Table 2.

Replication of previous candidate gene-association studies reported

Replication of previous literatureDISCOVeRY-BMT
Ref.GeneSNPDiseaseOutcomeGenomeN, initial/replicationEffect size*95% CI, initial/validationP, initial/replicationNHR95% CIP
6 CCR5 H1/H1 genotype† Mixed PFS R 163/— 1.4 1.1-1.7 .005 294 vs 2489 0.99 0.8-1.2 .92 
6 CCR5 D-R group 3 vs D-R group 1† Mixed OS M 140 vs 842 1.4 1.1-1.8 .004 270 vs 2237 0.97 0.8-1.2 .81 
6 CCR5 D-R group 3 vs D-R group 1† Mixed PFS M 140 vs 842 1.5 1.2-1.9 .001 270 vs 2237 1.01 0.8-1.2 .86 
6 CCR5 D-R group 3 vs D-R group 2† Mixed OS M 140 vs 139 1.6 1.2-2.1 .003 270 vs 252 0.84 0.6-1.1 .19 
6 CCR5 D-R group 3 vs D-R group 2† Mixed PFS M 140 vs 139 1.8 1.3-2.4 .001 270 vs 252 0.90 0.7-1.1 .37 
3 CD274 rs10975123 Mixed OS R 1157/— NP NP .03 2887 0.96 0.9-1.1 .48 
3 CD40 rs3765457 Mixed OS R 1157/— NP NP .03 2887 1.08 1-1.2 .16 
3 CD40 rs3765457 Mixed PFS R 1157/— NP NP .003 2886 1.1 1-1.2 .06 
3 CD40 rs3765457 Mixed TRM R 1157/— NP NP .002 2887 1.14 1-1.3 .10 
4 HMGB1‡ rs2249825 Mixed OS R 276/146 0.1/NS 0.02-0.9/NS .04/NS 2887 1.04 0.9-1.2 .48 
4 HMGB1‡ rs2249825 Mixed PFS R 276/146 0.3/NS 0.1-1/NS .05/NS 2886 1.06 1-1.2 .27 
7 IL1A rs1800587 Mixed OS M 90/— 0.2 0.05-0.6 <.01 2790 1.03 0.9-1.1 .57 
7 IL1A rs1800587 Mixed TRM M 90/— 0.2 0.05-0.7 .01 2790 1.07 0.9-1.2 .36 
7 IL1B rs16944 Mixed OS D 90/— 0.1 0.05-0.4 <.01 2793 0.99 0.9-1.1 .98 
7 IL1B rs16944 Mixed OS M 90/— 0.2 0.06-0.5 <.01 2790 1.04 0.9-1.1 .43 
7 IL1B rs16944 Mixed TRM R 90/— 0.3 0.1-1.1 .01 2887 1.6 0.9-1.2 .37 
7 IL1B rs16944 Mixed TRM D 90/— 0.1 0.04-0.4 <.01 2793 0.2 0.8-1.0 .20 
7 IL1B rs16944 Mixed TRM M 90/— 0.1 0.05-0.5 <.01 2790 0.99 0.9-1.1 .96 
5 NOD2/CARD15 3 SNPs§ ALL-AML OS M 196/— 1.6 1.1-2.4 .02 1820 1.03 0.9-1.2 .72 
5 NOD2/CARD15 3 SNPs§ ALL-AML TRM D 196/— 1.6 1.1-2.4 .02 1820 1.07 0.8-1.4 .61 
2 NOD2/CARD15 rs2066847 Mixed OS D 342/— 2.5 1.5-4.3 .001 2248 0.98 0.7-1.3 .89 
2 NOD2/CARD15 rs2066847 Mixed TRM D 342/— 2.9 .5-5.5 .001 2248 1.17 0.8-1.7 .45 
1 TGFB1 rs1800469 Mixed OS R 493/— 1.5 1-2.2 .031 2887 1.01 0.9-1.1 .89 
3 TNFSF4 rs10912564|| Mixed OS D 1157/1188 0.82/ 1.04 0.72-0.95/ 0.89-1.20 .009/0.64 2793 0.98 0.9-1.1 .58 
3 TNFSF4 rs10912564 Mixed PFS D 1157/1188 0.86/ 1.06 0.74-0.98/ 0.92-1.23 .03/0.44 2793 1 0.9-1.1 .93 
3 TNFSF4 rs10912564 Mixed TRM D 1157/1188 0.78/ 1.01 0.65-0.93/ 0.82-1.25 .006/0.91 2793 1 0.8-1.1 .50 
Replication of previous literatureDISCOVeRY-BMT
Ref.GeneSNPDiseaseOutcomeGenomeN, initial/replicationEffect size*95% CI, initial/validationP, initial/replicationNHR95% CIP
6 CCR5 H1/H1 genotype† Mixed PFS R 163/— 1.4 1.1-1.7 .005 294 vs 2489 0.99 0.8-1.2 .92 
6 CCR5 D-R group 3 vs D-R group 1† Mixed OS M 140 vs 842 1.4 1.1-1.8 .004 270 vs 2237 0.97 0.8-1.2 .81 
6 CCR5 D-R group 3 vs D-R group 1† Mixed PFS M 140 vs 842 1.5 1.2-1.9 .001 270 vs 2237 1.01 0.8-1.2 .86 
6 CCR5 D-R group 3 vs D-R group 2† Mixed OS M 140 vs 139 1.6 1.2-2.1 .003 270 vs 252 0.84 0.6-1.1 .19 
6 CCR5 D-R group 3 vs D-R group 2† Mixed PFS M 140 vs 139 1.8 1.3-2.4 .001 270 vs 252 0.90 0.7-1.1 .37 
3 CD274 rs10975123 Mixed OS R 1157/— NP NP .03 2887 0.96 0.9-1.1 .48 
3 CD40 rs3765457 Mixed OS R 1157/— NP NP .03 2887 1.08 1-1.2 .16 
3 CD40 rs3765457 Mixed PFS R 1157/— NP NP .003 2886 1.1 1-1.2 .06 
3 CD40 rs3765457 Mixed TRM R 1157/— NP NP .002 2887 1.14 1-1.3 .10 
4 HMGB1‡ rs2249825 Mixed OS R 276/146 0.1/NS 0.02-0.9/NS .04/NS 2887 1.04 0.9-1.2 .48 
4 HMGB1‡ rs2249825 Mixed PFS R 276/146 0.3/NS 0.1-1/NS .05/NS 2886 1.06 1-1.2 .27 
7 IL1A rs1800587 Mixed OS M 90/— 0.2 0.05-0.6 <.01 2790 1.03 0.9-1.1 .57 
7 IL1A rs1800587 Mixed TRM M 90/— 0.2 0.05-0.7 .01 2790 1.07 0.9-1.2 .36 
7 IL1B rs16944 Mixed OS D 90/— 0.1 0.05-0.4 <.01 2793 0.99 0.9-1.1 .98 
7 IL1B rs16944 Mixed OS M 90/— 0.2 0.06-0.5 <.01 2790 1.04 0.9-1.1 .43 
7 IL1B rs16944 Mixed TRM R 90/— 0.3 0.1-1.1 .01 2887 1.6 0.9-1.2 .37 
7 IL1B rs16944 Mixed TRM D 90/— 0.1 0.04-0.4 <.01 2793 0.2 0.8-1.0 .20 
7 IL1B rs16944 Mixed TRM M 90/— 0.1 0.05-0.5 <.01 2790 0.99 0.9-1.1 .96 
5 NOD2/CARD15 3 SNPs§ ALL-AML OS M 196/— 1.6 1.1-2.4 .02 1820 1.03 0.9-1.2 .72 
5 NOD2/CARD15 3 SNPs§ ALL-AML TRM D 196/— 1.6 1.1-2.4 .02 1820 1.07 0.8-1.4 .61 
2 NOD2/CARD15 rs2066847 Mixed OS D 342/— 2.5 1.5-4.3 .001 2248 0.98 0.7-1.3 .89 
2 NOD2/CARD15 rs2066847 Mixed TRM D 342/— 2.9 .5-5.5 .001 2248 1.17 0.8-1.7 .45 
1 TGFB1 rs1800469 Mixed OS R 493/— 1.5 1-2.2 .031 2887 1.01 0.9-1.1 .89 
3 TNFSF4 rs10912564|| Mixed OS D 1157/1188 0.82/ 1.04 0.72-0.95/ 0.89-1.20 .009/0.64 2793 0.98 0.9-1.1 .58 
3 TNFSF4 rs10912564 Mixed PFS D 1157/1188 0.86/ 1.06 0.74-0.98/ 0.92-1.23 .03/0.44 2793 1 0.9-1.1 .93 
3 TNFSF4 rs10912564 Mixed TRM D 1157/1188 0.78/ 1.01 0.65-0.93/ 0.82-1.25 .006/0.91 2793 1 0.8-1.1 .50 

—, no replication; D, donor; M, mismatch; R, recipient; Ref., reference number; NP indicates that the information on effect size was not presented in the original publication or the supplemental materials; NS, not significant.

*

Effect sizes for most studies were HRs, however, some studies reported odds ratio or RR.

†

CCR5 H1/H1 genotypes and risk groups defined using multiallelic models described in the original publication.6 

‡

Associations reported are for the initial cohort only; the second cohort reported no significant associations.

§

The NOD2/CARD15 3 SNP multiallelic model defined as presence of at least 1 copy of a minor allele in rs2066844 (SNP8), rs2066845 (SNP12), or rs2066847 (SNP13); rs2066847 (SNP13) in NOD2/CARD15 was the only variant selected from the Illumina HumanExome chip for replication and validation analyses as it was not available on the OmniExpress chip following imputation. Only R-D pairs 10 of 10 HLA matched were genotyped with the Illumina HumanExome chip (1768 and 480 AML, ALL, and MDS R-D pairs in cohorts 1 and 2, respectively).

||

rs10912564 was the only variant that met our criteria for further assessing heterogeneity defined as P value test for heterogeneity <.05 and I2 > 50 implemented in METAL software at Phet = .04; I2 = 76. This variant was not significant in cohort 1 (HR = 0.96; 95% CI, 0.87, 1.08; P = .56) but showed significance at P < .05 in the second cohort (HR = 1.19; 95% CI, 1.01, 1.41; P = .043). Given this evidence of heterogeneity, we used random-effect models to meta-analyze the SNP. The random-effect model P value (P = .55) showed that the variant was not significantly associated with OS (HR = 1.06; 95% CI, 0.87, 1.30).

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