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A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding

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Abstract

Genome-wide association studies (GWASs) have identified over 100 loci associated with rheumatoid arthritis (RA); however, the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown. In this study, we conducted an integrative genomic analysis incorporating multiple “omics” data and identified a functional regulatory DNA variant, rs56199421, and a plausible mechanism by which it regulates the expression of a putative RA risk gene, ORMDL Sphingolipid Biosynthesis Regulator 3 (ORMDL3). The T allele of rs56199421, located in the enhancer region of ORMDL3, exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity. Moreover, the T allele of rs56199421 is associated with elevated RA risk, and ORMDL3 expression is increased in RA patients. Thus, these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding, increases enhancer activity, and elevates the expression of the RA risk gene ORMDL3.

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Data Availability

All of the data generated during this study is available from the corresponding authors upon reasonable request.

Abbreviations

GWASs:

Genome-wide association studies

RA:

Rheumatoid arthritis

ORMDL3 :

ORMDL Sphingolipid Biosynthesis Regulator 3

ACPAs:

Anti-citrullinated protein antibodies

SNPs:

Single nucleotide polymorphisms

eQTLs:

Expression quantitative trait loci

IKZF3 :

IKARO S Family Zinc Finger 3

GSDMB :

Gasdermin B

SP1:

Sp1 transcription factor

LD:

Linkage disequilibrium

TSS:

Transcription start site

PBMCs:

Peripheral blood mononuclear cells

OA:

Osteoarthritis

ChIP-seq:

Chromatin immunoprecipitation sequencing

ENCODE:

Encyclopedia of DNA elements

GTEx:

Genotype-tissue expression

NCI:

National cancer institute

NHGRI:

National human genome research institute

NHLBI:

National heart, lung, and blood institute

NIDA:

National institute on drug abuse

NIMH:

National institute of mental health

NINDS:

National institute of neurological disorders and stroke

qRT–PCR:

Quantitative reverse transcription PCR

IHC:

Immunohistochemistry

ss-DNA:

Single-stranded DNA

ds-DNA:

Double-stranded DNA

CDS:

Coding sequence

SEM:

Standard error of the mean

DHSs:

DNase I hypersensitive sites

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (No. 31771451 to YL), Shanghai Municipal Science and Technology Major Project (No. 2017SHZDZX01 to YL), and the National Key R&D Program of China (No. 2021YFC2701001 to YL).

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  1. Wenjing Ye and Yiyun Yu have equally contributed to this work.

Authors and Affiliations

  1. Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Wenjing Ye, Yiyun Yu, Xiaoxia Zhu, Weiguo Wan, Hejian Zou & Zaihua Zhu

  2. Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 200040, China

    Wenjing Ye, Yiyun Yu, Xiaoxia Zhu, Weiguo Wan, Hejian Zou & Zaihua Zhu

  3. The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Yun Liu

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Contributions

YL, HZ, and ZZ designed and supervised the experiments. WY, YY, and ZZ performed the experiments. ZZ, XZ, and WW collected clinical samples. ZZ prepared figures and tables and wrote the manuscript. WY and YL revised manuscript. All of the authors have read and approved the final manuscript.

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Correspondence to Yun Liu, Hejian Zou or Zaihua Zhu.

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This study was approved by the Ethics Committees of Huashan Hospital, Fudan University (Number: 2012-137).

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Ye, W., Yu, Y., Zhu, X. et al. A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding. Phenomics 3, 485–495 (2023). https://doi.org/10.1007/s43657-023-00107-z

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