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Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations
  1. Yan Zhang1,
  2. Jing Yang1,
  3. Jing Zhang1,
  4. Liangdan Sun2,
  5. Nattiya Hirankarn3,
  6. Hai-Feng Pan4,
  7. Chak Sing Lau5,
  8. Tak Mao Chan5,
  9. Tsz Leung Lee1,
  10. Alexander Moon Ho Leung6,
  11. Chi Chiu Mok7,
  12. Lu Zhang1,
  13. Yongfei Wang1,
  14. Jiangshan Jane Shen1,
  15. Sik Nin Wong8,
  16. Ka Wing Lee9,
  17. Marco Hok Kung Ho1,
  18. Pamela Pui Wah Lee1,
  19. Brian Hon-Yin Chung1,
  20. Chun Yin Chong1,
  21. Raymond Woon Sing Wong5,
  22. Mo Yin Mok5,
  23. Wilfred Hing Sang Wong1,
  24. Kwok Lung Tong10,
  25. Niko Kei Chiu Tse11,
  26. Xiang-Pei Li12,
  27. Yingyos Avihingsanon13,
  28. Pornpimol Rianthavorn14,
  29. Thavatchai Deekajorndej14,
  30. Kanya Suphapeetiporn14,
  31. Vorasuk Shotelersuk14,
  32. Shirley King Yee Ying10,
  33. Samuel Ka Shun Fung10,
  34. Wai Ming Lai11,
  35. Chun-Ming Wong15,
  36. Irene Oi Lin Ng15,
  37. Maria-Merce Garcia-Barcelo16,
  38. Stacey S Cherny17,
  39. Yong Cui2,
  40. Pak Chung Sham17,18,
  41. Sen Yang2,
  42. Dong-Qing Ye3,
  43. Xue-Jun Zhang2,
  44. Yu Lung Lau1,
  45. Wanling Yang1,18
  1. 1Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
  2. 2State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China
  3. 3Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  4. 4Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
  5. 5Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  6. 6Department of Medicine, Queen Elizabeth Hospital, Hong Kong, Hong Kong
  7. 7Department of Medicine, Tuen Mun Hospital, New Territory, Hong Kong, Hong Kong
  8. 8Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong
  9. 9Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Hong Kong
  10. 10Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong
  11. 11Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong
  12. 12Department of Rheumatology, Anhui Provincial Hospital, Hefei, China
  13. 13Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  14. 14Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  15. 15Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  16. 16Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  17. 17Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  18. 18LKS Faculty of Medicine, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong
  1. Correspondence to Dr Wanling Yang, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Room 58, 7/F, Laboratory Block, 21 Sassoon Rd., Pokfulam, Hong Kong, Hong Kong; yangwl{at}hku.hk

Abstract

Objectives 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.

  • Systemic Lupus Erythematosus
  • Gene Polymorphism
  • Autoimmune Diseases

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