A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes

Cargill, Michele; Schrodi, Steven J.; Chang, Monica; Garcia, Veronica E.; Brandon, Rhonda; Callis, Kristina P.; Matsunami, Nori; Ardlie, Kristin G.; Civello, Daniel; Catanese, Joseph J.; Leong, Diane U.; Panko, Jackie M.; McAllister, Linda B.; Hansen, Christopher B.; Papenfuss, Jason; Prescott, Stephen M.; White, Thomas J.; Leppert, Mark F.; Krueger, Gerald G.; Begovich, Ann B.

doi:10.1086/511051

Cited by 1,086Psoriasis: Treatment and PathogenesisGenetic Associations and EpidemiologyDermatology and Skin Diseases

A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes

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Cargill, Michele, Schrodi, Steven J., Chang, Monica, Garcia, Veronica E., Brandon, Rhonda, Callis, Kristina P., Matsunami, Nori, Ardlie, Kristin G. +12 more·2007·The American Journal of Human Genetics

DOI 10.1086/511051PMC PMC1785338

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Abstract

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.

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Some regions contain expected associations across diseases and traits; the association of the same common polymorphisms in IL23R in Crohn's disease, psoriasis, and ankylosing spondylitis points to a shared molecular cause.
“4) Some regions contain expected associations across diseases and traits. Crohn’s disease, psoriasis, and ankylosing spondylitis have long been recognized to share clinical features; the association of the same common polymorphisms in IL23R in all three diseases points to a shared molecular cause (96, 109, 110).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [110]

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Authors: Cargill, M., Schrodi, S. J., Chang, M., Garcia, V. E., Brandon, R., Callis, K. P., Matsunami, N., Ardlie, K. G., Civello, D., Catanese, J. J., Leong, D. U., Panko, J. M., McAllister, L. B., Hansen, C. B., Papenfuss, J., Prescott, S. M., White, T. J., Leppert, M. F., Krueger, G. G., & Begovich, A. B.
Affiliations: Broad Institute (US)
SeraCare Life Sciences (United States) (US)
University of Utah (US)
Corresponding author: Begovich, Ann B.
ORCID: Schrodi, Steven J.
Chang, Monica
Ardlie, Kristin G.
Catanese, Joseph J.
Hansen, Christopher B.
Prescott, Stephen M.
Krueger, Gerald G.
Venue: The American Journal of Human Genetics
Publisher: Elsevier BV
Published: 2007-02
Volume: 80
Issue: 2
Pages: 273-290
ISSN: 0002-9297 (ISSN-L)
DOI: 10.1086/511051
PMC: PMC1785338
OpenAlex: W2110888991
Cited by: 1,086
References: 82
Citations by year: 2026: 13 · 2025: 20 · 2024: 28 · 2023: 22 · 2022: 23 · 2021: 31 · 2020: 31 · 2019: 41 · 2018: 33 · 2017: 38 · 2016: 59 · 2015: 54 · 2014: 66 · 2013: 84 · 2012: 97
FWCI: 44.10
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2360 d)
Locations: The American Journal of Human Genetics (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
LSHTM Research Online (London School of Hygiene and Tropical Medicine) (submittedVersion)
Funders: National Center for Research Resources (M01RR000064)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
Keywords: psoriasis, IL12B, IL23R, genetic susceptibility, single nucleotide polymorphisms, 3' untranslated region, rs3212227, IL-12, IL-23, IL12A, IL12RB1, IL12RB2, IL23A, haplotype association, missense mutations, Monte Carlo simulation, North American populations
MeSH terms: Adolescent, Adult, Bayes Theorem, Child, Female, Genetics, Population, Haplotypes, Humans, Male, Middle Aged, Monte Carlo Method, Psoriasis, Case-Control Studies, Receptors, Interleukin, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptors, Interleukin-12, Interleukin-12 Subunit p40

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A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes

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