04485nas a2201129 4500000000100000008004100001260001600042653001000058653001200068653002600080653003000106653001100136653003800147653003400185653001300219653001900232653001100251653002300262653001200285653000900297653003600306653001700342653002700359100001400386700001000400700001400410700001100424700000900435700001100444700001100455700001300466700001200479700001100491700001200502700001200514700001200526700001200538700001000550700001200560700001100572700001200583700001300595700001200608700001300620700001200633700001100645700001100656700001200667700001100679700001100690700001200701700001200713700001100725700001200736700001100748700001200759700001300771700001300784700001400797700001200811700001400823700001100837700001400848700001300862700001100875700001200886700001300898700000900911700001400920700001100934700001300945700001100958700001100969700001400980700001400994700000901008700001001017700001201027700001101039700001301050700001101063700001101074700001301085700001201098700001301110700001401123700001301137700001701150700001301167700001201180245005901192300001101251490000801262050001501270520205601285022001403341 2013 d c2013 Oct 24 10 aAdult 10 aDapsone 10 aDrug Hypersensitivity 10 aDrug Therapy, Combination 10 aFemale 10 aGenetic Predisposition to Disease 10 aGenome-Wide Association Study 10 agenotype 10 aHLA-B Antigens 10 aHumans 10 aLeprostatic Agents 10 aleprosy 10 aMale 10 aPolymorphism, Single Nucleotide 10 aRisk Factors 10 aSequence Analysis, DNA 1 aZhang F-R 1 aLiu H 1 aIrwanto A 1 aFu X-A 1 aLi Y 1 aYu G-Q 1 aYu Y-X 1 aChen M-F 1 aLow H-Q 1 aLi J-H 1 aBao F-F 1 aFoo J-N 1 aBei J-X 1 aJia X-M 1 aLiu J 1 aLiany H 1 aWang N 1 aNiu G-Y 1 aWang Z-Z 1 aShi B-Q 1 aTian H-Q 1 aLiu H-X 1 aMa S-S 1 aZhou Y 1 aYou J-B 1 aYang Q 1 aWang C 1 aChu T-S 1 aLiu D-C 1 aYu X-L 1 aSun Y-H 1 aNing Y 1 aWei Z-H 1 aChen S-L 1 aChen X-C 1 aZhang Z-X 1 aLiu Y-X 1 aPulit S L 1 aWu W-B 1 aZheng Z-Y 1 aYang R-D 1 aLong H 1 aLiu Z-S 1 aWang J-Q 1 aLi M 1 aZhang L-H 1 aWang H 1 aWang L-M 1 aXiao P 1 aLi J-L 1 aHuang Z-M 1 aHuang J-X 1 aLi Z 1 aLiu J 1 aXiong L 1 aYang J 1 aWang X-D 1 aYu D-B 1 aLu X-M 1 aZhou G-Z 1 aYan L-B 1 aShen J-P 1 aZhang G-C 1 aZeng Y-X 1 aBakker P I W 1 aChen S-M 1 aLiu J-J 00 aHLA-B*13:01 and the dapsone hypersensitivity syndrome. a1620-8 0 v369 aZHANG 2013 3 aBACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
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