental Biology
Zdroj: PLoS genetics, vol 12, iss 8
PLoS Genetics
PLoS Genetics, Vol 12, Iss 8, p e1006011 (2016)
ISSN: 1553-7404
Popis: Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.
Author Summary Precision medicine is an emerging approach that takes into account variability in genes, gene and protein expression, environment and lifestyle. Recent advances in high-throughput genome-wide genotyping, genomics, and proteomics coupled with the creation of large, highly-phenotyped clinical cohorts now allows for integration of these molecular data sets at the individual level. Here we use genome-wide genotyping and blood measurements of 88 biomarkers in 1,340 subjects from two large NIH-supported clinical cohorts of smokers (SPIROMICS and COPDGene) to identify more than 300 novel DNA variants that influence measurement of blood protein levels (pQTLs). We find that many DNA variants explain a large portion of the variability of measured protein expression in blood. Furthermore, we show that integration of DNA variants with blood biomarker levels can improve the ability of predictive models to reflect the relationship between biomarker and disease features (e.g., emphysema) within chronic obstructive pulmonary disease (COPD).
Databáze: OpenAIRE
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