The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus

P. G. Bronson; B. A. Goldstein; P. P. Ramsay; K. B. Beckman; J. A. Noble; J. A. Lane; M. F. Seldin; J. A. Kelly; J. B. Harley; K. L. Moser; P. M. Gaffney; T. W. Behrens; L. A. Criswell; L. F. Barcellos

doi:10.1038/gene.2011.36

The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus

P. G. Bronson, B. A. Goldstein, P. P. Ramsay, K. B. Beckman, J. A. Noble, J. A. Lane, M. F. Seldin, J. A. Kelly, J. B. Harley, K. L. Moser, P. M. Gaffney, T. W. Behrens, L. A. Criswell, L. F. Barcellos

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Abstract

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774*C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2×10 ^-3). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5×10 ^-3) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P _meta=2.5×10 ^-4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P _meta=1.9×10 ^-3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.

Original language	English (US)
Pages (from-to)	667-671
Number of pages	5
Journal	Genes and Immunity
Volume	12
Issue number	8
DOIs	https://doi.org/10.1038/gene.2011.36
State	Published - Dec 2011

Bibliographical note

Funding Information:
We would like to thank the International MS Genetics Consortium for contributing genetic data to this study. We also thank Suzanne May, Farren Briggs, Alan Hubbard and Gary Artim. This work was supported by an REF/Abbott Graduate Student Achievement Award from the American College of Rheumatology (PB), a Kirkland Scholar Award from the Mary Kirkland Center for Lupus Research (LAC), the Alliance for Lupus Research (JBH, KLM, LAC), the US Department of Veterans Affairs (JBH), Lupus Foundation Minnesota (KLM) and NIH grants F31-AI075609 (PGB), R01-AR44804 (LAC), R01-AR052300 (LAC), K24-AR02175 (LAC), P60 AR053308 (LAC), P01 AR049084 (JBH), R01 AR42460 (JBH), R01 AR043274-14 (KLM) and N01 AR62277 (JBH) from NIAMS, R37 AI24717 (JBH), P01 AI083194 (JBH), 5R01 A1063274-06 (PMG) from NIAID, and P20-RR020143 (JBH) from NCRR. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NIAID or NCRR. This study was performed in part in the General Clinical Research Center, Moffitt Hospital, UCSF, with funds provided by the National Center for Research Resources, 5-M01-RR-00079, US Public Health Service. This study makes use of data generated by the WTCCC; a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk, and funding for the project was provided by the Wellcome Trust under award 076113.

Keywords

CIITA
HLA
MHC2TA
autoimmunity
major histocompatibility complex
systemic lupus erythematosus

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10.1038/gene.2011.36

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Bronson, P. G., Goldstein, B. A., Ramsay, P. P., Beckman, K. B., Noble, J. A., Lane, J. A., Seldin, M. F., Kelly, J. A., Harley, J. B., Moser, K. L., Gaffney, P. M., Behrens, T. W., Criswell, L. A., & Barcellos, L. F. (2011). The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus. Genes and Immunity, 12(8), 667-671. https://doi.org/10.1038/gene.2011.36

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title = "The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus",

abstract = "The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774*C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2×10 -3). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5×10 -3) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P meta=2.5×10 -4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P meta=1.9×10 -3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.",

keywords = "CIITA, HLA, MHC2TA, autoimmunity, major histocompatibility complex, systemic lupus erythematosus",

author = "Bronson, {P. G.} and Goldstein, {B. A.} and Ramsay, {P. P.} and Beckman, {K. B.} and Noble, {J. A.} and Lane, {J. A.} and Seldin, {M. F.} and Kelly, {J. A.} and Harley, {J. B.} and Moser, {K. L.} and Gaffney, {P. M.} and Behrens, {T. W.} and Criswell, {L. A.} and Barcellos, {L. F.}",

note = "Funding Information: We would like to thank the International MS Genetics Consortium for contributing genetic data to this study. We also thank Suzanne May, Farren Briggs, Alan Hubbard and Gary Artim. This work was supported by an REF/Abbott Graduate Student Achievement Award from the American College of Rheumatology (PB), a Kirkland Scholar Award from the Mary Kirkland Center for Lupus Research (LAC), the Alliance for Lupus Research (JBH, KLM, LAC), the US Department of Veterans Affairs (JBH), Lupus Foundation Minnesota (KLM) and NIH grants F31-AI075609 (PGB), R01-AR44804 (LAC), R01-AR052300 (LAC), K24-AR02175 (LAC), P60 AR053308 (LAC), P01 AR049084 (JBH), R01 AR42460 (JBH), R01 AR043274-14 (KLM) and N01 AR62277 (JBH) from NIAMS, R37 AI24717 (JBH), P01 AI083194 (JBH), 5R01 A1063274-06 (PMG) from NIAID, and P20-RR020143 (JBH) from NCRR. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NIAID or NCRR. This study was performed in part in the General Clinical Research Center, Moffitt Hospital, UCSF, with funds provided by the National Center for Research Resources, 5-M01-RR-00079, US Public Health Service. This study makes use of data generated by the WTCCC; a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk, and funding for the project was provided by the Wellcome Trust under award 076113.",

year = "2011",

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T1 - The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus

AU - Bronson, P. G.

AU - Goldstein, B. A.

AU - Ramsay, P. P.

AU - Beckman, K. B.

AU - Noble, J. A.

AU - Lane, J. A.

AU - Seldin, M. F.

AU - Kelly, J. A.

AU - Harley, J. B.

AU - Moser, K. L.

AU - Gaffney, P. M.

AU - Behrens, T. W.

AU - Criswell, L. A.

AU - Barcellos, L. F.

N1 - Funding Information: We would like to thank the International MS Genetics Consortium for contributing genetic data to this study. We also thank Suzanne May, Farren Briggs, Alan Hubbard and Gary Artim. This work was supported by an REF/Abbott Graduate Student Achievement Award from the American College of Rheumatology (PB), a Kirkland Scholar Award from the Mary Kirkland Center for Lupus Research (LAC), the Alliance for Lupus Research (JBH, KLM, LAC), the US Department of Veterans Affairs (JBH), Lupus Foundation Minnesota (KLM) and NIH grants F31-AI075609 (PGB), R01-AR44804 (LAC), R01-AR052300 (LAC), K24-AR02175 (LAC), P60 AR053308 (LAC), P01 AR049084 (JBH), R01 AR42460 (JBH), R01 AR043274-14 (KLM) and N01 AR62277 (JBH) from NIAMS, R37 AI24717 (JBH), P01 AI083194 (JBH), 5R01 A1063274-06 (PMG) from NIAID, and P20-RR020143 (JBH) from NCRR. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NIAID or NCRR. This study was performed in part in the General Clinical Research Center, Moffitt Hospital, UCSF, with funds provided by the National Center for Research Resources, 5-M01-RR-00079, US Public Health Service. This study makes use of data generated by the WTCCC; a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk, and funding for the project was provided by the Wellcome Trust under award 076113.

PY - 2011/12

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N2 - The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774*C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2×10 -3). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5×10 -3) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P meta=2.5×10 -4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P meta=1.9×10 -3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.

AB - The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774*C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2×10 -3). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5×10 -3) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P meta=2.5×10 -4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P meta=1.9×10 -3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.

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The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus

Abstract

Bibliographical note

Keywords

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