A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

Lara Bossini-Castillo; Jose Ezequiel Martin; Jasper Broen; Olga Gorlova; Carmen P. Simeón; Lorenzo Beretta; Madelon C. Vonk; Jose Luis Callejas; Ivan Castellví; Patricia Carreira; Francisco José García-Hernández; Mónica Fernández Castro; Marieke J.H. Coenen; Gabriela Riemekasten; Torsten Witte; Nicolas Hunzelmann; Alexander Kreuter; Jörg H.W. Distler; Bobby P. Koeleman; Alexandre E. Voskuyl; Annemie J. Schuerwegh; Øyvind Palm; Roger Hesselstrand; Annika Nordin; Paolo Airó; Claudio Lunardi; Raffaella Scorza; Paul Shiels; Jacob M. van Laar; Ariane Herrick; Jane Worthington; Christopher Denton; Filemon K. Tan; Frank C. Arnett; Sandeep K. Agarwal; Shervin Assassi; Carmen Fonseca; Maureen D. Mayes; Timothy R.D.J. Radstake; Javier Martin

doi:10.1093/hmg/ddr522

A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

Lara Bossini-Castillo, Jose Ezequiel Martin, Jasper Broen, Olga Gorlova, Carmen P. Simeón, Lorenzo Beretta, Madelon C. Vonk, Jose Luis Callejas, Ivan Castellví, Patricia Carreira, Francisco José García-Hernández, Mónica Fernández Castro, Marieke J.H. Coenen, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H.W. Distler, Bobby P. Koeleman, Alexandre E. VoskuylAnnemie J. Schuerwegh, Øyvind Palm, Roger Hesselstrand, Annika Nordin, Paolo Airó, Claudio Lunardi, Raffaella Scorza, Paul Shiels, Jacob M. van Laar, Ariane Herrick, Jane Worthington, Christopher Denton, Filemon K. Tan, Frank C. Arnett, Sandeep K. Agarwal, Shervin Assassi, Carmen Fonseca, Maureen D. Mayes, Timothy R.D.J. Radstake, Javier Martin

Epidemiology

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

71 Scopus citations

Abstract

A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH5 1.92 3 10 ^-5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 ^-3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 ^-4 OR 5 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH5 2.82 3 10 ^-9 OR 5 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

Original language	English (US)
Article number	ddr522
Pages (from-to)	926-933
Number of pages	8
Journal	Human molecular genetics
Volume	21
Issue number	4
DOIs	https://doi.org/10.1093/hmg/ddr522
State	Published - Feb 2012

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddr522

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Bossini-Castillo, L., Martin, J. E., Broen, J., Gorlova, O., Simeón, C. P., Beretta, L., Vonk, M. C., Callejas, J. L., Castellví, I., Carreira, P., García-Hernández, F. J., Castro, M. F., Coenen, M. J. H., Riemekasten, G., Witte, T., Hunzelmann, N., Kreuter, A., Distler, J. H. W., Koeleman, B. P., ... Martin, J. (2012). A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Human molecular genetics, 21(4), 926-933. Article ddr522. https://doi.org/10.1093/hmg/ddr522

Bossini-Castillo, L, Martin, JE, Broen, J, Gorlova, O, Simeón, CP, Beretta, L, Vonk, MC, Callejas, JL, Castellví, I, Carreira, P, García-Hernández, FJ, Castro, MF, Coenen, MJH, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Distler, JHW, Koeleman, BP, Voskuyl, AE, Schuerwegh, AJ, Palm, Ø, Hesselstrand, R, Nordin, A, Airó, P, Lunardi, C, Scorza, R, Shiels, P, van Laar, JM, Herrick, A, Worthington, J, Denton, C, Tan, FK, Arnett, FC, Agarwal, SK, Assassi, S, Fonseca, C, Mayes, MD, Radstake, TRDJ & Martin, J 2012, 'A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations', Human molecular genetics, vol. 21, no. 4, ddr522, pp. 926-933. https://doi.org/10.1093/hmg/ddr522

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title = "A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations",

abstract = "A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH5 1.92 3 10 -5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 -3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 -4 OR 5 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH5 2.82 3 10 -9 OR 5 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.",

author = "Lara Bossini-Castillo and Martin, {Jose Ezequiel} and Jasper Broen and Olga Gorlova and Sime{\'o}n, {Carmen P.} and Lorenzo Beretta and Vonk, {Madelon C.} and Callejas, {Jose Luis} and Ivan Castellv{\'i} and Patricia Carreira and Garc{\'i}a-Hern{\'a}ndez, {Francisco Jos{\'e}} and Castro, {M{\'o}nica Fern{\'a}ndez} and Coenen, {Marieke J.H.} and Gabriela Riemekasten and Torsten Witte and Nicolas Hunzelmann and Alexander Kreuter and Distler, {J{\"o}rg H.W.} and Koeleman, {Bobby P.} and Voskuyl, {Alexandre E.} and Schuerwegh, {Annemie J.} and {\O}yvind Palm and Roger Hesselstrand and Annika Nordin and Paolo Air{\'o} and Claudio Lunardi and Raffaella Scorza and Paul Shiels and {van Laar}, {Jacob M.} and Ariane Herrick and Jane Worthington and Christopher Denton and Tan, {Filemon K.} and Arnett, {Frank C.} and Agarwal, {Sandeep K.} and Shervin Assassi and Carmen Fonseca and Mayes, {Maureen D.} and Radstake, {Timothy R.D.J.} and Javier Martin",

year = "2012",

month = feb,

doi = "10.1093/hmg/ddr522",

language = "English (US)",

volume = "21",

pages = "926--933",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

AU - Bossini-Castillo, Lara

AU - Martin, Jose Ezequiel

AU - Broen, Jasper

AU - Gorlova, Olga

AU - Simeón, Carmen P.

AU - Beretta, Lorenzo

AU - Vonk, Madelon C.

AU - Callejas, Jose Luis

AU - Castellví, Ivan

AU - Carreira, Patricia

AU - García-Hernández, Francisco José

AU - Castro, Mónica Fernández

AU - Coenen, Marieke J.H.

AU - Riemekasten, Gabriela

AU - Witte, Torsten

AU - Hunzelmann, Nicolas

AU - Kreuter, Alexander

AU - Distler, Jörg H.W.

AU - Koeleman, Bobby P.

AU - Voskuyl, Alexandre E.

AU - Schuerwegh, Annemie J.

AU - Palm, Øyvind

AU - Hesselstrand, Roger

AU - Nordin, Annika

AU - Airó, Paolo

AU - Lunardi, Claudio

AU - Scorza, Raffaella

AU - Shiels, Paul

AU - van Laar, Jacob M.

AU - Herrick, Ariane

AU - Worthington, Jane

AU - Denton, Christopher

AU - Tan, Filemon K.

AU - Arnett, Frank C.

AU - Agarwal, Sandeep K.

AU - Assassi, Shervin

AU - Fonseca, Carmen

AU - Mayes, Maureen D.

AU - Radstake, Timothy R.D.J.

AU - Martin, Javier

PY - 2012/2

Y1 - 2012/2

N2 - A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH5 1.92 3 10 -5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 -3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 -4 OR 5 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH5 2.82 3 10 -9 OR 5 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

AB - A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH5 1.92 3 10 -5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 -3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 -4 OR 5 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH5 2.82 3 10 -9 OR 5 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

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A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

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