The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study

Virpi Leppä; Ida Surakka; Pentti J. Tienari; Irina Elovaara; Alastair Compston; Stephen Sawcer; Neil Robertson; Philip L. de Jager; Cristin Aubin; David A. Hafler; Annette Bang Oturai; Helle Bach Søndergaard; Finn Sellebjerg; Per Soelberg Sørensen; Bernhard Hemmer; Sabine Cepok; Juliane Winkelmann; Heinz Erich Wichmann; Manuel Comabella; Marta F. Bustamante; Xavier Montalban; Tomas Olsson; Ingrid Kockum; Jan Hillert; Lars Alfredsson; An Goris; Bénédicte Dubois; Inger Lise Mero; Cathrine Smestad; Elisabeth G. Celius; Hanne F. Harbo; Sandra D'Alfonso; Laura Bergamaschi; Maurizio Leone; Giovanni Ristori; Ludwig Kappos; Stephen L. Hauser; Isabelle Cournu-Rebeix; Bertrand Fontaine; Steven Boonen; Chris Polman; Aarno Palotie; Leena Peltonen; Janna Saarela

doi:10.1371/journal.pone.0018813

The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study

Virpi Leppä, Ida Surakka, Pentti J. Tienari, Irina Elovaara, Alastair Compston, Stephen Sawcer, Neil Robertson, Philip L. de Jager, Cristin Aubin, David A. Hafler, Annette Bang Oturai, Helle Bach Søndergaard, Finn Sellebjerg, Per Soelberg Sørensen, Bernhard Hemmer, Sabine Cepok, Juliane Winkelmann, Heinz Erich Wichmann, Manuel Comabella, Marta F. BustamanteXavier Montalban, Tomas Olsson, Ingrid Kockum, Jan Hillert, Lars Alfredsson, An Goris, Bénédicte Dubois, Inger Lise Mero, Cathrine Smestad, Elisabeth G. Celius, Hanne F. Harbo, Sandra D'Alfonso, Laura Bergamaschi, Maurizio Leone, Giovanni Ristori, Ludwig Kappos, Stephen L. Hauser, Isabelle Cournu-Rebeix, Bertrand Fontaine, Steven Boonen, Chris Polman, Aarno Palotie, Leena Peltonen, Janna Saarela

Dipartimento di Scienze della Salute

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

Background: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.

Lingua originale	Inglese
Numero di articolo	e18813
Rivista	PLoS ONE
Volume	6
Numero di pubblicazione	4
DOI	https://doi.org/10.1371/journal.pone.0018813
Stato di pubblicazione	Pubblicato - 2011

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Leppä, V., Surakka, I., Tienari, P. J., Elovaara, I., Compston, A., Sawcer, S., Robertson, N., de Jager, P. L., Aubin, C., Hafler, D. A., Oturai, A. B., Søndergaard, H. B., Sellebjerg, F., Sørensen, P. S., Hemmer, B., Cepok, S., Winkelmann, J., Wichmann, H. E., Comabella, M., ... Saarela, J. (2011). The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study. PLoS ONE, 6(4), Articolo e18813. https://doi.org/10.1371/journal.pone.0018813

@article{182311c8cbc24308a4c1f61c164f86db,

title = "The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study",

abstract = "Background: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.",

author = "Virpi Lepp{\"a} and Ida Surakka and Tienari, {Pentti J.} and Irina Elovaara and Alastair Compston and Stephen Sawcer and Neil Robertson and {de Jager}, {Philip L.} and Cristin Aubin and Hafler, {David A.} and Oturai, {Annette Bang} and S{\o}ndergaard, {Helle Bach} and Finn Sellebjerg and S{\o}rensen, {Per Soelberg} and Bernhard Hemmer and Sabine Cepok and Juliane Winkelmann and Wichmann, {Heinz Erich} and Manuel Comabella and Bustamante, {Marta F.} and Xavier Montalban and Tomas Olsson and Ingrid Kockum and Jan Hillert and Lars Alfredsson and An Goris and B{\'e}n{\'e}dicte Dubois and Mero, {Inger Lise} and Cathrine Smestad and Celius, {Elisabeth G.} and Harbo, {Hanne F.} and Sandra D'Alfonso and Laura Bergamaschi and Maurizio Leone and Giovanni Ristori and Ludwig Kappos and Hauser, {Stephen L.} and Isabelle Cournu-Rebeix and Bertrand Fontaine and Steven Boonen and Chris Polman and Aarno Palotie and Leena Peltonen and Janna Saarela",

year = "2011",

doi = "10.1371/journal.pone.0018813",

language = "English",

volume = "6",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

}

Leppä, V, Surakka, I, Tienari, PJ, Elovaara, I, Compston, A, Sawcer, S, Robertson, N, de Jager, PL, Aubin, C, Hafler, DA, Oturai, AB, Søndergaard, HB, Sellebjerg, F, Sørensen, PS, Hemmer, B, Cepok, S, Winkelmann, J, Wichmann, HE, Comabella, M, Bustamante, MF, Montalban, X, Olsson, T, Kockum, I, Hillert, J, Alfredsson, L, Goris, A, Dubois, B, Mero, IL, Smestad, C, Celius, EG, Harbo, HF, D'Alfonso, S, Bergamaschi, L, Leone, M, Ristori, G, Kappos, L, Hauser, SL, Cournu-Rebeix, I, Fontaine, B, Boonen, S, Polman, C, Palotie, A, Peltonen, L & Saarela, J 2011, 'The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study', PLoS ONE, vol. 6, n. 4, e18813. https://doi.org/10.1371/journal.pone.0018813

TY - JOUR

T1 - The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis

T2 - A multicenter case-control study

AU - Leppä, Virpi

AU - Surakka, Ida

AU - Tienari, Pentti J.

AU - Elovaara, Irina

AU - Compston, Alastair

AU - Sawcer, Stephen

AU - Robertson, Neil

AU - de Jager, Philip L.

AU - Aubin, Cristin

AU - Hafler, David A.

AU - Oturai, Annette Bang

AU - Søndergaard, Helle Bach

AU - Sellebjerg, Finn

AU - Sørensen, Per Soelberg

AU - Hemmer, Bernhard

AU - Cepok, Sabine

AU - Winkelmann, Juliane

AU - Wichmann, Heinz Erich

AU - Comabella, Manuel

AU - Bustamante, Marta F.

AU - Montalban, Xavier

AU - Olsson, Tomas

AU - Kockum, Ingrid

AU - Hillert, Jan

AU - Alfredsson, Lars

AU - Goris, An

AU - Dubois, Bénédicte

AU - Mero, Inger Lise

AU - Smestad, Cathrine

AU - Celius, Elisabeth G.

AU - Harbo, Hanne F.

AU - D'Alfonso, Sandra

AU - Bergamaschi, Laura

AU - Leone, Maurizio

AU - Ristori, Giovanni

AU - Kappos, Ludwig

AU - Hauser, Stephen L.

AU - Cournu-Rebeix, Isabelle

AU - Fontaine, Bertrand

AU - Boonen, Steven

AU - Polman, Chris

AU - Palotie, Aarno

AU - Peltonen, Leena

AU - Saarela, Janna

PY - 2011

Y1 - 2011

N2 - Background: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.

AB - Background: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.

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U2 - 10.1371/journal.pone.0018813

DO - 10.1371/journal.pone.0018813

M3 - Article

SN - 1932-6203

VL - 6

JO - PLoS ONE

JF - PLoS ONE

IS - 4

M1 - e18813

ER -

The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: A multicenter case-control study

Abstract

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