African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Gudny Ella Thorlacius; Erna V. Ivarsdottir; Saedis Saevarsdottir; Kristjan H.S. Moore; Sigurjon A. Gudjonsson; Bjarni V. Halldorsson; Hilma Holm; Aslaug Jonasdottir; Frosti Jonsson; Snaedis Kristmundsdottir; Gisli Masson; Olafur T. Magnusson; Gudmundur L. Norddahl; Asmundur Oddsson; Thorunn A. Olafsdottir; Pall I. Olason; Aron Skaftason; Lilja Stefansdottir; Arni Sturluson; Unnur Thorsteinsdottir; Gudmar Thorleifsson; Valentin Y. Walker; Florian Zink; Eirikur Steingrimsson; Daniel F. Gudbjartsson; Ingileif Jonsdottir; Agnar Helgason; Patrick Sulem; Kari Stefansson

doi:10.1038/s41588-025-02398-6

African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Gudny Ella Thorlacius
, Erna V. Ivarsdottir
, Saedis Saevarsdottir
, Kristjan H.S. Moore
, Sigurjon A. Gudjonsson
, Bjarni V. Halldorsson
, Hilma Holm
, Aslaug Jonasdottir
, Frosti Jonsson
, Snaedis Kristmundsdottir
, Gisli Masson
, Olafur T. Magnusson
, Gudmundur L. Norddahl
, Asmundur Oddsson
, Thorunn A. Olafsdottir
, Pall I. Olason
, Aron Skaftason
, Lilja Stefansdottir
, Arni Sturluson
, Unnur Thorsteinsdottir

Gudmar Thorleifsson, Valentin Y. Walker, Florian Zink, Eirikur Steingrimsson, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Agnar Helgason, Patrick Sulem, Kari Stefansson

University of Iceland, Landspitali

Research output: Contribution to journal › Letter › peer-review

Abstract

Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus¹ but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβ^E502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (OR_meta = 3.8, P_meta = 5.3 × 10⁻²⁰, n = 1,243) and SLE (OR_meta = 3.2, P_meta = 1.0 × 10⁻¹⁹, n = 1,697). In this cohort, IKKβ^E502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies.

Original language	English
Pages (from-to)	2980-2986
Number of pages	7
Journal	Nature Genetics
Volume	57
Issue number	12
DOIs	https://doi.org/10.1038/s41588-025-02398-6
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright: © The Author(s) 2025.

Other keywords

Adult
Black People/genetics
Black or African American/genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
I-kappa B Kinase/genetics
Lupus Erythematosus, Cutaneous/genetics
Lupus Erythematosus, Systemic/genetics
Male
Middle Aged
Mutation, Missense
Polymorphism, Single Nucleotide
gigtarlæknisfræði
náttúrufræðingar

Access to Document

10.1038/s41588-025-02398-6

https://iris.landspitali.is/ws/files/246861260/s41588-025-02398-6.pdfLicence: CC BY-NC-ND

Cite this

Thorlacius, G. E., Ivarsdottir, E. V., Saevarsdottir, S., Moore, K. H. S., Gudjonsson, S. A., Halldorsson, B. V., Holm, H., Jonasdottir, A., Jonsson, F., Kristmundsdottir, S., Masson, G., Magnusson, O. T., Norddahl, G. L., Oddsson, A., Olafsdottir, T. A., Olason, P. I., Skaftason, A., Stefansdottir, L., Sturluson, A., ... Stefansson, K. (2025). African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk. Nature Genetics, 57(12), 2980-2986. https://doi.org/10.1038/s41588-025-02398-6

@article{b7f18ffa0f624ce5a6da31c7f606550d,

title = "African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk",

abstract = "Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4\% of CLE cases and 6.4\% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies.",

keywords = "Adult, Black People/genetics, Black or African American/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, I-kappa B Kinase/genetics, Lupus Erythematosus, Cutaneous/genetics, Lupus Erythematosus, Systemic/genetics, Male, Middle Aged, Mutation, Missense, Polymorphism, Single Nucleotide, gigtarl{\ae}knisfr{\ae}{\dh}i, n{\'a}tt{\'u}rufr{\ae}{\dh}ingar",

author = "Thorlacius, \{Gudny Ella\} and Ivarsdottir, \{Erna V.\} and Saedis Saevarsdottir and Moore, \{Kristjan H.S.\} and Gudjonsson, \{Sigurjon A.\} and Halldorsson, \{Bjarni V.\} and Hilma Holm and Aslaug Jonasdottir and Frosti Jonsson and Snaedis Kristmundsdottir and Gisli Masson and Magnusson, \{Olafur T.\} and Norddahl, \{Gudmundur L.\} and Asmundur Oddsson and Olafsdottir, \{Thorunn A.\} and Olason, \{Pall I.\} and Aron Skaftason and Lilja Stefansdottir and Arni Sturluson and Unnur Thorsteinsdottir and Gudmar Thorleifsson and Walker, \{Valentin Y.\} and Florian Zink and Eirikur Steingrimsson and Gudbjartsson, \{Daniel F.\} and Ingileif Jonsdottir and Agnar Helgason and Patrick Sulem and Kari Stefansson",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41588-025-02398-6",

language = "English",

volume = "57",

pages = "2980--2986",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

Thorlacius, GE, Ivarsdottir, EV, Saevarsdottir, S, Moore, KHS, Gudjonsson, SA, Halldorsson, BV, Holm, H, Jonasdottir, A, Jonsson, F, Kristmundsdottir, S, Masson, G, Magnusson, OT, Norddahl, GL, Oddsson, A, Olafsdottir, TA, Olason, PI, Skaftason, A, Stefansdottir, L, Sturluson, A, Thorsteinsdottir, U, Thorleifsson, G, Walker, VY, Zink, F, Steingrimsson, E, Gudbjartsson, DF, Jonsdottir, I , Helgason, A, Sulem, P & Stefansson, K 2025, 'African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk', Nature Genetics, vol. 57, no. 12, pp. 2980-2986. https://doi.org/10.1038/s41588-025-02398-6

TY - JOUR

T1 - African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

AU - Thorlacius, Gudny Ella

AU - Ivarsdottir, Erna V.

AU - Saevarsdottir, Saedis

AU - Moore, Kristjan H.S.

AU - Gudjonsson, Sigurjon A.

AU - Halldorsson, Bjarni V.

AU - Holm, Hilma

AU - Jonasdottir, Aslaug

AU - Jonsson, Frosti

AU - Kristmundsdottir, Snaedis

AU - Masson, Gisli

AU - Magnusson, Olafur T.

AU - Norddahl, Gudmundur L.

AU - Oddsson, Asmundur

AU - Olafsdottir, Thorunn A.

AU - Olason, Pall I.

AU - Skaftason, Aron

AU - Stefansdottir, Lilja

AU - Sturluson, Arni

AU - Thorsteinsdottir, Unnur

AU - Thorleifsson, Gudmar

AU - Walker, Valentin Y.

AU - Zink, Florian

AU - Steingrimsson, Eirikur

AU - Gudbjartsson, Daniel F.

AU - Jonsdottir, Ingileif

AU - Helgason, Agnar

AU - Sulem, Patrick

AU - Stefansson, Kari

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/12

Y1 - 2025/12

N2 - Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies.

AB - Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies.

KW - Adult

KW - Black People/genetics

KW - Black or African American/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - I-kappa B Kinase/genetics

KW - Lupus Erythematosus, Cutaneous/genetics

KW - Lupus Erythematosus, Systemic/genetics

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - gigtarlæknisfræði

KW - náttúrufræðingar

UR - https://www.scopus.com/pages/publications/105022450117

U2 - 10.1038/s41588-025-02398-6

DO - 10.1038/s41588-025-02398-6

M3 - Letter

C2 - 41249843

SN - 1061-4036

VL - 57

SP - 2980

EP - 2986

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Abstract

Bibliographical note

Other keywords

Access to Document

Fingerprint

Cite this