Predominant HLA Alleles and Haplotypes in Mild Adverse Drug Reactions Caused by Allopurinol in Vietnamese Patients with Gout.

Chu Van Son,Le Thi Hong Nhung,Nguyen Thi Hong Loan,Tran Ngoc Que,Pham Dinh Tung,Nguyen Thi Van Anh,Nguyen Dinh Thang,Tran Huyen Trang,Nguyen Van Hung,Nguyen Ba Khanh,Nguyen Van Lieu,Le Xuan Thinh

doi:10.3390/diagnostics11091611

Abstract

Allopurinol (ALP) is commonly used as a drug for gout treatment. However, ALP is known to cause cutaneous adverse reactions (CARs) in patients. The HLA-B*58:01 allele is considered a biomarker of severe CAR (SCAR) in patients with gout, with symptoms of Stevens Johnson syndrome, and with toxic epidermal necrolysis. However, in patients with gout and mild cutaneous adverse drug reactions (MCARs), the role of HLA-allele polymorphisms has not been thoroughly investigated. In this study, 50 samples from ALP-tolerant patients and ALP-induced MCARs patients were genotyped in order to examine the polymorphisms of their HLA-A and HLA-B alleles. Our results showed that the frequencies of HLA-A*02:01/HLA-A*24:02 and HLA-A*02:01/HLA-A*29:01, the dual haplotypes in HLA-A, in patients with ALP-induced MCARs were relatively high, at 33.3% (7/21), which was HLA-B*58:01-independent, while the frequency of these dual haplotypes in the HLA-A locus in ALP-tolerant patients was only 3.45% (1/29). The HLA-B*58:01 allele was detected in 38% (8/21) of patients with ALP-induced MCARs, and in 3.45% (1/29) of ALP-tolerant patients. Notably, although HLA-B*58:01 may be a cause for the occurrence of MCARs in patients with gout, this correlation was not as strong as that previously reported in patients with SCAR. In conclusion, in addition to the HLA-B*58:01 allele, the presence of the dual haplotypes of HLA-A*02:01/HLA-A*24:02 and/or HLA-A*02:01/HLA-A*29:01 in the HLA-A locus may also play an important role in the appearance of ALP-induced MCARs in the Vietnamese population. The obtained primary data may contribute to the development of suitable treatments for patients with gout not only in Vietnam but also in other Asian countries.

Highlights

Allopurinol (ALP) is an analog of purine hypoxanthine, and is commonly prescribed for the treatment of hyperuricemia and gout
The results demonstrated that the frequency of the single HLA-B* 58:01 allele in Vietnamese patients with gout with ALP-induced mild cutaneous adverse reactions (MCARs) was the highest (38.1%; 8 of 21)
It is well known that the presence of HLA-B* 58:01 is closely related to the occurrence of severe adverse drug reactions (SJS, Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), TEN, and drug reaction with eosinophilia and systemic symptoms (DRESS)) in the skin of patients (SCARs) when ALP is used for gout treatment, especially for Black and Asian people rather than white people [11,12,13,14,15,16,17,18,19,20,21,22,29]

Summary

Introduction

Allopurinol (ALP) is an analog of purine hypoxanthine, and is commonly prescribed for the treatment of hyperuricemia and gout. ALP can decrease the level of uric acid by inhibiting xanthine oxidase, which plays an important role in converting xanthine and hypoxanthine to uric acid. ALP may cause hypersensitivity in patients with gout. It is the most common cause of severe cutaneous adverse reactions (SCARs), including Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and mild cutaneous adverse reactions (MCARs) [5]. SJS and TEN are life-threatening conditions associated with fever, hepatitis, an increased number of white blood cells, acute renal failure and mild symptoms, and are a cause of pain, itchiness and unpleasantness for patients [1,6]

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