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J Eur Acad Dermatol Venereol. 2018 Aug 31. doi: 10.1111/jdv.15227. [Epub ahead of print]

Investigation of the predisposing factor of pemphigus and its clinical subtype through a genome-wide association and next generation sequence analysis.

Sun Y1,2,3,4, Liu H1,2,3,4, Yang B1,2, Wang C2,4, Foo JN5, Bao F2,4, Irwanto A5, Yu G2,4, Fu X2,4, Wang Z2,4, You J2,4, Liu J2,4, Zhou G1,2, Liu J5, Zhang F1,2,3,4,6.

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Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, China.
School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China.
Human Genetics, Genome Institute of Singapore, A*STAR, Singapore city, Singapore.
National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong, China.



Pemphigus is an autoimmune blistering disease with pemphigus vulgaris (PV) and foliaceus (PF) as the two major histological subtypes. Associations with HLA molecules have been suggested, but specific HLA risk variants as well as non-HLA risk variants remain to be discovered.


We performed a two-stage genome-wide association study in the Chinese Han population through a genome-wide discovery analysis and follow-up validation analysis in a total number of 210 PV, 159 PF and 2493 healthy controls. HLA imputation as well as high coverage next generation sequencing based HLA genotyping was employed to investigate the association of classical HLA alleles and amino acid change.


We have discovered independent novel associations with PF at rs2178077 on 12q24.33, located next to RAN (PPF = 1.57 × 10-9 ) and rs3888722 within the MHC region (P = 6.73 × 10-9 ). For the HLA variants, we confirmed independent genome-wide level risk associations in HLA-DQB1 and HLA-DRB1, with DQB1*05:03 to be the strongest association with PV (P = 8.59 × 10-68 , OR = 31.16) and PF (P = 4.84 × 10-17 , OR = 5.64). In addition, DRB1*14 was demonstrated to be a second independent variants (P = 4.2 × 10-63 , OR = 35.47) for PV, while DRB1*04:06 was demonstrated to be the second independent signal (P = 7.44 × 10-13 , OR = 5.58) for PF.


These findings advance our understanding of the genetic basis of pemphigus susceptibility and may offer opportunities for risk prediction and preventive treatment for pemphigus, in particular for PV.


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