The association between HLA-B variants and amoxicillin-induced severe cutaneous adverse reactions in Chinese han population

Abstract

Background: Amoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs.

Methodology: Four patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins.

Results: Compared with AMX-tolerant controls, a significant association of HLA-B*15:01 with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68-1275.67; p = 7.34 × 10^-3]. Moreover, 75% carriers of HLA-B*15:01 in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, p = 5.18 × 10^-4]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis.

Conclusion: Our findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

Keywords: HLA-B; amoxicillin; severe cutaneous adverse reactions; variants; whole-exome sequencing.

FIGURE 1

Binding modes of Amoxicillin in four HLA proteins and the sequence alignment. The binding modes of amoxicillin (AMX) in HLA-B*15:01 (A), HLA-B*15:02 (B), HLA-B*35:05 (C) and HLA -B*46:01 (D) are shown in the green cartoon representation. AMX (yellow carbons) and HLA residues (green carbons or pink carbons) that involve ligand bindings are shown in the stick representation. Hydrogen bonds are displayed as red dashed lines, π-π hydrophobic interactions and cation-π hydrophobic interactions are shown as blue dashed lines. For clarity, two-dimensional schematic representations of the AMX-HLA interactions are shown next to the three-dimensional models. In the sequence alignment (E) results, identical residues are shown with a red background; partially conserved residues are shown as white letter with a red background; Non-conserved residues are displayed with a green background, with the first type residue colored in yellow and the second type residue colored in black, and these residues are denoted as red stars at the bottom.