title: Increased risk of strontium ranelate-related SJS/TEN is associated with HLA.
abstract: Severe adverse drug reactions (ADR) of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some patients receiving strontium ranelate have been reported, but the risk factors are unclear. We show that HLA-A*33:03 and B*58:01 are significantly associated with patients who developed SJS/TEN; and provide the first evidence that genetic risk factors are involved in strontium ranelate-associated SJS/TEN.
  
  
  
  In this study, HLA as a genetic risk factor was assessed among osteoporotic patients prescribed with strontium ranelate that developed severe cutaneous adverse drug reactions (SCARs) compared with those who were tolerant.
  
  
  
  Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) of patients was HLA typed using sequencing-based typing method to determine their HLA profiles.
  
  
  
  Osteoporotic patients who are currently on strontium ranelate were enrolled in the study (n = 76). Tolerant controls were defined as patients who received strontium ranelate for a minimum of 3 months (range 3 months to 8 years) with no reports of any cutaneous reactions as these reactions usually occur within the first 12 weeks after starting treatment. Retrospective cases of SJS/TEN were also identified (n = 5). The majority of the accrued samples were of Han Chinese descent: controls (n = 72) and cases (n = 4). All cases and controls were genotyped at four HLA genes, namely HLA-A, HLA-B, HLA-C, and HLA-DRB1. In comparing the samples of Han Chinese descent (72 controls and 4 cases), we found significant associations with HLA-A*33:03 (p = 0.002) and HLA-B*58:01 (p = 0.023). There was no significant association with any HLA-C or HLA-DRB1 alleles.
  
  
  
  This study reveals that the occurrence of SJS/TEN in Han Chinese patients receiving strontium ranelate is HLA associated. This has important clinical implications for understanding the underlying mechanisms for this ADR as well as evaluating the potential role of genetic pre-screening for osteoporotic patients who may be prescribed strontium ranelate.
authors.affiliation: Department of Dermatology, Singapore General Hospital, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore.
authors.forename: M X
authors.initials: MX
authors.lastname: Shen
authors.affiliation: National Skin Center, Singapore, Singapore.
authors.forename: Y L
authors.initials: YL
authors.lastname: Lim
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore.|Dermatology Department, Changi General Hospital, Singapore, Singapore.
authors.forename: Y K
authors.initials: YK
authors.lastname: Tay
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore.|Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors.forename: M M F
authors.initials: MM
authors.lastname: Chan
authors.affiliation: Department of Dermatology, Singapore General Hospital, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: S M
authors.initials: SM
authors.lastname: Pang
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore.
authors.forename: Z W
authors.initials: ZW
authors.lastname: Xiao
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore.|Menopause Unit and Family Medicine Service, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: S B
authors.initials: SB
authors.lastname: Ang
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore. ren_ee_chee@immunol.a-star.edu.sg.|Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. ren_ee_chee@immunol.a-star.edu.sg.
authors.forename: E C
authors.initials: EC
authors.lastname: Ren
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D010024:Osteoporosis / Q000188:drug therapy; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome / Q000235:genetics*; D013876:Thiophenes / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D015234:HLA-A Antigens; C082945:HLA-A*33 antigen; D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; D013876:Thiophenes; C081587:strontium ranelate
keywords: ADR; Genetic risk; HLA; SJS/TEN; Strontium ranelate