Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Sample
2.2. Cytokine Measurement and Analysis
2.3. Genotyping, Quality Control, and Imputation
2.4. Genome-Wide Association Study
2.5. Conditional and Joint Analysis
2.6. Credible Set Analysis
2.7. Colocalisation Analysis
2.8. MetaXcan Analysis
2.9. Lookup of Cytokine Coding Genes
3. Results
3.1. Genome-Wide Association Study and Secondary Analyses
3.2. Known Associations
3.2.1. Vascular Endothelial Growth Factor and Interleukin 12
3.2.2. Interleukin 1β
3.3. Novel Associations
3.3.1. Interleukin 1β
3.3.2. Interleukin 10
3.3.3. Macrophage Inflammatory Protein 1α
3.4. Lookup of Cytokine-Coding Genes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trait | Statistics |
---|---|
Age [years] | 62 (18–94) |
Males/Females | 239 (60%)/161 (40%) |
Body mass index [kg/m2] | 26.3 (15.0–54.3) |
Current smoking | 117 (29%) |
Years of smoking (current and former smoker) | 14 (0–65) |
Years of smoking (only current smoker) | 25 (4–60) |
Chronic kidney disease | 39 (10%) |
Chronic liver disease | 9 (2%) |
Diabetes | 83 (21%) |
Antibiotic therapy prior to hospitalisation | 100 (25%) |
Locus | Lead SNP | Cytoband | Physical Position | Physical Nearby Genes (Distance to Lead SNP (kb)) | Best Associated Trait | Effect Allele | Other Allele | Allele Frequency | Beta | SE | p-Value | #SNPs in Credible Set (First: 95%, Second: 99%) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
#1 | rs116606423 | 2p16.3 | 50123457 | RPL7P13 (17), NRXN1 (22) | IL-1β | G | T | 0.02 | 1.39 | 0.25 | 3.46 × 10−8 | 3484 3819 |
#2 | rs139453626 | 3p21.31 | 47700006 | SMARCC1 (0), CSPG5 (78), RN7SL870P (98), DHX30 (140) | IL-10 | G | A | 0.02 | 2.42 | 0.42 | 2.39 × 10−8 | - |
#3 | rs7763440 | 6p21.1 | 43926708 | C6orf223 (42), MRPL14 (150), TMEM63B (170), VEGFA (170) | VEGF | A | G | 0.45 | −0.65 | 0.07 | 1.58 × 10−20 | 10 12 |
#4 | rs145122044 | 7q11.23 | 76485397 | UPK3B (0), FDPSP7 (110), DTX2P1 (120), DTX2P1-UPK3BP1-PMS2P11 (120) | MIP-1α (CCL3) | C | T | 0.01 | 1.54 | 0.27 | 1.55 × 10−8 | 3230 3631 |
#5 | rs62505830 | 8p12 | 36121891 | RN7SKP201 (2.1), MTND6P19 (15), RNU6-533P (45) | IL-1β | T | C | 0.01 | 1.72 | 0.30 | 2.55 × 10−8 | 814 944 |
#6 | rs36002018 | 9q34.12 | 133656053 | ABL1 (0), EXOSC2 (76), PRDM12 (98), QRFP (110) | IL-10 | T | A | 0.02 | 1.75 | 0.31 | 4.52 × 10−8 | 2534 3160 |
#7 | rs75237116 | 10p13 | 12655293 | CAMK1D (0), MIR4480 (34), MIR548Q (110), RNU6ATAC39P (160) | MIP-1α (CCL3) | T | C | 0.01 | 1.64 | 0.27 | 2.28 × 10−9 | 3945 4541 |
#8 | rs6481492 | 10p12.1 | 28207393 | ARMC4 (0), RPL36AP55 (13), MPP7 (130), RN7SKP132 (130) | IL-1β | C | T | 0.06 | 0.79 | 0.13 | 2.76 × 10−9 | 29 50 |
#9 | rs11223001 | 11q25 | 132161625 | NTM (0), NTM-IT (6.6), OPCML (120), RNU6-1182P (230) | MIP-1α (CCL3) | G | A | 0.01 | 1.56 | 0.27 | 1.73 × 10−8 | - |
#10 | rs118008913 | 15q14 | 39036672 | C15orf53 (44), RASGRP1 (180) | MIP-1α (CCL3) | G | A | 0.02 | 1.10 | 0.20 | 4.81 × 10−8 | 3397 3761 |
#11 | rs117439842 | 17q21.32 | 45933872 | SP6 (0.63), SCRN2 (15), LRRC46 (19), MRPL10 (25), OSBPL7 (35), SP2 (40) | IL-1β | T | G | 0.01 | 1.96 | 0.32 | 1.51 × 10−9 | 10 23 |
#12 | rs8082167 | 17q22 | 52494156 | ISCA1P3 (61) | MIP-1α (CCL3) | T | C | 0.02 | 1.31 | 0.23 | 1.22 × 10−8 | 2838 3247 |
#13 | rs76920584 | 18q21.2 | 51386971 | - | IL-1β | C | T | 0.01 | 1.49 | 0.26 | 2.11 × 10−8 | 194 1687 |
#14 | rs3788792 | Xq13.1 | 71585878 | HDAC8 (0), RNU2-68P (11), CITED1 (59), PIN4 (63) | MIP-1α (CCL3) | T | C | 0.02 | 1.17 | 0.19 | 2.74 × 10−9 | - |
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Kühnapfel, A.; Horn, K.; Klotz, U.; Kiehntopf, M.; Rosolowski, M.; Loeffler, M.; Ahnert, P.; Suttorp, N.; Witzenrath, M.; Scholz, M. Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia. Genes 2022, 13, 111. https://doi.org/10.3390/genes13010111
Kühnapfel A, Horn K, Klotz U, Kiehntopf M, Rosolowski M, Loeffler M, Ahnert P, Suttorp N, Witzenrath M, Scholz M. Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia. Genes. 2022; 13(1):111. https://doi.org/10.3390/genes13010111
Chicago/Turabian StyleKühnapfel, Andreas, Katrin Horn, Ulrike Klotz, Michael Kiehntopf, Maciej Rosolowski, Markus Loeffler, Peter Ahnert, Norbert Suttorp, Martin Witzenrath, and Markus Scholz. 2022. "Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia" Genes 13, no. 1: 111. https://doi.org/10.3390/genes13010111