Table 2.
Top genome‐wide associations and HLA associations with agranulocytosis induced by sulfasalazine in the discovery cohort
| Associations | CHR | SNP | BP | Alleles (major/minor) | N | MAF case | MAF ‘control | OR [95% CI] | P | Nearby gene |
|---|---|---|---|---|---|---|---|---|---|---|
| a. Genome‐wide | ||||||||||
| Adjusted by sex and | 6 | rs9266634 | 31346978 | A/T | 5,183 | 0.81 | 0.44 | 5.37 [2.97, 9.69] | 2.55 × 10−8 | HLA‐B |
| genetic PC 1‐4 | 20 | rs202233001 | 21735353 | C/CACA | 5,081 | 0.14 | 0.03 | 6.76 [3.41, 13.38] | 4.19 × 10−8 | PAX1 |
| Adjusted by sex, genetic PC 1‐4 and rs9266634 | 5 | rs111876221 | 79535200 | A/G | 5,152 | 0.10 | 0.02 | 12.65 [5.15, 31.1] | 3.22 × 10−8 | SERINC5 |
| Adjusted by sex, genetic PC 1‐4, rs9266634 and rs111876221 | 1 | rs113887891 | 117006870 | G/T | 5,041 | 0.13 | 0.02 | 9.52 [4.24, 21.37] | 4.78 × 10−8 | LINC01762 |
| Adjusted by sex, genetic PC 1‐4, rs9266634, rs111876221 and rs113887891 | 1 | rs12082628 | 239797706 | A/G | 4,872 | 0.09 | 0.01 | 14.99 [5.75, 39.04] | 3.00 × 10−8 | CHRM3 |
| b. HLA | ||||||||||
| 6 | HLA‐C*14:02 | 31346171 | A/P | 5,206 | 0.07 | 0.01 | 7.72 [2.90, 20.58] | 4.36 × 10−5 | ||
| Adjusted by sex and | 6 | HLA‐B*08:01 | 31431272 | A/P | 5,206 | 0.26 | 0.11 | 2.92 [1.71, 4.99] | 8.37 × 10−5 | |
| PC 1‐4 | 6 | HLA‐C*02:06 | 31346171 | A/P | 5,206 | 0.01 | 0.00 | 92.68 [8.02, 1071] | 2.86 × 10−4 | |
| 6 | HLA‐B*08:01 | 31431272 | A/P | 5,206 | 0.26 | 0.11 | 3.24 [1.88‐5.57] | 2.26 × 10−5 | ||
| Adjusted by sex, PC 1‐4 | 6 | HLA‐C*07:01 | 31346171 | A/P | 5,206 | 0.29 | 0.14 | 2.72 [1.62, 4.57] | 1.49 × 10−4 | |
| and HLA‐C*14:02 | 6 | HLA‐A*31:01 | 30019970 | A/P | 5,206 | 0.10 | 0.03 | 3.72 [1.63, 8.47] | 1.74 × 10−3 | |
| Adjusted by sex, PC 1‐4, | 6 | HLA‐C*02:02 | 31346171 | A/P | 5,206 | 0.15 | 0.06 | 3.52 [1.81, 6.84] | 2.09 × 10−4 | |
| HLA‐C*14:02 | 6 | HLA‐A*31:01 | 30019970 | A/P | 5,206 | 0.10 | 0.03 | 4.24 [1.83, 9.82] | 7.57 × 10−4 | |
| and B*08:01 | 6 | HLA‐C*07:02 | 31346171 | A/P | 5,206 | 0.25 | 0.15 | 2.67 [1.50, 4.77] | 8.51 × 10−4 | |
| Adjusted by sex, PC 1‐4, | 6 | HLA‐B*07:02 | 31431272 | A/P | 5,206 | 0.24 | 0.15 | 3.57 [1.90, 6.72] | 7.74 × 10−5 | |
| HLA‐C*14:02, B*08:01 | 6 | HLA‐C*07:02 | 31346171 | A/P | 5,206 | 0.25 | 0.15 | 3.16 [1.74, 5.75] | 1.67 × 10−4 | |
| and C*02:02 | 6 | HLA‐A*31:01 | 30019970 | A/P | 5,206 | 0.10 | 0.03 | 3.87 [1.64, 9.12] | 1.99 × 10−3 | |
| Adjusted by sex, PC 1‐4, | 6 | HLA‐A*3101 | 30019970 | A/P | 5,206 | 0.10 | 0.03 | 4.42 [1.83, 10.68] | 9.48 × 10−4 | |
| HLA‐C*14:02, B*08:01, | 6 | HLA‐B*5101 | 31431272 | A/P | 5,206 | 0.14 | 0.05 | 3.18 [1.25, 8.11] | 1.55 × 10−2 | |
| C*02:02 and B*07:02 | 6 | HLA‐B*5501 | 31431272 | A/P | 5,206 | 0.03 | 0.01 | 5.48 [1.23, 24.31] | 2.53 × 10−2 |
a. Top GWAS results based on 9,380,034 SNPs after imputation in 36 patients with sulfasalazine‐induced agranulocytosis vs. all 5,170 controls. All results were adjusted for sex and four genetic principal components (PC). No genome‐wide significant signals were left after adjusting for four SNP variants. b. Odds ratios for the top HLA alleles for patients with sulfasalazine‐induced agranulocytosis. The effect was modeled per increase of one present HLA allele. Chromosomal location is according to the Genome Reference Consortium human assembly GRCh37. Complete lists of associated SNPs and HLA types are available in the appendix.
GWAS = genome‐wide association study, CHR = chromosome, PC = genetic principal components, SNP = single nucleotide polymorphism, BP = base pair, N = number, MAF = minor allele frequency, OR [95% CI] = odds ratio with 95% confidence interval. When referring to HLA allele: A = absent, P = present.