Editorial

Page 1 of 3

Causal variants in autoimmune disease: a commentary on a

recent published fine-mapping algorithm analysis in genome-wide
association studies study
Jiunn-Diann Lin1,2,3, Chao-Wen Cheng1
1
Graduate Institute of Clinical Medicine, 2Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine,
Taipei Medical University, Taipei, Taiwan; 3Division of Endocrinology, Department of Internal Medicine, Shuang-Ho Hospital, Taipei Medical
University, New Taipei City, Taiwan
Correspondence to: Chao-Wen Cheng, PhD. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St.,
Taipei 110, Taiwan. Email: ccheng@tmu.edu.tw.
Provenance: This is a Guest Editorial commissioned by Section Editor Mingzhu Gao, MD (Department of Laboratory Medicine, Wuxi Second
Hospital, Nanjing Medical University, Wuxi, China).
Comment on: Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2015;518:337-43.

Submitted Dec 02, 2016. Accepted for publication Jan 04, 2017.
doi: 10.21037/atm.2017.02.26
View this article at: http://dx.doi.org/10.21037/atm.2017.02.26

Genome-wide association studies (GWAS), have become in non-coding and around 60% variants were located in
the most powerful tool to search the numerous potential immune-cell transcription factor binding sites (enhancer),
risk genetic loci for the susceptibility of many complicated which contribute to activating or modulating T or B cell
diseases in recent years. However, despite of the more immune response. However, only 10–20% risk variants
comprehensive analysis of GWAS, there are some appear to act directly classical recognizable transcription
limitations for the method. First, it is difficult to identify factor binding sites to regulate gene expression while the
true causal variants due to the haplotype construction 80–90% of non-coding genetic variants functions directly
based on the linkage disequilibrium. Besides, most causal by modifying the non-classical regulatory sequence. In
variants identified by GWAS were non-coding variants. addition, most non-coding risk variants, including those
Although it has been suggested non-coding causal variants that alter gene expression, affect non-canonical sequence
may contribute to epigenetic regulation, such as histone determinants not well-explained by current gene regulatory
acetylation, methylation or DNA methylation, mRNA models.
splicing and the regulation of RNA transcription. The It has been well established that principle pathogenesis of
mechanisms of action, and the cellular states and processes autoimmune diseases is majorly attributed to predisposing
in which they function were largely unknown. In a recent genetic background and environmental factors (2).
study, Farh et al. developed a fine-mapping algorithm to Numerous genetic studies in the past have been utilized
identify candidate causal genetic variants in 21 autoimmune to look for the candidate genetic variants or loci for the
diseases from 39 GWAS studies (1). Through integrated susceptibility of autoimmune diseases, and found that most
predictions with transcription and cis-regulatory map of the impact of genetic variants on the disease pathogenesis
for several kinds of immune and non-immune cell types, are very subtle (3). Most autoimmune diseases related
including resting and stimulated CD4+ T cell, regulatory studies in the past have centered on genes participated
cell, B cell and monocytes, etc., they had provided the in the process of antigen presenting cell mediated
unique information about the distributions and features of T-cell activation, including human leukocyte antigen-
causal variants in the susceptibility of autoimmune diseases. autoantigen-T cell receptor signals, and co-stimulatory
Accordingly, more than 90% susceptible variants are reside factors, including cytotoxic T-lymphocyte associated factor

© Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2017;5(6):151
Page 2 of 3 Lin and Cheng. Causal variants in autoimmune disease

4 (CTLA-4), protein tyrosine phosphatase 22, CD40, its biological function and release of the complete BAFF
CD28, inducible T-cell co-stimulator, etc. (3). The studies protein, and by merging with the BAFF protein to form
on B-cell triggering or activation in autoimmune diseases heterotrimers, which restrains the binding ability of the
are limited. This study had also addressed that the signals of BAFF to BAFF receptor (12,13). Interestingly, rs2893321
the causal variants were abundant in both stimulated B-cell is very adjacent to exon 3, though without direct evidences
and T-cell enhancers, which implied the impact of B-cell support; it may associate with the splicing process of BAFF
activation in regulation the susceptibility of autoimmune mRNA and followed by altering BAFF function.
diseases is higher than we expected. In conclusion, Farh et al. delineated important concepts
Recent findings in study the genetic variants of on the global view and localized pattern of causal genetic
interferon regulatory factor 8 (IRF8) and B-cell activating variants in autoimmune diseases. Majority localized in the
factor (BAFF) in autoimmune diseases were also supported non-coding regions, these causal variants can be mapped
their observations. IRF8, one kind of specific transcription to enhancers and frequently coincide with nucleosome-
factors, is well-established to contribute to myeloid cell and depleted sites bound by immune-related transcription
B cell differentiation and maturation, antibody production factors. Although validation and interpretation of non-
and modulate type 1 interferon (INF) activity (4). The coding causal variants remains challenging, understanding
association analysis disclosed that intronic SNP rs17445836 their regulatory mechanisms could provide the potential
of IRF8 was strongly linked to the development of systemic strategy for therapeutic intervention in autoimmune
lupus erythematosus (SLE) (5) and multiple sclerosis (MS) (6). diseases.
The rs17445836 was associated with anti-double-stranded
DNA (dsDNA) autoantibodies in SLE patients and
Acknowledgements
associated with decreased serum type I IFN. Furthermore,
rs17445836 was associated with increased IRF8 expression None.
in B cells of SLE patient (5). In autoimmune thyroid
diseases (AITD), rs17445836 was associated with the
Footnote
occurrence of Hashimoto’s thyroiditis but not Graves’
disease. In addition, rs17445836 was associated with the Conflicts of Interest: The authors have no conflicts of interest
presence and levels of circulating anti-microsomal antibody to declare.
in AITD (7). The intronic SNP rs17445836 in IRF8 located
in the non-coding region may present as a B-cell enhancer
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Cite this article as: Lin JD, Cheng CW. Causal variants in
autoimmune disease: a commentary on a recent published
fine-mapping algorithm analysis in genome-wide association
studies study. Ann Transl Med 2017;5(6):151. doi: 10.21037/
atm.2017.02.26

© Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2017;5(6):151