Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Maureen D. Mayes; Lara Bossini-Castillo; Olga Gorlova; José Ezequiel Martin; Xiaodong Zhou; Wei V. Chen; Shervin Assassi; Jun Ying; Filemon K. Tan; Frank C. Arnett; John D. Reveille; Sandra Guerra; María Teruel; Francisco David Carmona; Peter K. Gregersen; Annette T. Lee; Elena López-Isac; Eguzkine Ochoa; Patricia Carreira; Carmen Pilar Simeón; Iván Castellví; Miguel Ángel González-Gay; Alexandra Zhernakova; Leonid Padyukov; Marta Alarcón-Riquelme; Cisca Wijmenga; Matthew Brown; Lorenzo Beretta; Gabriela Riemekasten; Torsten Witte; Nicolas Hunzelmann; Alexander Kreuter; Jörg H.W. Distler; Alexandre E. Voskuyl; Annemie J. Schuerwegh; Roger Hesselstrand; Annika Nordin; Paolo Airó; Claudio Lunardi; Paul Shiels; Jacob M. Van Laar; Ariane Herrick; Jane Worthington; Christopher Denton; Fredrick M. Wigley; Laura K. Hummers; John Varga; Monique E. Hinchcliff; Murray Baron; Marie Hudson; Janet E. Pope; Daniel E. Furst; Dinesh Khanna; Kristin Phillips; Elena Schiopu; Barbara M. Segal; Jerry A. Molitor; Richard M. Silver; Virginia D. Steen; Robert W. Simms; Robert A. Lafyatis; Barri J. Fessler; Tracy M. Frech; Firas Alkassab; Peter Docherty; Elzbieta Kaminska; Nader Khalidi; Henry Niall Jones; Janet Markland; David Robinson; Jasper Broen; Timothy R.D.J. Radstake; Carmen Fonseca; Bobby P. Koeleman; Javier Martin

doi:10.1016/j.ajhg.2013.12.002

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Maureen D. Mayes, Lara Bossini-Castillo, Olga Gorlova, José Ezequiel Martin, Xiaodong Zhou, Wei V. Chen, Shervin Assassi, Jun Ying, Filemon K. Tan, Frank C. Arnett, John D. Reveille, Sandra Guerra, María Teruel, Francisco David Carmona, Peter K. Gregersen, Annette T. Lee, Elena López-Isac, Eguzkine Ochoa, Patricia Carreira, Carmen Pilar SimeónIván Castellví, Miguel Ángel González-Gay, Alexandra Zhernakova, Leonid Padyukov, Marta Alarcón-Riquelme, Cisca Wijmenga, Matthew Brown, Lorenzo Beretta, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H.W. Distler, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Roger Hesselstrand, Annika Nordin, Paolo Airó, Claudio Lunardi, Paul Shiels, Jacob M. Van Laar, Ariane Herrick, Jane Worthington, Christopher Denton, Fredrick M. Wigley, Laura K. Hummers, John Varga, Monique E. Hinchcliff, Murray Baron, Marie Hudson, Janet E. Pope, Daniel E. Furst, Dinesh Khanna, Kristin Phillips, Elena Schiopu, Barbara M. Segal, Jerry A. Molitor, Richard M. Silver, Virginia D. Steen, Robert W. Simms, Robert A. Lafyatis, Barri J. Fessler, Tracy M. Frech, Firas Alkassab, Peter Docherty, Elzbieta Kaminska, Nader Khalidi, Henry Niall Jones, Janet Markland, David Robinson, Jasper Broen, Timothy R.D.J. Radstake, Carmen Fonseca, Bobby P. Koeleman, Javier Martin

School of Medicine

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129 Scopus citations

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Original language	English (US)
Pages (from-to)	47-61
Number of pages	15
Journal	American journal of human genetics
Volume	94
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2013.12.002
State	Published - Jan 2 2014

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2013.12.002

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Mayes, M. D., Bossini-Castillo, L., Gorlova, O., Martin, J. E., Zhou, X., Chen, W. V., Assassi, S., Ying, J., Tan, F. K., Arnett, F. C., Reveille, J. D., Guerra, S., Teruel, M., Carmona, F. D., Gregersen, P. K., Lee, A. T., López-Isac, E., Ochoa, E., Carreira, P., ... Martin, J. (2014). Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. American journal of human genetics, 94(1), 47-61. https://doi.org/10.1016/j.ajhg.2013.12.002

Mayes, MD, Bossini-Castillo, L, Gorlova, O, Martin, JE, Zhou, X, Chen, WV, Assassi, S, Ying, J, Tan, FK, Arnett, FC, Reveille, JD, Guerra, S, Teruel, M, Carmona, FD, Gregersen, PK, Lee, AT, López-Isac, E, Ochoa, E, Carreira, P, Simeón, CP, Castellví, I, González-Gay, MÁ, Zhernakova, A, Padyukov, L, Alarcón-Riquelme, M, Wijmenga, C, Brown, M, Beretta, L, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Distler, JHW, Voskuyl, AE, Schuerwegh, AJ, Hesselstrand, R, Nordin, A, Airó, P, Lunardi, C, Shiels, P, Van Laar, JM, Herrick, A, Worthington, J, Denton, C, Wigley, FM , Hummers, LK, Varga, J, Hinchcliff, ME, Baron, M, Hudson, M, Pope, JE, Furst, DE, Khanna, D, Phillips, K, Schiopu, E, Segal, BM, Molitor, JA, Silver, RM, Steen, VD, Simms, RW, Lafyatis, RA, Fessler, BJ, Frech, TM, Alkassab, F, Docherty, P, Kaminska, E, Khalidi, N, Jones, HN, Markland, J, Robinson, D, Broen, J, Radstake, TRDJ, Fonseca, C, Koeleman, BP & Martin, J 2014, 'Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis', American journal of human genetics, vol. 94, no. 1, pp. 47-61. https://doi.org/10.1016/j.ajhg.2013.12.002

@article{ba7bea9e503e4df486ff71dabe9ebceb,

title = "Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis",

abstract = "In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.",

author = "Mayes, {Maureen D.} and Lara Bossini-Castillo and Olga Gorlova and Martin, {Jos{\'e} Ezequiel} and Xiaodong Zhou and Chen, {Wei V.} and Shervin Assassi and Jun Ying and Tan, {Filemon K.} and Arnett, {Frank C.} and Reveille, {John D.} and Sandra Guerra and Mar{\'i}a Teruel and Carmona, {Francisco David} and Gregersen, {Peter K.} and Lee, {Annette T.} and Elena L{\'o}pez-Isac and Eguzkine Ochoa and Patricia Carreira and Sime{\'o}n, {Carmen Pilar} and Iv{\'a}n Castellv{\'i} and Gonz{\'a}lez-Gay, {Miguel {\'A}ngel} and Alexandra Zhernakova and Leonid Padyukov and Marta Alarc{\'o}n-Riquelme and Cisca Wijmenga and Matthew Brown and Lorenzo Beretta and Gabriela Riemekasten and Torsten Witte and Nicolas Hunzelmann and Alexander Kreuter and Distler, {J{\"o}rg H.W.} and Voskuyl, {Alexandre E.} and Schuerwegh, {Annemie J.} and Roger Hesselstrand and Annika Nordin and Paolo Air{\'o} and Claudio Lunardi and Paul Shiels and {Van Laar}, {Jacob M.} and Ariane Herrick and Jane Worthington and Christopher Denton and Wigley, {Fredrick M.} and Hummers, {Laura K.} and John Varga and Hinchcliff, {Monique E.} and Murray Baron and Marie Hudson and Pope, {Janet E.} and Furst, {Daniel E.} and Dinesh Khanna and Kristin Phillips and Elena Schiopu and Segal, {Barbara M.} and Molitor, {Jerry A.} and Silver, {Richard M.} and Steen, {Virginia D.} and Simms, {Robert W.} and Lafyatis, {Robert A.} and Fessler, {Barri J.} and Frech, {Tracy M.} and Firas Alkassab and Peter Docherty and Elzbieta Kaminska and Nader Khalidi and Jones, {Henry Niall} and Janet Markland and David Robinson and Jasper Broen and Radstake, {Timothy R.D.J.} and Carmen Fonseca and Koeleman, {Bobby P.} and Javier Martin",

note = "Funding Information: This study was supported by National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation (CORT) grant P50AR054144, NIH grant KL2RR024149-04, NIH NIAMS grant N01-AR02251, and NIH National Center for Research Resources grant 3UL1RR024148. This study was supported by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 and SAF2012-34435 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucia, and RD08/0075 and RD12/0009/0004 from the Redes Tem{\'a}ticas de Investigaci{\'o}n Cooperativa en Salud (Red de Investigaci{\'o}n en Inflamaci{\'o}n y Enfermedades Reum{\'a}ticas). We are indebted to the Immunochip Consortium for provision of the control data. We are grateful to Julio Charles, Marilyn Perry, Suzanne S. Taillefer (National Study Coordinator for the Canadian Scleroderma Research Group), Sofia Vargas, Sonia Garc{\'i}a, and Gema Robledo. We also thank the Scleroderma Foundation, the Spanish Scleroderma Patient Group, the Canadian Scleroderma Patient Group, the Federation of European Scleroderma Associations, National DNA Bank Carlos III (University of Salamanca), the European League against Rheumatism Scleroderma Trials and Research group, the German Network of Systemic Sclerosis, and the affected individuals, friends, spouses, and others who generously provided the samples for these studies. ",

year = "2014",

month = jan,

day = "2",

doi = "10.1016/j.ajhg.2013.12.002",

language = "English (US)",

volume = "94",

pages = "47--61",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

AU - Mayes, Maureen D.

AU - Bossini-Castillo, Lara

AU - Gorlova, Olga

AU - Martin, José Ezequiel

AU - Zhou, Xiaodong

AU - Chen, Wei V.

AU - Assassi, Shervin

AU - Ying, Jun

AU - Tan, Filemon K.

AU - Arnett, Frank C.

AU - Reveille, John D.

AU - Guerra, Sandra

AU - Teruel, María

AU - Carmona, Francisco David

AU - Gregersen, Peter K.

AU - Lee, Annette T.

AU - López-Isac, Elena

AU - Ochoa, Eguzkine

AU - Carreira, Patricia

AU - Simeón, Carmen Pilar

AU - Castellví, Iván

AU - González-Gay, Miguel Ángel

AU - Zhernakova, Alexandra

AU - Padyukov, Leonid

AU - Alarcón-Riquelme, Marta

AU - Wijmenga, Cisca

AU - Brown, Matthew

AU - Beretta, Lorenzo

AU - Riemekasten, Gabriela

AU - Witte, Torsten

AU - Hunzelmann, Nicolas

AU - Kreuter, Alexander

AU - Distler, Jörg H.W.

AU - Voskuyl, Alexandre E.

AU - Schuerwegh, Annemie J.

AU - Hesselstrand, Roger

AU - Nordin, Annika

AU - Airó, Paolo

AU - Lunardi, Claudio

AU - Shiels, Paul

AU - Van Laar, Jacob M.

AU - Herrick, Ariane

AU - Worthington, Jane

AU - Denton, Christopher

AU - Wigley, Fredrick M.

AU - Hummers, Laura K.

AU - Varga, John

AU - Hinchcliff, Monique E.

AU - Baron, Murray

AU - Hudson, Marie

AU - Pope, Janet E.

AU - Furst, Daniel E.

AU - Khanna, Dinesh

AU - Phillips, Kristin

AU - Schiopu, Elena

AU - Segal, Barbara M.

AU - Molitor, Jerry A.

AU - Silver, Richard M.

AU - Steen, Virginia D.

AU - Simms, Robert W.

AU - Lafyatis, Robert A.

AU - Fessler, Barri J.

AU - Frech, Tracy M.

AU - Alkassab, Firas

AU - Docherty, Peter

AU - Kaminska, Elzbieta

AU - Khalidi, Nader

AU - Jones, Henry Niall

AU - Markland, Janet

AU - Robinson, David

AU - Broen, Jasper

AU - Radstake, Timothy R.D.J.

AU - Fonseca, Carmen

AU - Koeleman, Bobby P.

AU - Martin, Javier

N1 - Funding Information: This study was supported by National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation (CORT) grant P50AR054144, NIH grant KL2RR024149-04, NIH NIAMS grant N01-AR02251, and NIH National Center for Research Resources grant 3UL1RR024148. This study was supported by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 and SAF2012-34435 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucia, and RD08/0075 and RD12/0009/0004 from the Redes Temáticas de Investigación Cooperativa en Salud (Red de Investigación en Inflamación y Enfermedades Reumáticas). We are indebted to the Immunochip Consortium for provision of the control data. We are grateful to Julio Charles, Marilyn Perry, Suzanne S. Taillefer (National Study Coordinator for the Canadian Scleroderma Research Group), Sofia Vargas, Sonia García, and Gema Robledo. We also thank the Scleroderma Foundation, the Spanish Scleroderma Patient Group, the Canadian Scleroderma Patient Group, the Federation of European Scleroderma Associations, National DNA Bank Carlos III (University of Salamanca), the European League against Rheumatism Scleroderma Trials and Research group, the German Network of Systemic Sclerosis, and the affected individuals, friends, spouses, and others who generously provided the samples for these studies.

PY - 2014/1/2

Y1 - 2014/1/2

N2 - In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

AB - In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

UR - http://www.scopus.com/inward/record.url?scp=84891817885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891817885&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2013.12.002

DO - 10.1016/j.ajhg.2013.12.002

M3 - Article

C2 - 24387989

AN - SCOPUS:84891817885

SN - 0002-9297

VL - 94

SP - 47

EP - 61

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

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