title: Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.
abstract: OBJECTIVE
  Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility.
  
  
  METHODS
  The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction.
  
  
  RESULTS
  Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets.
  
  
  CONCLUSIONS
  Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Jing
authors: J
authors: Yang
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Jing
authors: J
authors: Zhang
authors: State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.
authors: Liangdan
authors: L
authors: Sun
authors: Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Nattiya
authors: N
authors: Hirankarn
authors: Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
authors: Hai-Feng
authors: HF
authors: Pan
authors: Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Chak Sing
authors: CS
authors: Lau
authors: Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Tak Mao
authors: TM
authors: Chan
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Tsz Leung
authors: TL
authors: Lee
authors: Department of Medicine, Queen Elizabeth Hospital, Hong Kong, Hong Kong.
authors: Alexander Moon Ho
authors: AM
authors: Leung
authors: Department of Medicine, Tuen Mun Hospital, New Territory, Hong Kong, Hong Kong.
authors: Chi Chiu
authors: CC
authors: Mok
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Lu
authors: L
authors: Zhang
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Yongfei
authors: Y
authors: Wang
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Jiangshan Jane
authors: JJ
authors: Shen
authors: Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong.
authors: Sik Nin
authors: SN
authors: Wong
authors: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Hong Kong.
authors: Ka Wing
authors: KW
authors: Lee
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Marco Hok Kung
authors: MH
authors: Ho
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Pamela Pui Wah
authors: PP
authors: Lee
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Brian Hon-Yin
authors: BH
authors: Chung
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Chun Yin
authors: CY
authors: Chong
authors: Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Raymond Woon Sing
authors: RW
authors: Wong
authors: Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Mo Yin
authors: MY
authors: Mok
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Wilfred Hing Sang
authors: WH
authors: Wong
authors: Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
authors: Kwok Lung
authors: KL
authors: Tong
authors: Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
authors: Niko Kei Chiu
authors: NK
authors: Tse
authors: Department of Rheumatology, Anhui Provincial Hospital, Hefei, China.
authors: Xiang-Pei
authors: XP
authors: Li
authors: Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Yingyos
authors: Y
authors: Avihingsanon
authors: Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Pornpimol
authors: P
authors: Rianthavorn
authors: Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Thavatchai
authors: T
authors: Deekajorndej
authors: Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Kanya
authors: K
authors: Suphapeetiporn
authors: Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Vorasuk
authors: V
authors: Shotelersuk
authors: Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
authors: Shirley King Yee
authors: SK
authors: Ying
authors: Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
authors: Samuel Ka Shun
authors: SK
authors: Fung
authors: Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
authors: Wai Ming
authors: WM
authors: Lai
authors: Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Chun-Ming
authors: CM
authors: Wong
authors: Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Irene Oi Lin
authors: IO
authors: Ng
authors: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Maria-Merce
authors: MM
authors: Garcia-Barcelo
authors: Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Stacey S
authors: SS
authors: Cherny
authors: State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.
authors: Yong
authors: Y
authors: Cui
authors: Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong LKS Faculty of Medicine, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Pak Chung
authors: PC
authors: Sham
authors: State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.
authors: Sen
authors: S
authors: Yang
authors: Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Dong-Qing
authors: DQ
authors: Ye
authors: State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.
authors: Xue-Jun
authors: XJ
authors: Zhang
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Yu Lung
authors: YL
authors: Lau
authors: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong LKS Faculty of Medicine, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong.
authors: Wanling
authors: W
authors: Yang
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics*; D018122:B7-1 Antigen / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D059470:Tetraspanins; D019014:fas Receptor / Q000235:genetics
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D018122:B7-1 Antigen; C574052:LHFPL6 protein, human; D015514:Oncogene Proteins, Fusion; D059470:Tetraspanins; D019014:fas Receptor
keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus