A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

Robert R. Graham; Sergey V. Kozyrev; Emily C. Baechler; M. V.Prasad Linga Reddy; Robert M. Plenge; Jason W. Bauer; Ward A. Ortmann; Thearith Koeuth; Ma Francisca González Escribano; Bernardo Pons-Estel; Michelle Petri; Mark Daly; Peter K. Gregersen; Javier Martín; David Altshuler; Timothy W. Behrens; Marta E. Alarcón-Riquelme

doi:10.1038/ng1782

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

Robert R. Graham, Sergey V. Kozyrev, Emily C. Baechler, M. V.Prasad Linga Reddy, Robert M. Plenge, Jason W. Bauer, Ward A. Ortmann, Thearith Koeuth, Ma Francisca González Escribano, Bernardo Pons-Estel, Michelle Petri, Mark Daly, Peter K. Gregersen, Javier Martín, David Altshuler, Timothy W. Behrens, Marta E. Alarcón-Riquelme

Medicine - Rheumatic and Autoimmune

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

572 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease¹ characterized by activation of the type I interferon (IFN) pathway^2-4. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE⁵ in four independent case-control cohorts (P = 4.4 × 10^-16) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5′ donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Original language	English (US)
Pages (from-to)	550-555
Number of pages	6
Journal	Nature Genetics
Volume	38
Issue number	5
DOIs	https://doi.org/10.1038/ng1782
State	Published - May 2006

Bibliographical note

Funding Information:
We thank H. Yin and the members of the Uppsala Genome Center for help with sequencing and S. Young, J. Novitzke, L. Kyle, K. Espe, C. Gillett, P. Gaffney and K. Moser for assistance. The Swedish samples were obtained from the Lupus cohort at Karolinska University Hospital, Solna. This work was supported by grants from the Swedish Research Council (M.E.A.-R.), the Clas Groschinski Foundation (M.E.A.-R.), the Marcus Borsgtröms Foundation (M.E.A.-R.), the Torsten and Ragnar Söderberg’s Foundation (M.E.A.-R.), the Swedish Association against Rheumatism (M.E.A.-R.), the Alliance for Lupus Research (M.E.A.-R., T.W.B.), the Lupus Research Institute (T.W.B.), the Mary Kirkland Center for Lupus Research (T.W.B.), the Lupus Foundation of Minnesota (T.W.B.), the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) (T.W.B.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH (R.R.G., E.C.B., T.W.B.) and the Ministerio de Ciencia y Tecnología (SAF2003-3460; J.M.). The Johns Hopkins Lupus Cohort is supported by NIH grant AR 43727, and the Johns Hopkins General Clinical Research Center is supported by NIH M01-RR-00052.

Access

10.1038/ng1782

OpenUrl availability

Full text

Cite this

Graham, R. R., Kozyrev, S. V., Baechler, E. C., Reddy, M. V. P. L., Plenge, R. M., Bauer, J. W., Ortmann, W. A., Koeuth, T., Escribano, M. F. G., Pons-Estel, B., Petri, M., Daly, M., Gregersen, P. K., Martín, J., Altshuler, D., Behrens, T. W., & Alarcón-Riquelme, M. E. (2006). A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nature Genetics, 38(5), 550-555. https://doi.org/10.1038/ng1782

Graham, RR, Kozyrev, SV, Baechler, EC, Reddy, MVPL, Plenge, RM, Bauer, JW, Ortmann, WA, Koeuth, T, Escribano, MFG, Pons-Estel, B, Petri, M, Daly, M, Gregersen, PK, Martín, J, Altshuler, D, Behrens, TW & Alarcón-Riquelme, ME 2006, 'A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus', Nature Genetics, vol. 38, no. 5, pp. 550-555. https://doi.org/10.1038/ng1782

@article{b040e3e658324f85aae07b3bd2d85454,

title = "A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus",

abstract = "Systemic lupus erythematosus (SLE) is a complex autoimmune disease1 characterized by activation of the type I interferon (IFN) pathway2-4. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE5 in four independent case-control cohorts (P = 4.4 × 10-16) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5′ donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.",

author = "Graham, {Robert R.} and Kozyrev, {Sergey V.} and Baechler, {Emily C.} and Reddy, {M. V.Prasad Linga} and Plenge, {Robert M.} and Bauer, {Jason W.} and Ortmann, {Ward A.} and Thearith Koeuth and Escribano, {Ma Francisca Gonz{\'a}lez} and Bernardo Pons-Estel and Michelle Petri and Mark Daly and Gregersen, {Peter K.} and Javier Mart{\'i}n and David Altshuler and Behrens, {Timothy W.} and Alarc{\'o}n-Riquelme, {Marta E.}",

note = "Funding Information: We thank H. Yin and the members of the Uppsala Genome Center for help with sequencing and S. Young, J. Novitzke, L. Kyle, K. Espe, C. Gillett, P. Gaffney and K. Moser for assistance. The Swedish samples were obtained from the Lupus cohort at Karolinska University Hospital, Solna. This work was supported by grants from the Swedish Research Council (M.E.A.-R.), the Clas Groschinski Foundation (M.E.A.-R.), the Marcus Borsgtr{\"o}ms Foundation (M.E.A.-R.), the Torsten and Ragnar S{\"o}derberg{\textquoteright}s Foundation (M.E.A.-R.), the Swedish Association against Rheumatism (M.E.A.-R.), the Alliance for Lupus Research (M.E.A.-R., T.W.B.), the Lupus Research Institute (T.W.B.), the Mary Kirkland Center for Lupus Research (T.W.B.), the Lupus Foundation of Minnesota (T.W.B.), the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) (T.W.B.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH (R.R.G., E.C.B., T.W.B.) and the Ministerio de Ciencia y Tecnolog{\'i}a (SAF2003-3460; J.M.). The Johns Hopkins Lupus Cohort is supported by NIH grant AR 43727, and the Johns Hopkins General Clinical Research Center is supported by NIH M01-RR-00052.",

year = "2006",

month = may,

doi = "10.1038/ng1782",

language = "English (US)",

volume = "38",

pages = "550--555",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

AU - Graham, Robert R.

AU - Kozyrev, Sergey V.

AU - Baechler, Emily C.

AU - Reddy, M. V.Prasad Linga

AU - Plenge, Robert M.

AU - Bauer, Jason W.

AU - Ortmann, Ward A.

AU - Koeuth, Thearith

AU - Escribano, Ma Francisca González

AU - Pons-Estel, Bernardo

AU - Petri, Michelle

AU - Daly, Mark

AU - Gregersen, Peter K.

AU - Martín, Javier

AU - Altshuler, David

AU - Behrens, Timothy W.

AU - Alarcón-Riquelme, Marta E.

N1 - Funding Information: We thank H. Yin and the members of the Uppsala Genome Center for help with sequencing and S. Young, J. Novitzke, L. Kyle, K. Espe, C. Gillett, P. Gaffney and K. Moser for assistance. The Swedish samples were obtained from the Lupus cohort at Karolinska University Hospital, Solna. This work was supported by grants from the Swedish Research Council (M.E.A.-R.), the Clas Groschinski Foundation (M.E.A.-R.), the Marcus Borsgtröms Foundation (M.E.A.-R.), the Torsten and Ragnar Söderberg’s Foundation (M.E.A.-R.), the Swedish Association against Rheumatism (M.E.A.-R.), the Alliance for Lupus Research (M.E.A.-R., T.W.B.), the Lupus Research Institute (T.W.B.), the Mary Kirkland Center for Lupus Research (T.W.B.), the Lupus Foundation of Minnesota (T.W.B.), the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) (T.W.B.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH (R.R.G., E.C.B., T.W.B.) and the Ministerio de Ciencia y Tecnología (SAF2003-3460; J.M.). The Johns Hopkins Lupus Cohort is supported by NIH grant AR 43727, and the Johns Hopkins General Clinical Research Center is supported by NIH M01-RR-00052.

PY - 2006/5

Y1 - 2006/5

N2 - Systemic lupus erythematosus (SLE) is a complex autoimmune disease1 characterized by activation of the type I interferon (IFN) pathway2-4. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE5 in four independent case-control cohorts (P = 4.4 × 10-16) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5′ donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease1 characterized by activation of the type I interferon (IFN) pathway2-4. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE5 in four independent case-control cohorts (P = 4.4 × 10-16) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5′ donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

UR - http://www.scopus.com/inward/record.url?scp=33646368404&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646368404&partnerID=8YFLogxK

U2 - 10.1038/ng1782

DO - 10.1038/ng1782

M3 - Article

C2 - 16642019

AN - SCOPUS:33646368404

SN - 1061-4036

VL - 38

SP - 550

EP - 555

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

Abstract

Bibliographical note

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this