A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Wouter J Venema; Sanne Hiddingh; Jorg van Loosdregt; John Bowes; Brunilda Balliu; Joke H de Boer; Jeannette Ossewaarde-van Norel; Susan D Thompson; Carl D Langefeld; Aafke de Ligt; Lars T van der Veken; Peter H L Krijger; Wouter de Laat; Jonas J W Kuiper

doi:10.1016/j.xgen.2023.100460

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Wouter J Venema, Sanne Hiddingh, Jorg van Loosdregt, John Bowes, Brunilda Balliu, Joke H de Boer, Jeannette Ossewaarde-van Norel, Susan D Thompson, Carl D Langefeld, Aafke de Ligt, Lars T van der Veken, Peter H L Krijger, Wouter de Laat, Jonas J W Kuiper^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.

Original language	English
Article number	100460
Journal	Cell genomics
Volume	4
Issue number	1
Early online date	29 Nov 2023
DOIs	https://doi.org/10.1016/j.xgen.2023.100460
Publication status	Published - 10 Jan 2024

Keywords

ERAP2
GWAS
SNP
alternative splicing
autoimmunity
birdshot
eQTL
haplotype
rs2248374

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1-s2.0-S2666979X2300304X-mainFinal published version, 4.27 MBLicence: CC BY-NC-ND

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Venema, W. J., Hiddingh, S., van Loosdregt, J., Bowes, J., Balliu, B., de Boer, J. H., Ossewaarde-van Norel, J., Thompson, S. D., Langefeld, C. D., de Ligt, A., van der Veken, L. T., Krijger, P. H. L., de Laat, W., & Kuiper, J. J. W. (2024). A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs. Cell genomics, 4(1), Article 100460. https://doi.org/10.1016/j.xgen.2023.100460

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title = "A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs",

abstract = "Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.",

keywords = "ERAP2, GWAS, SNP, alternative splicing, autoimmunity, birdshot, eQTL, haplotype, rs2248374",

author = "Venema, {Wouter J} and Sanne Hiddingh and {van Loosdregt}, Jorg and John Bowes and Brunilda Balliu and {de Boer}, {Joke H} and {Ossewaarde-van Norel}, Jeannette and Thompson, {Susan D} and Langefeld, {Carl D} and {de Ligt}, Aafke and {van der Veken}, {Lars T} and Krijger, {Peter H L} and {de Laat}, Wouter and Kuiper, {Jonas J W}",

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Venema, WJ, Hiddingh, S, van Loosdregt, J, Bowes, J, Balliu, B, de Boer, JH, Ossewaarde-van Norel, J, Thompson, SD, Langefeld, CD, de Ligt, A, van der Veken, LT, Krijger, PHL, de Laat, W & Kuiper, JJW 2024, 'A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs', Cell genomics, vol. 4, no. 1, 100460. https://doi.org/10.1016/j.xgen.2023.100460

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T1 - A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

AU - Venema, Wouter J

AU - Hiddingh, Sanne

AU - van Loosdregt, Jorg

AU - Bowes, John

AU - Balliu, Brunilda

AU - de Boer, Joke H

AU - Ossewaarde-van Norel, Jeannette

AU - Thompson, Susan D

AU - Langefeld, Carl D

AU - de Ligt, Aafke

AU - van der Veken, Lars T

AU - Krijger, Peter H L

AU - de Laat, Wouter

AU - Kuiper, Jonas J W

PY - 2024/1/10

Y1 - 2024/1/10

N2 - Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.

AB - Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.

KW - ERAP2

KW - GWAS

KW - SNP

KW - alternative splicing

KW - autoimmunity

KW - birdshot

KW - eQTL

KW - haplotype

KW - rs2248374

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VL - 4

JO - Cell genomics

JF - Cell genomics

IS - 1

M1 - 100460

ER -

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

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