A large meta-analysis identifies genes associated with anterior uveitis

Sahar Gelfman, Arden Moscati, Santiago Mendez Huergo, Rujin Wang, Veera Rajagopal, Neelroop Parikshak, Vijay Kumar Pounraja, Esteban Chen, Michelle Leblanc, Ralph Hazlewood, Jan Freudenberg, Blerta Cooper, Ann J. Ligocki, Charles G. Miller, Tavé Zyl, Jonathan Weyne, Carmelo Romano, Botir Sagdullaev, Olle Melander, Aris Baras, Eli A. Stahl () and Giovanni Coppola ()
Additional contact information
Sahar Gelfman: Regeneron Genetics Center
Arden Moscati: Regeneron Genetics Center
Santiago Mendez Huergo: Regeneron Pharmaceuticals
Rujin Wang: Regeneron Genetics Center
Veera Rajagopal: Regeneron Genetics Center
Neelroop Parikshak: Regeneron Genetics Center
Vijay Kumar Pounraja: Regeneron Genetics Center
Esteban Chen: Regeneron Genetics Center
Michelle Leblanc: Regeneron Genetics Center
Ralph Hazlewood: Regeneron Pharmaceuticals
Jan Freudenberg: Regeneron Genetics Center
Blerta Cooper: Regeneron Pharmaceuticals
Ann J. Ligocki: Regeneron Pharmaceuticals
Charles G. Miller: Regeneron Pharmaceuticals
Tavé Zyl: Regeneron Pharmaceuticals
Jonathan Weyne: Regeneron Pharmaceuticals
Carmelo Romano: Regeneron Pharmaceuticals
Botir Sagdullaev: Regeneron Pharmaceuticals
Olle Melander: Lund University
Aris Baras: Regeneron Genetics Center
Eli A. Stahl: Regeneron Genetics Center
Giovanni Coppola: Regeneron Genetics Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.

Date: 2023
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DOI: 10.1038/s41467-023-43036-1

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