Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Statement
2.2. Study Design and Participants
2.3. Genotype Data and Quality Control
2.4. Multidimensional Scaling and Identification of Genetic Outliers
2.5. Imputation
2.6. Candidate Gene and Genome-Wide Association Analyses
3. Results
3.1. Cohort Characteristics
3.2. Association Analyses in the Discovery Cohort (MIA/MIN-CH and MIA-CH)
3.2.1. Candidate Gene Analyses
3.2.2. Genome-Wide Association Analyses
3.2.3. Replication in Independent Cohorts
3.3. GWAS Meta-Analysis across Independent Cohorts
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cohort | MIA/MIN-CH | EuDAC-DE | EuDAC-ES | |||
---|---|---|---|---|---|---|
Cases | Controls | Cases | Controls | Cases | Controls | |
N = 45 | N = 191 | N = 12 | N = 92 | N = 29 | N = 181 | |
ANC < 500/uL | 30 (67) | - | 12 | - | 29 | - |
Sex, male (%) | 13 (42) | 17 (45) | 4 (33) | 41 (44.5) | 6 (21) | 87 (48) |
Age, years (%) | ||||||
<25 | 7 (23) | 1 (3) | 2 (16.6) | NA | 3 (10.3) | NA |
25–44 | 11 (35) | 6 (16) | 6 (50) | NA | 6 (21) | NA |
45–64 | 10 (32) | 15 (39) | 2 (16.6) | NA | 12 (41.4) | NA |
65–74 | 3 (10) | 9 (24) | 2 (16.6) | NA | 5 (17) | NA |
>74 | - | 7 (18) | - | NA | 3 (10.3) | NA |
BMI, median (range) | 24 (19–47) | 28 (16–39) | NA | NA | NA | NA |
Latency time * a/treatment duration b, days | 17 (1–204) | 25 (1–5297) | 33.5 (4–9855) | NA | 11.5 (1–235) | NA |
CHR | SNP | Alleles (Minor/Major) | BP | MAF Cases MIA/MIN-CH| EuDAC-ES| EuDAC-DE | MAF Controls MIA/MIN-CH| EuDAC-ES| EuDAC-DE | OR [95%] | p-Value | Gene Region | HetISq |
---|---|---|---|---|---|---|---|---|---|
1 | rs11583606 | T/C | 92349247 | 0.10| 014| 0.083 | 0.023| 0.025| 0.027 | 7.0 [3.37–14.5] | 1.72 × 10−7 | TGFBR3 | 0 |
1 | rs149072800 | C/T | 92445720 | 0.089| 0.12| 0.083 | 0.020| 0.019| 0.022 | 7.81 [3.57–17.1] | 2.66 × 10−7 | BRDT | 0 |
1 | rs146378328 | G/A | 92528047 | 0.089| 0.10| 0.083 | 0.018| 0.019| 0.021 | 8.31 [3.69–18.7] | 2.93 × 10−7 | EPHX4 | 0 |
1 | rs75499485 | G/A | 92486274 | 0.089| 0.10| 0.083 | 0.020| 0.019| 0.021 | 7.96 [3.56–17.8] | 4.23 × 10−7 | EPHX4 | 0 |
12 | rs112917452 | C/A | 15638858 | 0.067| 0.15| 0.042 | 0.016| 0.027| 0.016 | 7.30 [3.29–16.20] | 9.92 × 10−7 | PTPRO | 0 |
12 | rs118135416 | A/G | 15638914 | 0.067| 0.15| 0.042 | 0.016| 0.027| 0.016 | 7.30 [3.29–16.20] | 9.92 × 10−7 | PTPRO | 0 |
12 | rs7135120 | T/C | 15626920 | 0.067| 0.15| 0.042 | 0.016| 0.027| 0.016 | 7.30 [3.29–16.20] | 9.92 × 10−7 | PTPRO | 0 |
12 | rs143843248 | T/C | 15633812 | 0.067| 0.15| 0.041 | 0.016| 0.027| 0.016 | 7.30 [3.29–16.20] | 9.92 × 10−7 | PTPRO | 0 |
13 | rs73163933 | A/G | 33968020 | 0.12| 0.086| 0.21 | 0.036| 0.027| 0.054 | 5.36 [2.73–10.5] | 1.01 × 10−6 | STARD13 | 0 |
1 | rs78201766 | G/A | 92379078 | 0.10| 0.14| 0.083 | 0.026| 0.030| 0.027 | 5.65 [2.81–11.34] | 1.12 × 10−6 | TGFBR3 | 0 |
CHR | SNP | Alleles (Minor/Major) | BP | MAF Cases MIA/MIN-CH| EuDAC-ES| EuDAC-DE | MAF Controls MIA/MIN-CH| EuDAC-ES| EuDAC-DE | OR [95%] | p-Value | Gene Region | HetISq |
---|---|---|---|---|---|---|---|---|---|
9 | rs55898176 | T/C | 26715294 | 0.27| 0.24| 0.25 | 0.065| 0.12| 0.081 | 4.01 [2.41–6.68] | 1.01 × 10−7 | - | 21.7 |
9 | rs112223975 | C/G | 26715828 | 0.27| 0.24| 0.25 | 0.065| 0.12| 0.081 | 3.89 [2.34–6.48] | 1.50 × 10−7 | - | 28.6 |
9 | rs11790418 | G/A | 26713012 | 0.27| 0.24| 0.25 | 0.065| 0.12| 0.098 | 3.81 [2.29–6.35] | 2.54 × 10−7 | - | 29.3 |
9 | rs1434481 | G/C | 26711134 | 0.27| 0.24| 0.25 | 0.065| 0.11| 0.098 | 3.81 [2.29–6.35] | 2.54 × 10−7 | - | 29.3 |
9 | rs28475568 | G/C | 26709933 | 0.27| 0.24| 0.25 | 0.065| 0.11| 0.098 | 3.81 [2.29–6.35] | 2.54 × 10−7 | - | 29.3 |
9 | rs28649995 | A/G | 26709912 | 0.27| 0.24| 0.25 | 0.065| 0.11| 0.098 | 3.81 [2.29–6.35] | 2.54 × 10−7 | - | 14.6 |
9 | rs56285046 | A/G | 26714950 | 0.28| 0.24| 0.25 | 0.073| 0.12| 0.092 | 3.70 [2.27–6.05] | 3.25 × 10−7 | - | 0 |
9 | rs77949268 | A/G | 26738366 | 0.27| 0.26| 0.25 | 0.078| 0.12| 0.10 | 3.59 [2.20–5.87] | 3.74 × 10−7 | - | 0 |
9 | rs4427239 | A/G | 113270601 | 0.16| 0.15| 0.041 | 0.029| 0.041| 0.016 | 5.47 [2.81–10.65] | 5.75 × 10−7 | SVEP1 | 0 |
9 | rs10759436 | C/T | 113268650 | 0.15| 0.15| 0.041 | 0.029| 0.041| 0.016 | 5.81 [2.92–11.54] | 8.13 × 10−7 | SVEP1 | 0 |
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Cismaru, A.L.; Rudin, D.; Ibañez, L.; Liakoni, E.; Bonadies, N.; Kreutz, R.; Carvajal, A.; Lucena, M.I.; Martin, J.; Sancho Ponce, E.; Molokhia, M.; Eriksson, N.; EuDAC collaborators; Krähenbühl, S.; Largiadèr, C.R.; Haschke, M.; Hallberg, P.; Wadelius, M.; Amstutz, U. Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes 2020, 11, 1275. https://doi.org/10.3390/genes11111275
Cismaru AL, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Carvajal A, Lucena MI, Martin J, Sancho Ponce E, Molokhia M, Eriksson N, EuDAC collaborators, Krähenbühl S, Largiadèr CR, Haschke M, Hallberg P, Wadelius M, Amstutz U. Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes. 2020; 11(11):1275. https://doi.org/10.3390/genes11111275
Chicago/Turabian StyleCismaru, Anca Liliana, Deborah Rudin, Luisa Ibañez, Evangelia Liakoni, Nicolas Bonadies, Reinhold Kreutz, Alfonso Carvajal, Maria Isabel Lucena, Javier Martin, Esther Sancho Ponce, Mariam Molokhia, Niclas Eriksson, EuDAC collaborators, Stephan Krähenbühl, Carlo R. Largiadèr, Manuel Haschke, Pär Hallberg, Mia Wadelius, and Ursula Amstutz. 2020. "Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations" Genes 11, no. 11: 1275. https://doi.org/10.3390/genes11111275