HLA–DRB1 AND DQB1 GENE POLYMORPHISM IS ASSOCIATED WITH MULTIDRUG–RESISTANT TUBERCULOSIS IN KOREAN PATIENTS

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TITLE: HLA–DRB1 AND DQB1 GENE POLYMORPHISM IS ASSOCIATED WITH MULTIDRUG–RESISTANT TUBERCULOSIS IN KOREAN PATIENTS

M. H. Park,¹ E. Y. Song,¹ H. J. Park,¹ S. Y. Kwon,² S. K. Han,² Y. S. Shim.²

¹Department of Clinical Pathology, Seoul National University College of Medicine, Seoul, Korea; ²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Multidrug–resistant tuberculosis (MDR–TB: resistant to at least isoniazid and rifampicin) is among the most worrisome elements of antibiotic resistance. Acquired MDR–TB (with previous treatment history for tuberculosis) is considered to be produced by the selection of MDR strains due to inadequate treatment, but the pathogenesis of primary MDR–TB (without previous treatment history) is not fully understood and suggested to be affected by host genetic factors. There are numerous reports about genetic changes of MDR–TB strains, but little has been known about genetic susceptibility of host to MDR–TB. We have investigated HLA–DRB1 and DQB1 gene polymorphisms in 53 Korean MDR–TB (32 primary and 21 acquired) patients and 200 healthy controls using reverse SSO, PCR–RFLP and PCR–SSCP methods. The phenotype frequency of DRB1*08032 was significantly higher in MDR–TB patients (34.0%: primary 28.1%, acquired 42.9%) than in normal controls (14.5%) (odds ratio = 3.03 [95% CI 1.52–6.05], p = 0.001, corrected p = 0.03). The frequency of HLA–DQB1*0601, strongly associated with DRB1*08032 in Koreans, was also significantly higher in MDR–TB patients (35.8%: primary 37.5%, acquired 33.3%) than in normal controls (15.5%) (OR = 3.05 [95% CI 1.54–6.01], p = 0.0009, corrected p = 0.01). For clinical subgroups according to the extent of lung lesion (34 far–advanced, 16 moderately–advanced, 3 extrapulmonary), significant associations were observed only in far–advanced group compared with normal controls for DRB1*08032 (38.2% vs 14.5%, OR = 3.65 [1.65–8.09], p = 0.0008, corrected p = 0.02) and for DQB1*0601 (38.2% vs 15.5%, OR = 3.37 [1.53–7.44], p = 0.002, corrected p = 0.03). Our results suggest that HLA–DRB1*08032–DQB1*0601 haplotype is strongly associated with genetic susceptibility to MDR–TB and disease progression in Koreans. %DRB1*0803–DQB1*0601 haplotype shows a limited ethnic distribution, and is common in Asians (haplotype frequency 4%) but very rare in Caucasians or Blacks. To our knowledge, this is the first report on the HLA association with MDR–TB and further studies are needed to know that whether ethnic variations in HLA or closely linked genetic factors are associated with regional distribution of MDR–TB worldwide.