Abstract
Susceptibility to primary biliary cholangitis (PBC) is in part genetically determined. In our previous PBC genome-wide association study (GWAS) in 1118 Han Chinese PBC and 4036 controls, we noted that multiple SNPs in the runt-related transcription factor 3 (RUNX3) regions showed a nominally significant association. The tag SNP rs7529070 was genotyped using a TaqMan assay in a separately collected 1435 PBC and 3205 controls. A meta-analysis with a combined 2553 PBC and 7241 controls showed that rs7529070 is still nominally associated with PBC (p = 1.7 × 10–4, odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08–1.28). Further analysis indicated that the risk allele of rs7529070 (G allele) is in complete linkage disequilibrium (LD) (r2 = 1) with the G allele of rs4648889, which is known to be associated with increased RUNX3 expression. Bioinformatic analysis with existing expression data showed that the expression of RUNX3 is significantly increased in PBC patients (p = 0.001) and the expression level is correlated with disease severity. Consistently, we also found significantly increased RUNX3 expression (p < 0.01) in the livers of dnTGFβRII mice (a PBC mouse model). This study suggests that the RUNX3 locus may associate with PBC in Han Chinese.
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Abbreviations
- PBC:
-
Primary biliary cirrhosis
- GWAS:
-
Genome-wide association study/studies
- RUNX3:
-
Runt-related transcription factor 3
- SNP:
-
Single nucleotide polymorphism
- LD:
-
Linkage disequilibrium
- PsA:
-
Psoriatic arthritis
- AS:
-
Ankylosing spondylitis
- SLE:
-
Systematic lupus erythematosus
- SSc:
-
Systematic sclerosis
- RA:
-
Rheumatoid arthritis
- RAF:
-
Risk allele frequency
- CHB:
-
Chinese Han Beijing
- CHS:
-
Chinese Han South
- GEO:
-
Gene Expression Omnibus
- IL17:
-
Interleukin 17
- IFN-γ:
-
Interferon gamma
- Th17:
-
T helper 17
- TGF-β:
-
Transforming growth factor beta
- IRF4:
-
Interferon regulatory factor 4
- AASLD:
-
American Association for the Study of Liver Diseases
- AMA:
-
Antimitochondrial antibody
- PBS:
-
Phosphate-buffered saline
- PCR:
-
Polymerase chain reaction
- HRPT:
-
Hypoxanthine–guanine phosphoribosyltransferase
- OR:
-
Odds ratio
- CI:
-
Confidence interval
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Acknowledgments
We thank all participating members of the Jiangsu Provincial PBC Collaboration Group for providing patient samples and clinical information. We would like to thank the patients for their participation in this study.
Funding
This work was supported in part by grants from the National Natural Science Foundation of China (No. 81870397 to X.D.L.; No. 81770381 to X.J.S.; 81620108002, 81771732, 81830016 to X.M.), from the Jiangsu Provincial Research Fund (BE2017713 to X.D.L; BL2018657 to Y.T.), Zhishan Young Scholar Program of SEU and the Fundamental Research Funds for the Central Universities (X.J.S).
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Conceptualization: X.D.L and X.J.S. Data curation, R.J, M.Z, P.J, and Q.W. Formal analysis, R.J, C.W, X.D.L, and X.J.S. Funding acquisition, X.M, X.D.L, and X.J.S. Investigation, R.J, M.Z, P.J, and Q.W. Methodology, R.J and X.D.L. Project administration, C.W and S.H.Y. Resources, L.L, W.C, Y.T, and X.M. Software, R.J and C.W. Supervision, X.D.L and X.J.S. Validation, R.J, C.W, and X.D.L. Visualization, R.J and C.W. Writing—original draft, R.J, X.D.L, and X.J.S. Writing—review and editing, M.E.G, M.F.S, and Z.X.L.
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251_2020_1192_MOESM1_ESM.docx
Supplementary file1: Fig. S1 The LD plot of significant SNPs associated with PBC in RUNX3 locus. All SNPs were analyzed by HaploView v4.2. Darker color denotes a higher correlation between markers (r2), which was defined according to the confidence interval method (Gabriel et al. 2002). The plot of pair-wise linkage disequilibrium (LD) and haplotype analysis of significant SNPs in RUNX3 was drawn by using 1118 Han Chinese PBC samples from previously genotyped GWAS data. (DOCX 28.1 KB)
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Jawed, R., Zhang, M., Wang, C. et al. Replication study and meta-analysis indicate a suggestive association of RUNX3 locus with primary biliary cholangitis. Immunogenetics 72, 467–474 (2020). https://doi.org/10.1007/s00251-020-01192-4
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DOI: https://doi.org/10.1007/s00251-020-01192-4