Table 2.
Top HLA alleles and Haplotypes, locus, and amino acid residue hits from analysis of 4,645 Participants (800 with BL) in EMBLEM and Malawi.
| Category | Variant | Infoa | Eff. Allele/Ref. Alleleb | Combined Frequencyc | Meta-analysisd | Meta-analysise | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | OR (95% CI) | Pmeta | Phet | OR (95% CI) | Pcondition | Phet | ||||
| HLA allele | DQA1*04:01 | 0.99 | – | 0.08 | 0.12 | 1.61 (1.32, 1.97) | 3.71 × 10−6 | 0.92 | 1.29 (1.03, 1.63) | 0.030 | 0.94 |
| Class II haplotype | DRB1*03:02-DQA1*04:01-DQB1*04:02 | – | – | 0.06 | 0.10 | 1.58 (1.25, 1.99) | 1.08 × 10−4 | 0.83 | – | – | – |
| SNP | rs2040406 | 0.98 | G/A | 0.28 | 0.36 | 1.43 (1.26, 1.63) | 4.62 × 10−8 | 0.84 | 1.68 (1.09, 2.59) | 0.019 | 0.54 |
| Imputed residue | Gln 53 in HLA-DQA1 chainf | 0.98 | – | 0.32 | 0.38 | 1.36 (1.20, 1.55) | 2.06 × 10−6 | 0.60 | 0.79 (0.52, 1.21) | 0.28 | 0.36 |
AA amino acid residue, HLA human leukocyte antigen, OR odds ratio, CI confidence interval. All statistical tests are 2-sided.
aImputation information (R2) was obtained from SNP2HLA.
bEffect allele/reference allele.
cFor locus rs2040406, the numbers indicate frequencies for the effect allele.
dEstimates were obtained from generalized linear mixed models (GLMMs), adjusting for sex, age (continuous), Plasmodium falciparum positivity, population substructure using the top 3 principal components (PCs) and genetic relatedness using a genetic relationship matrix. Association statistics were conducted by a fixed-effect meta-analysis across four countries. P values were corrected for multiple comparisons using Bonferroni adjustment (P < 2.7 × 10−4 for 187 classical HLA alleles and P < 1.1 × 10−6 for other 46,350 variants in the HLA region). Cochran’s heterogeneity p value was obtained.
eThe three HLA variants (DQA1*04:01, rs2040406, and Gln-53) were included in one model to determine if effects for one variant were independent of the other two.
fPosition 53 is polymorphic with three common residues: Q (Glutamine), K (Lysine), and R (Arginine). L (Leucine) is rare in our population. The analysis compared glutamine versus other variants at position 53.