We next examined potential interactions between the
ERAP1 and
ERAP2 association signals and between HLA-Aw19 and
ERAP1/ERAP2 signals by calculating the cumulative effects of HLA-Aw19, ERAP1, and ERAP2 genotypes on BSCR risk using the 286 cases and the 4014 A29 carriers from GHS cohort 1. First, we performed an analysis of
ERAP2-rs10044354 risk haplotype, the top non-MHC signal in Kuiper et al.,
8 stratified by single (A29/–) versus double (A29/AW19) Aw19 background, which yielded a trend of increased risk with additional
ERAP2-rs10044354-T variant alleles, particularly on the double A29/AW19 background (
Fig. 3A). We found the highest risk to be the combination of rs10044354-TT and two copies of Aw19 with 12 cases and 34 controls (OR = 9.9; 95% CI, 4.4–21.2;
P = 1.66e-07) (
Supplementary Table S3). A similar analysis of the
ERAP1-rs27432 risk haplotype, our top non-MHC association, stratified by single (A29/–) versus double (A29/AW19) Aw19 background, yielded the same trend of increased risk with additional
ERAP1-rs27432-G variant alleles, particularly on the double A29/AW19 background (OR = 6.2; 95% CI, 2.7–15.51;
P = 1.54e-06) (
Fig. 3B,
Supplementary Table S4). We next calculated the combined effects of the
ERAP1 risk haplotype tagged by rs27432, and the
ERAP2 risk haplotype tagged by rs10044354 (
Fig. 3C). We found that the highest risk was conferred by the combination of
ERAP1-rs27432-GG and
ERAP2-rs10044354-TT (OR = 3.6; 05% CI, 1.62–9.45;
P = 4.03e-04) (
Supplementary Table S5), and, as mentioned above, our data are consistent with additive effects of the variants/haplotypes. We next combined all risk haplotypes to a single risk analysis. Due to the small number of cases, we combined the genotypes of intermediate genotypes into four main groups: (1) homozygous to the protective alleles in both
ERAP1 and
ERAP2; (2) homozygous in one and heterozygous in the other; (3) homozygous risk allele in either
ERAP1 or
ERAP2; and (4) homozygous risk allele in both
ERAP1 or
ERAP2 (
Fig. 3D,
Supplementary Table S6). We found a gradual increase in risk with the addition of each risk allele, with the highest risk presented when carrying homozygous risk alleles in both ERAP1 and ERAP2, on top of two copies of A19 alleles (OR = 13.53; 95% CI, 3.79–54.77;
P = 1.17e-05). These results suggest that both
ERAP1 and/or
ERAP2 confer greater BSCR risk, which is further increased in the double Aw19 background.