Chung Ming Huang

Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study

Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. Design National prospective cohort study. Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening. Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

Polymorphisms of the interleukin-4 gene in Chinese patients with systemic lupus erythematosus in Taiwan

We aimed to evaluate the relationship between two polymorphisms of the IL4 gene (-590T=C and intron 3) and systemic lupus erythematosus in Chinese patients in Taiwan. This study included 91 patients with systemic lupus erythematosus (SLE) and 163 unrelated, age matched healthy controls living in the same area. The typing of -590T=C and intron 3 VNTR (variable number of tandem repeats) polymorphisms were performed by PCR-RFLP and PCR, respectively. Allelic frequencies and carriage rates between SLE patients and controls were compared, and the relationship between allelic frequencies and clinical manifestations of SLE was evaluated. The genotype frequencies of IL-4 intron 3 were found to differ significantly between SLE patients with and without discoid rash (chi-square test, P = 0.035). The allelic frequency of intron 3 RP1 was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.70, 95% CI 2.04 - 6.72, ϰ2 test, P = 0.029). The RP1=RP1 homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 6.04, 95% CI 2.81 - 12.95, P = 0.01). The allelic frequency of -590T was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.44, 95% CI 1.88 - 6.31, chi-square test, P = 0.04). The T=T homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 5.41, 95% CI 2.50 - 11.68, P = 0.02). We describe a novel association between RP1=RP1 and T=T homozygous carriage and patients with discoid rash. The role of the intron 3 polymorphism of the IL4 gene in SLE remains unclear and further substantiation based on larger patient samples is needed.

Association of TNF-α gene polymorphisms with systemic lupus erythematosus in Taiwanese patients

Tumour necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiological and pathogenic effects that lead to tissue destruction. Studies on the association of TNF-α genetic polymorphisms with systemic lupus erythematosus (SLE) have yielded inconclusive results. We investigated the association of TNF-α genetic polymorphisms (−1031T/C, −863C/A, −857T/C, −308A/G and +489A/G) with SLE in Taiwanese patients and controls. Our results indicate that 1) the frequency of the A-allele at −863 position was significantly higher in SLE patients (odds ratio = 1.46; 95% CI = 1.02–2.08); 2) the frequency of the A-allele at +489 position was significantly higher in SLE patients (odds ratio = 1.79; 95% CI = 1.21–2.65); 3) the AA or GA genotype frequencies at +489 position were significantly increased in SLE patients (AA genotype: odds ratio = 11.20; 95% CI = 1.36–92.55; GA genotype: odds ratio = 1.63; 95% CI = 1.03–2.58); 4) no significant association of TNF-α haplotypic distributions was observed, except for the haplotypes TCCGA, CACGA and CCCGG; and 5) the genotype frequency of the polymorphisms at −1031 was significantly different in patients with antinuclear antibodies (P = 0.022). The allele and genotype frequencies of the polymorphisms at −863 were not significantly different. The genotype frequency of the polymorphisms at −857 was significantly different in patients with haematological disorder (P = 0.025). The frequency of A allele of the polymorphisms at −308 was significantly increased in patients with malar rash (P = 0.033), discoid rash (P = 0.023), photosensitivity (P = 0.037), oral ulcers (P = 0.002) and serositis (P = 0.029). The genotype frequency of the polymorphisms at +489 was significantly different in patients with discoid rash and photosensitivity (data not shown; discoid rash, P = 0.031; photosensitivity, P = 0.044). These results suggest that TNF-α genetic polymorphisms contribute to SLE susceptibility in the Taiwanese population.

Interleukin-1β and interleukin-1 receptor antagonist gene polymorphisms in rheumatoid arthritis

The purpose of this study was to evaluate if IL-1β (IL-1β promoter and IL-1β exon 5) and IL-1 receptor antagonist (IL-1Ra) gene polymorphisms act as markers of susceptibility to or severity of RA. The study included 104 RA patients and 103 normal controls. No significant difference was observed in the cytokine allelic frequencies of IL-1β promoter and IL-1β exon 5 between patients with RA and healthy controls. In addition, there was no significant association in the cytokine carriage rates of I and II allele of IL-1Ra between RA patients and healthy controls. In contrast, the IV allele of IL-1Ra was significantly increased in RA patients with low inflammatory activity (P = 0.03). This study indicated that allelic frequency and carriage rate of IL-1β (IL-1β promoter and IL-1β exon 5) and IL-1Ra (I and II allele) do not differ significantly between normal controls and RA patients in Taiwan. However, the carriage rate of IV allele of IL-1Ra was high in the RA patients with low inflammatory activity.The purpose of this study was to evaluate if IL-1beta (IL-1beta promoter and IL-1beta exon 5) and IL-1receptor antagonist (IL-1Ra) gene polymorphisms act as markers of susceptibility to or severity of RA. The study included 104 RA patients and 103 normal controls. No significant difference was observed in the cytokine allelic frequencies of IL-1beta promoter and IL-1beta exon 5 between patients with RA and healthy controls. In addition, there was no significant association in the cytokine carriage rates of I and II allele of IL-1Ra between RA patients and healthy controls. In contrast, the IV allele of IL-1Ra was significantly increased in RA patients with low inflammatory activity (P=0.03). This study indicated that allelic frequency and carriage rate of IL-1beta (IL-1beta promoter and IL-1beta exon 5) and IL-1Ra (I and II allele) do not differ significantly between normal controls and RA patients in Taiwan. However, the carriage rate of IV allele of IL-1Ra was high in the RA patients with low inflammatory activity.

Disease association of the interleukin-18 promoter polymorphisms in Taiwan Chinese systemic lupus erythematosus patients.

Interleukin (IL)-18, an important mediator of innate and adaptive immunity, plays multiple roles in chronic inflammation, in autoimmune diseases, in a variety of cancers and in number of infectious diseases. IL-18 promoter polymorphisms have been also noted associated with various inflammatory diseases. We investigated the association of IL-18 promoter polymorphisms (−656T/G, −607A/C and −137C/G) with systemic lupus erythematosus (SLE) in Taiwan Chinese patients and controls. Six haplotypes (hts) were identified from the three promoter polymorphisms. The genotype distribution of the ht1 (GCC), ht2 (TAC), ht4 (GAC) and ht5 (TCC) were different in patients and controls (P<0.002). Moreover, the haplotype and genotype frequencies of ht1 were significantly increased in patients with discoid rash (P=0.045, odds ratio (OR): 2.01, 95% confidence interval (CI): 1.01–4.00; P=0.027, OR: 5.13, 95% CI: 1.41–18.68). In addition, the homozygous genotype ht1/ht1 was significant increased in patients with serositis (P=0.015, OR: 9.78, 95% CI: 1.55–61.73). These observations suggest that the three promoter polymorphisms contribute to the genetic background of SLE pathogenesis.

Interleukin-1 receptor antagonist gene polymorphism in chinese patients with systemic lupus erythematosus.

Abstract: The purpose of this study was to determine whether IL-1 receptor antagonist (IL-1Ra) gene polymorphism is a marker of susceptibility to or severity of systemic lupus erythematosus (SLE) in Chinese patients. The study included 52 Chinese patients with SLE. One hundred and three unrelated, healthy individuals living in central Taiwan served as controls. From genomic DNA, the polymorphism of the gene for IL-1Ra was typed. Allelic frequencies and carriage rates were compared between SLE patients and controls. The relationship between allelic frequencies and clinical manifestations of SLE was evaluated. We found an increased frequency of IL1RN*2 in the SLE patients compared to normal controls (χ2= 4.15, P<0.05), with an odds ratio (of allele frequency) of 2.63 (95% confidence interval 1.00–6.96). The carriage rate of IL1RN*2 was also higher in the SLE patients (6.8% in the controls vs. 17.3% in the SLE patients). We observed increased frequencies of malar rash and photosensitivity among patients with IL1RN*2 (77.8%) compared to patients without the allele (48.8%). However, this difference did not reach statistical significance (χ2 = 2.51, P= 0.11). This study indicated that the frequency of IL1RN*2 is higher in Chinese SLE patients than in Chinese normal controls in Taiwan. However, there was no association between the frequency of IL1RN*2 and clinical manifestations.

Polymorphisms in the DNA repair gene XRCC1 and associations with systemic lupus erythematosus risk in the Taiwanese Han Chinese population

XRCC1 plays a central role in mammalian DNA repair processes. Two polymorphisms of XRCC1, rs1799782 (Arg > Trp at codon 194) and rs25487 (Arg > Gln at codon 399), are common in the Han Chinese population. Our objective was to analyze the relationship between these two functional single-nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE) in the Taiwanese Han Chinese population. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) on 172 SLE patients and 160 normal controls. Our data indicate that the frequency of A/G at codon 399 differed between patients and controls (p = 0.01; odds ratio: 1.80; 95% confidence interval: 1.17—2.75), but the allelic frequency analysis did not reveal significant differences. For the SNP at codon 194, there were no differences in either allelic or genotype frequencies between SLE patients and normal subjects. Clinical association studies of SLE symptoms revealed the involvement of the A/G polymorphism at codon 399 in SLE pathogenesis. Our results indicate that a functional SNP at codon 399 of XRCC1 is associated with the development of SLE. Lupus (2009) 18, 1246—1251.

Lack of association of interleukin-1β gene polymorphisms in Chinese patients with systemic lupus erythematosus

Abstract The purpose of this study was to examine whether interleukin-1β (IL-1β) (promoter and exon 5) gene polymorphisms were markers of susceptibility or clinical manifestation in Chinese patients with systemic lupus erythematosus (SLE). The study included 52 Chinese patients with SLE. In addition, 103 unrelated healthy individuals living in central Taiwan served as control subjects. From genomic DNA, polymorphisms of the gene for IL-1β promoter and exon 5 were typed. Allelic frequencies were compared between SLE patients and control subjects. The relationship between allelic frequencies and clinical manifestations of SLE was evaluated. No significant differences were observed in the allelic frequencies of the IL-1β promoter and IL-1β exon 5 between patients with SLE and healthy control subjects. Additionally, we did not detect any association of IL-1β promoter and the exon 5 genotype with the clinical and laboratory profiles in SLE patients. The results from the present study suggest that the polymorphisms of the IL-1β promoter and IL-1β exon 5 are not related to SLE patients in Taiwan

Interleukin-18 gene polymorphism, but not interleukin-2 gene polymorphism, is associated with rheumatoid arthritis

To investigate whether polymorphisms of IL-2 and IL-18 genes are associated with rheumatoid arthritis (RA), polymorphisms of IL-2 and IL-18 genes were detected by polymerase-chain-reaction-based restriction analysis in the patients with RA and normal controls. The results for the IL-18 gene revealed a significant difference between the patients and the normal controls (p = 0.000003), but there was no significant difference for the IL-2 gene (p = 0.876). The IL-18 gene 105A allele was associated with RA in Chinese patients. Individuals possessing the 105A allele had a higher incidence of RA. A lack of association of IL-2 gene polymorphism between RA patients and healthy individuals was noted. The results of this study provide genetic evidence that IL-18-105A/C polymorphism may play an effective role in RA.

Association of TAP2 gene polymorphisms in Chinese patients with rheumatoid arthritis

The aim of this study was to investigate the association between the polymorphism of transporters associated with antigen processing (TAP1/TAP2) genes and rheumatoid arthritis in Chinese patients. A total of 100 RA patients and 99 healthy control subjects were enrolled. Analyses with polymerase chain reaction (PCR) based restrictions were used to identify the polymorphisms of the TAP1 and TAP2 genes, which were mapped on chromosome 6. There was a significant difference in the distribution of the TAP2 gene codon 565 polymorphism frequency between the RA patients and healthy control subjects (p<0.001). The odds ratio for the risk of the ‘A’ allele in RA patients was 1.60 (95% CI: 0.82–2.92). No statistical associations in the distribution of the TAP1 gene polymorphism frequency were found between RA patients and controls. There were some physical links found between TAP1/TAP2 gene polymorphism loci. However, there was no linkage observed from TAP1/TAP2 gene polymorphisms and HLA-DRB1*04 between RA patients and healthy controls. We concluded that the TAP2 gene codon 565 ‘A’ allele was associated with RA in Chinese patients in Taiwan. Individuals possessing the ‘A’ allele had a higher incidence of RA. A lack of association of TAP1 gene polymorphisms between RA patients and healthy individuals was noted. The results of this study provide genetic evidence that TAP2 gene codon 565 polymorphism may play a role in RA.