Table 1.
Statistically significant variants from meta-analysis, false-positive report probabilities (FPRPs), and cumulative epidemiological evidence.
| Gene | Variant | Alleles | Ethnicity | MAF† | Studies | Number evaluation | Risk of meta-analysis | PQ | Amount of evidence | Replication | Protection from bias | Reason for bias exemption | Venice criteria grade§ | FPRP values at prior probability of 0.05 and OR of 1.5 | Cumulative epidemiological evidence¶ | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample size (case/control) | Genetic models | Effect model | OR (95% CI) | Pvalue | I (%) | N‡minor | Grade | Grade | Pegger | ||||||||||||
| POU5F1B | rs6983267 | G > T | Overall | 0.47 | 10 | 30673 (7504/23169) | Allelic | F | 1.129 (1.086 − 1.174) | ≤0.01 | 28.1 | 0.19 | 29188 | A | B | Ca | 0.25 | No | ABC | ≤0.01 | Moderate |
| 9 | 27428 (7018/20410) | Dominant | F | 1.175 (1.107 − 1.247) | ≤0.01 | 0.0 | 0.48 | 20223 | A | A | A | 0.33 | No | AAA | ≤0.01 | Strong | |||||
| 9 | 27428 (7018/20410) | Recessive | F | 1.158 (1.091 − 1.228) | ≤0.01 | 27.6 | 0.19 | 6725 | A | B | A | 0.28 | No | ABA | ≤0.01 | Strong | |||||
| miR-146a | rs2910164 | G > C | Overall | 0.32 | 12 | 16737 (4857/11880) | Dominant | R | 1.144 (1.003 − 1.304) | ≤0.01 | 57.0 | ≤0.01 | 8639 | A | C | Ca | 0.89 | No | ACC | 0.46 | Weak |
| FOXE1 | rs71369530 | >14-Ala vs. ≤14-Ala | Caucasian | 0.24 | 4 | 1271 (576/695) | Allelic | R | 1.836 (1.353 − 2.492) | ≤0.01 | 64.5 | 0.04 | 757 | B | C | A | 0.27 | No | BCA | 0.02 | Moderate |
| FOXE1 | rs907580 | C > T | Caucasian | 0.26 | 3 | 6884 (497/6387) | Allelic | R | 1.593 (1.184 − 2.145) | ≤0.01 | 67.6 | 0.05 | 3733 | A | C | A | 0.80 | No | ACA | 0.11 | Weak |
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| NKX2-1 | rs944289 | C > T | Overall | 0.55 | 17 | 65182 (9467/55715) | Allelic | F | 1.304 (1.255 − 1.355) | ≤0.01 | 45.5 | 0.02 | 72278 | A | B | A | 0.40 | No | ABA | ≤0.01 | Strong |
| 10 | 16277 (5187/11090) | Dominant | F | 1.609 (1.465 − 1.767) | ≤0.01 | 26.3 | 0.20 | 12706 | A | B | A | 0.24 | No | ABA | ≤0.01 | Strong | |||||
| 10 | 16277 (5187/11090) | Recessive | F | 1.414 (1.301 − 1.536) | ≤0.01 | 40.5 | 0.09 | 5073 | A | B | A | 0.14 | No | ABA | ≤0.01 | Strong | |||||
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| FOXE1 | rs965513 | G > A | Overall | 0.34 | 18 | 61943 (8167/53776) | Allelic | R | 1.703 (1.575 − 1.842) | ≤0.01 | 66.7 | ≤0.01 | 43701 | A | C | A | 0.13 | No | ACA | ≤0.01 | Moderate |
| 9 | 14348 (3680/10668) | Dominant | R | 1.694 (1.429 − 2.010) | ≤0.01 | 68.4 | ≤0.01 | 7542 | A | C | A | 0.17 | No | ACA | ≤0.01 | Moderate | |||||
| 9 | 14348 (3680/10668) | Recessive | F | 1.954 (1.729 − 2.208) | ≤0.01 | 46.4 | 0.06 | 1599 | A | B | Cd | 0.02 | No | ABC | ≤0.01 | Moderate | |||||
| DIRC3 | rs966423 | T > C | Overall | 0.50 | 5 | 9604 (4953/4651) | Allelic | F | 1.227 (1.153 − 1.306) | ≤0.01 | 0.0 | 0.44 | 9931 | A | A | A | 0.13 | No | AAA | ≤0.01 | Strong |
| FOXE1 | rs1443434 | T > G | Caucasian | 0.39 | 4 | 9627 (2453/7174) | Allelic | R | 1.392 (1.084 − 1.787) | ≤0.01 | 78.7 | ≤0.01 | 7800 | A | C | A | 0.54 | No | ACA | 0.20 | Weak |
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| FOXE1 | rs1867277 | G > A | Caucasian | 0.39 | 12 | 21820 (5654/16166) | Allelic | F | 1.503 (1.426 − 1.583) | ≤0.01 | 43.7 | 0.05 | 18169 | A | B | A | 0.47 | No | ABA | ≤0.01 | Strong |
| 6 | 10702 (2958/7744) | Dominant | R | 1.702 (1.352 − 2.143) | ≤0.01 | 65.4 | ≤0.01 | 6892 | A | C | A | 0.21 | No | ACA | ≤0.01 | Moderate | |||||
| 6 | 10702 (2958/7744) | Recessive | F | 1.703 (1.498 − 1.937) | ≤0.01 | 44.4 | 0.11 | 1809 | A | B | A | 0.20 | No | ABA | ≤0.01 | Strong | |||||
| FOXE1 | rs2439302 | C > G | Overall | 0.35 | 4 | 9265 (3146/6119) | Allelic | F | 1.325 (1.240 − 1.415) | ≤0.01 | 25.6 | 0.26 | 7409 | A | B | A | 0.42 | No | ABA | ≤0.01 | Strong |
| FOXE1 | rs30215269 | T > C | Caucasian | 0.39 | 3 | 6997 (684/6313) | Allelic | R | 1.634 (1.254 − 2.127) | ≤0.01 | 62.0 | 0.07 | 5555 | A | C | A | 0.99 | No | ACA | 0.97 | Weak |
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| MTHFR C677T | rs1801133 | C > T | Overall | 0.30 | 8 | 6267 (2902/3365) | Allelic | R | 1.418 (1.114 − 1.806) | ≤0.01 | 71.4 | ≤0.01 | 4276 | A | C | A | 0.39 | No | ACA | 0.12 | Weak |
| 9 | 7454 (3447/4007) | Dominant | R | 1.383 (1.081 − 1.769) | ≤0.01 | 69.0 | ≤0.01 | 4337 | A | C | A | 0.31 | No | ACA | 0.20 | Weak | |||||
| 8 | 6267 (2902/3365) | Recessive | F | 1.258 (1.081 − 1.464) | ≤0.01 | 43.1 | 0.09 | 843 | B | B | A | 0.95 | No | BBA | 0.06 | Moderate | |||||
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| RET A45A | rs1800858 | G > A | Overall | 0.31 | 8 | 4620 (1867/2753) | Allelic | F | 0.898 (0.818 − 0.987) | 0.03 | 18.9 | 0.28 | 2885 | A | A | Cab | 0.24 | No | AAC | 0.33 | Weak |
| 7 | 4462 (1809/2653) | Dominant | F | 0.867 (0.764 − 0.984) | 0.03 | 11.0 | 0.35 | 2358 | A | A | Cb | 0.55 | No | AAC | 0.34 | Weak | |||||
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| RET G691S | rs1799939 | G > A | Overall | 0.21 | 12 | 6643 (2853/3790) | Allelic | R | 1.352 (1.171 − 1.561) | ≤0.01 | 53.8 | ≤0.01 | 2934 | A | C | A | 0.12 | No | ACA | ≤0.01 | Moderate |
| 12 | 6643 (2853/3790) | Dominant | R | 1.386 (1.155 − 1.664) | ≤0.01 | 55.6 | ≤0.01 | 2475 | A | C | A | 0.63 | No | ACA | ≤0.01 | Moderate | |||||
| 12 | 6643 (2853/3790) | Recessive | R | 1.535 (1.224 − 1.924) | ≤0.01 | 0.0 | 0.90 | 459 | B | A | A | 0.29 | No | BAA | ≤0.01 | Strong | |||||
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| RET S836S | rs1800862 | C > T | Caucasian | 0.04 | 14 | 6654 (2701/3953) | Allelic | F | 1.129 (1.008 − 1.409) | 0.04 | 21.8 | 0.22 | 637 | B | B | Cab | 0.74 | No | BBC | 0.88 | Weak |
| 9 | 5791 (2250/3541) | Dominant | F | 1.283 (1.058 − 1.557) | ≤0.01 | 36.6 | 0.13 | 500 | B | B | Cd | ≤0.01 | No | BBC | 0.19 | Weak | |||||
| RET S904S | rs1800863 | C > G | Overall | 0.19 | 6 | 3073 (1178/1895) | Recessive | F | 1.578 (1.090 − 2.286) | 0.02 | 0.0 | 0.75 | 124 | B | A | A | 0.48 | No | BAA | 0.43 | Weak |
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| TERT | rs2736100 | T > G | Asian | 0.39 | 5 | 10104 (5052/5052) | Allelic | F | 1.430 (1.352 − 1.512) | ≤0.01 | 22.6 | 0.27 | 8802 | A | B | A | 0.49 | No | ABA | ≤0.01 | Strong |
| 5 | 10104 (5052/5052) | Dominant | F | 1.535 (1.411 − 1.668) | ≤0.01 | 15.5 | 0.32 | 6768 | A | A | A | 0.95 | No | AAA | ≤0.01 | Strong | |||||
| 5 | 10104 (5052/5052) | Recessive | F | 1.666 (1.509 − 1.839) | ≤0.01 | 0.0 | 0.72 | 2034 | A | A | A | 0.64 | No | AAA | ≤0.01 | Strong | |||||
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| XRCC3 A17893G | rs1799794 | A > G | Overall | 0.29 | 4 | 2477 (1106/1371) | Allelic | R | 1.275 (1.008 − 1.613) | 0.04 | 71.2 | 0.02 | 1519 | A | C | Cc | 0.33 | No | ACC | 0.47 | Weak |
| 4 | 2477 (1106/1371) | Dominant | R | 1.321 (1.023 − 1.705) | 0.03 | 55.4 | 0.08 | 1184 | A | C | Cc | 0.73 | No | ACC | 0.43 | Weak | |||||
| 4 | 2477 (1106/1371) | Recessive | F | 1.383 (1.092 − 1.750) | ≤0.01 | 29.8 | 0.23 | 335 | B | B | Cc | 0.74 | No | BBC | 0.15 | Weak | |||||
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| XRCC3 | rs861539 | C > T | Overall | 0.24 | 11 | 5978 (2413/3565) | Allelic | R | 1.363 (1.193 − 1.559) | ≤0.01 | 53.9 | 0.02 | 3142 | A | C | Cd | 0.03 | No | ACC | ≤0.01 | Moderate |
| 11 | 5978 (2413/3565) | Dominant | R | 1.357 (1.135 − 1.622) | ≤0.01 | 56.9 | ≤0.01 | 2570 | A | C | A | 0.35 | No | ACA | 0.62 | Weak | |||||
| 11 | 5978 (2413/3565) | Recessive | F | 1.709 (1.428 − 2.046) | ≤0.01 | 19.6 | 0.26 | 572 | B | A | Cd | ≤0.01 | No | BAC | ≤0.01 | Moderate | |||||
F: meta-analysis was performed under the fixed-effects model. R: meta-analysis was performed under the random-effects model. Overall: two or more ethnicities were reported in the study. †Frequency of minor allele in controls. ‡Number of test allele or genotype. §Venice criteria grades are amount of evidence, replication of the association, and protection from bias. ¶Cumulative epidemiological evidence as graded by the combination of results from the Venice criteria and FPRP. aThe grade of C is given because the OR value is between 0.87 and 1.15, and the association is not replicated by GWAS or GWAS meta-analysis. bThe grade of C is given for no significant association existed by excluding the first published study. cThe grade of C is given for no significant association existed by excluding studies deviated from the HWE in the controls. dThe grade of C is given for significant publication bias (Pegger ≤0.05)