Table 4.
Genetic variants associated with irAE development.
| Author | Sample size | Cancer type | Type of ICI studied | Genetic analysis approach | Toxicity type | Chr | SNPs | Effect size (95% CI) | P value | Mapped gene/nearest genes |
|---|---|---|---|---|---|---|---|---|---|---|
| Abdel-Wahab102 | 89 (44 cases, 45 controls) | Melanoma | Anti-CTLA-4, anti-PD-1/PDL1, combined ICI | All tagging SNPs | ≥Grade 2 irAE | 5 | rs11743438 | 4.30 (2.3–8.0) | 5.56 × 10–6 | GABRP |
| 5 | rs11743735 | 4.50 (2.3–8.8) | 8.34 × 10–6 | GABRP | ||||||
| 20 | JHU_20.57183980 | 6.90 (2.7–17.6) | 8.85 × 10–6 | DSC2 | ||||||
| 2 | rs56328422 | 4.20 (2.1–8.4) | 4.14 × 10–5 | BAZ2B | ||||||
| 3 | rs35807769 | 4.90 (2.2–11.1) | 6.07 × 10–5 | Near genes ZPLD1 and MIR548AB | ||||||
| 5 | rs3026321 | 19.80 (2.6–152.7) | 6.31 × 10–5 | SEMA5A | ||||||
| 5 | rs1276216 | 6.40 (2.3–17.6) | 8.18 × 10–5 | Near genes LOC105374704 and CDH6 | ||||||
| 2 | rs919682 | 4.60 (2.1–10.1) | 8.29 × 10–5 | OSBPL6 | ||||||
| 2 | JHU_2.179128562 | 4.60 (2.1–10.1) | 8.29 × 10–5 | AGPS | ||||||
| 21 | rs239731 | 11.30 (2.5–50.4) | 8.56 × 10–5 | LOC102724355 | ||||||
| 5 | JHU_5.9269447 | 3.50 (1.9–6.5) | 8.61 × 10–5 | SEMA5A | ||||||
| 2 | rs359975 | 8.50 (2.4–29.9) | 9.41 × 10–5 | Near genes CFAP65 and LOC100129175 | ||||||
| 3 | rs11711517 | 0.16 (0.07–0.37) | 2.39 × 10–6 | LOC105377125 | ||||||
| 15 | JHU_15.93602126 | 0.24 (0.13–0.46) | 8.89 × 10–6 | RGMA | ||||||
| 15 | JHU_15.93604000 | 0.24 (0.13–0.46) | 8.89 × 10–6 | RGMA | ||||||
| 18 | rs470753 | 0.16 (0.07–0.40) | 1.65 × 10–5 | Near genes LINC01924 and CDH7 | ||||||
| 15 | rs4778080 | 0.24 (0.12–0.47) | 1.92 × 10–5 | RGMA | ||||||
| 12 | rs2117997 | 0.22 (0.10–0.45) | 2.44 × 10–5 | ANKRD42 | ||||||
| 6 | rs55733913 | 0.16 (0.06–0.42) | 3.98 × 10–5 | PACRG | ||||||
| 12 | rs7954686 | 0.16 (0.06–0.42) | 3.98 × 10–5 | FAR2 | ||||||
| 3 | rs6440251 | 0.13 (0.04–0.40) | 5.15 × 10–5 | LOC105374140 | ||||||
| 14 | JHU_14.101799748 | 0.11 (0.03–0.38) | 5.20 × 10–5 | Near genes LINC02285 and LINC00524 | ||||||
| 18 | rs4800887 | 0.25 (0.13–0.50) | 5.74 × 10–5 | Near genes CDH2 and MIR302F | ||||||
| 3 | rs162263 | 0.24 (0.12–0.49) | 5.88 × 10–5 | ROBO1 | ||||||
| 9 | rs10814859 | 0.24 (0.12–0.49) | 5.88 × 10–5 | GLIS3 | ||||||
| 3 | kgp3960064 | 0.28 (0.15–0.53) | 6.76 × 10–5 | ROBO1 | ||||||
| 3 | rs2062059 | 0.28 (0.15–0.53) | 7.37 × 10–5 | Near genes DCBLD2 and MIR548G | ||||||
| 8 | rs12548560 | 0.28 (0.14–0.53) | 8.95 × 10–5 | PVT1 | ||||||
| 6 | rs66502444 | 0.16 (0.06–0.43) | 9.11 × 10–5 | PACRG | ||||||
| 8 | rs6993547 | 0.16 (0.06–0.43) | 9.11 × 10–5 | PREX2 | ||||||
| Bins57 | 322 (96 cases, 226 controls) | NSCLC | Anti-PD-1 | Small scale candidate study | Elevated liver transaminases | 12 | rs2301756* | 2.31 (1.02–5.21)a | 0.041 | PTPN11 (SHP2) |
| Rheumatological toxicity | 12 | rs2069705* | 6.04 (1.53–23.86)a | 0.019 | IFNG | |||||
| Treatment-related adverse events | 2 | rs2227981* | 0.45 (0.21–0.98)a | 0.041 | PDCD1 804C>T (PD-1) | |||||
| Queirolo103 | 173 (10 cases, 163 control) | Melanoma | Anti-CTLA-4 | Small scale candidate study | Endocrinopathies | 2 | rs4553808 (A/G or G/G genotypes) | 0.09 (0.02–0.43)a,b | 0.003 | CTLA-4–1661A>G |
| Cappelli59 | 753 (27 cases, 726 controls) | Mixed (largest cohort Melanoma) | Anti-PD-1/CTLA-4, anti-PD-1/PD-L1+/− anti-CD73 or anti-LAG3 | HLA specific approach | Inflammatory arthritis | 6 | HLA DRB1*04: 05 | 8.60 (1.70–43.40) | 0.040 | HLA |
| Magis60 | 163 (5 cases, 158 controls) | Melanoma | Anti-PD-1 | HLA specific approach | Acute type 1 diabetes | 6 | HLA DRB1*04:01, DRB1*04:05, DRB1*03:01 | NA | NA | HLA |
| Refae56 | 94 (15 cases, 79 controls) | Advanced cancer (largest cohort NSCLC) | Anti-PD-1/PDL1 | Medium scale candidate study | Serious ≥grade 3 irAE | 12 | rs246079 | 0.09 (0.02–0.36)c | <0.001 | UNG |
| 9 | rs10964859 | 6.08 (1.52–24.33)b | 0.014 | IFNW1 | ||||||
| 9 | rs4143815 | 8.11 (2.09–31.40)b | 0.003 | PD-L1 | ||||||
| 19 | rs12979860 | 3.72 (1.09–12.68)b | 0.036 | IFNL4 | ||||||
| 2 | rs3087243 | 3.19 (1.01–10.27)b | 0.048 | CTLA4 | ||||||
| 2 | rs11571302 | 4.06 (1.23–13.38)b | 0.018 | CTLA4 | ||||||
| 2 | rs7565213 | 3.73 (1.14–12.19)b | 0.026 | CTLA4 | ||||||
| Iafolla62 | 101 (23 cases, 78 controls) | Mixed (largest cohort triple negative breast cancer) | Anti-PD-1 | HLA specific approach | ≥Grade 2 irAE | 6 | HLA-A | 1.03 (0.23–4.62)d | 0.970 | HLA |
| 6 | HLA-B | 1.32 (0.24–7.26)d | 0.750 | HLA | ||||||
| 6 | HLA-C | 0.81 (0.24–2.78)d | 0.740 | HLA | ||||||
| 6 | HLA-A, -B and -C | 0.58 (0.21–1.62)d | 0.300 | HLA | ||||||
| Hasan Ali58 | 102 (59 cases, 43 controls) | Advanced cancer | Anti-PD-1 | HLA specific approach | Pruritus | 6 | HLA-DRB1*11:01 | 4.53 (X21,95 = 9.45) | 0.002 | HLA |
| Colitis | 6 | HLA-DQB1*03:01 | 3.94 (X21,95 = 5.67) | 0.017 | HLA | |||||
| Luo69 | 729 (95 cases, 634 controls) | NSCLC | Anti-PD-1 or combined anti-PD-1 and CTLA-4 | All tagging SNPs | Thyroid disorders | 6 | rs9268543 | NA | 7.5 × 10–7 | HLA |
| Kirchhoff104 | 69 (30 cases, 39 controls | Melanoma | Anti-CTLA-4 | Whole exome sequencing and detection of ~1000 autoimmune variants | Serious ≥grade 3 irAE | 19 | rs504963 | 2.57 | 0.006 | 3’UTR of FUT2 |
| 6 | rs1738074 | 2.21 | 0.025 | TAGAP | ||||||
| Montaudié70 | 57 (33 cases, 24 controls) | Melanoma | Anti-PD-1, Anti-CTLA-4, combined anti-PD-1 and anti-CTLA-4 | All tagging SNPs | Any grade irAE | 2 | rs782637 | NA | 4.10 × 10–8 | PNPT1 |
| 2 | rs78259 | NA | 3.40 × 10–7 | PNPT1 | ||||||
| 2 | rs7882572 | NA | 3.80 × 10–7 | PNPT1 | ||||||
| 2 | rs3762513 | NA | 6.60 × 10–7 | CFAP36 | ||||||
| 11 | rs7481951 | NA | 3.10 × 10–5 | ANO5 | ||||||
| 2 | rs4988956 | NA | 3.80 × 10–4 | IL1RL1 | ||||||
| Yano61 | 11 cases | Melanoma, NSCLC, gastric | Anti-PD-1, anti-CTLA-4 | HLA specific approach | Pituitary disorders | 6 | HLA-DR15 | NA | 1.40 × 10–3 | HLA |
| 6 | HLA-DR1502 | NA | 0.002 | HLA | ||||||
| 6 | HLA-Cw12 | NA | 0.001 | HLA | ||||||
| 6 | HLA-B52 | NA | 0.003 | HLA | ||||||
| Marschner105 | 167 (39 cases. 128 controls) | Melanoma, lung | Anti-PD-1/PDL1 | Small scale candidate study | Serious ≥grade 3 irAE | 5 | rs2910164 (C/C genotype) | 6.78 (1.87–24.60) | 0.004 | MIR146A |
| Groha65 | 1751 (339 cases, 1412 controls) | Mixed (largest cohort NSCLC) | Anti-PD-1/PD-L1, combined ICI, anti-CTLA-4 | All tagging SNPs | All grade irAE | 8 | rs16906115 | HR = 2.0 (1.6–2.5) | 3.8 × 10–9 | IL-7 |
| 1 | rs75824728* | HR = 1.9 (1.5–2.4) | 8.4 × 10–9 | IL22RA1 | ||||||
| 4 | rs113861051* | HR = 2.0 (1.6–2.6) | 1.1 × 10–8 | Near genes LINC02484 and ARAP2 | ||||||
| Weidhaas68 | 161 (45 cases, 116 controls) | Mixed (largest cohort melanoma) | Anti-PD-1/PD-L1 | Candidate study (50 common variants mapping to regions expected to disrupt miRNAs) | ≥Grade 2 irAE | 7 | rs9374 | AUC 0.82 (in a panel) | <0.001 | RAC1 |
| Udagawa66 | 622 (520 cases, 102 controls) | Mixed (largest cohort lung) | Anti-PD-1 | All tagging SNPs | All ≥grade 1 irAE | 21 | rs469490 | 5.15 (2.39–13.22) | 2.97 × 10–7 | Near genes APP and CYYR1-AS1 |
| ≥Grade 1 Thyroid irAE | 15 | rs8023690 | 4.09 (2.21–8.15) | 2.59 × 10–7 | Near genes RGMA and LINC02207 |
Studies investigating on genetic determinants of irAE were reviewed up till October 2022. Effect sizes for all studies are reported in odds ratios and 95% CI unless indicated otherwise.
Chr chromosome, CI confidence interval, HR hazard ratio, ICI immune checkpoint inhibitor, irAE immune-related adverse events, NA not available, NSCLC non-small cell lung cancer, SNPs single nucleotide polymorphism.
aUnivariate analysis.
bUnder recessive model.
cUnder dominant model.
dSummary statistics based on HLA-1 loci heterozygosity relative to homozygosity.
*Did not validate in independent sample sets.