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Ann Rheum Dis. 2016 May;75(5):891-8. doi: 10.1136/annrheumdis-2014-206367. Epub 2015 Apr 10.

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

Author information

1
Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
2
State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.
3
Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
4
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
5
Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
6
Department of Medicine, Queen Elizabeth Hospital, Hong Kong, Hong Kong.
7
Department of Medicine, Tuen Mun Hospital, New Territory, Hong Kong, Hong Kong.
8
Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong.
9
Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Hong Kong.
10
Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
11
Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong.
12
Department of Rheumatology, Anhui Provincial Hospital, Hefei, China.
13
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
14
Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
15
Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
16
Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
17
Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
18
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.
19
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.

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.

KEYWORDS:

Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus

PMID:
25862617
DOI:
10.1136/annrheumdis-2014-206367
[Indexed for MEDLINE]

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