Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus

Paula S. Ramos; Adrienne H. Williams; Julie T. Ziegler; Mary E. Comeau; Richard T. Guy; Christopher J. Lessard; He Li; Jeffrey C. Edberg; Raphael Zidovetzki; Lindsey A. Criswell; Patrick M. Gaffney; Deborah Cunninghame Graham; Robert R. Graham; Jennifer A. Kelly; Kenneth M. Kaufman; Elizabeth E. Brown; Graciela S. Alarcõn; Michelle A. Petri; John D. Reveille; Gerald McGwin; Luis M. Vilá; Rosalind Ramsey-Goldman; Chaim O. Jacob; Timothy J. Vyse; Betty P. Tsao; John B. Harley; Robert P. Kimberly; Marta E. Alarcõn-Riquelme; Carl D. Langefeld; Kathy L. Moser

doi:10.1002/art.30356

Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus

Paula S. Ramos, Adrienne H. Williams, Julie T. Ziegler, Mary E. Comeau, Richard T. Guy, Christopher J. Lessard, He Li, Jeffrey C. Edberg, Raphael Zidovetzki, Lindsey A. Criswell, Patrick M. Gaffney, Deborah Cunninghame Graham, Robert R. Graham, Jennifer A. Kelly, Kenneth M. Kaufman, Elizabeth E. Brown, Graciela S. Alarcõn, Michelle A. Petri, John D. Reveille, Gerald McGwinLuis M. Vilá, Rosalind Ramsey-Goldman, Chaim O. Jacob, Timothy J. Vyse, Betty P. Tsao, John B. Harley, Robert P. Kimberly, Marta E. Alarcõn-Riquelme, Carl D. Langefeld, Kathy L. Moser

School of Medicine

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

39 Scopus citations

Abstract

Objective The overexpression of interferon (IFN)-inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN-responsive genes in SLE. Methods We systematically evaluated association of SLE with a total of 1,754 IFN pathway-related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3-stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons. Results A total of 15,166 single-nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 Ã - 10^-12), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 Ã - 10^-4), the heat-shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 Ã - 10 ^-3), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 Ã - 10^-2). Conclusion This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.

Original language	English (US)
Pages (from-to)	2049-2057
Number of pages	9
Journal	Arthritis and rheumatism
Volume	63
Issue number	7
DOIs	https://doi.org/10.1002/art.30356
State	Published - Jul 2011

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology
Pharmacology (medical)

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Ramos, P. S., Williams, A. H., Ziegler, J. T., Comeau, M. E., Guy, R. T., Lessard, C. J., Li, H., Edberg, J. C., Zidovetzki, R., Criswell, L. A., Gaffney, P. M., Graham, D. C., Graham, R. R., Kelly, J. A., Kaufman, K. M., Brown, E. E., Alarcõn, G. S., Petri, M. A., Reveille, J. D., ... Moser, K. L. (2011). Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus. Arthritis and rheumatism, 63(7), 2049-2057. https://doi.org/10.1002/art.30356

Ramos, PS, Williams, AH, Ziegler, JT, Comeau, ME, Guy, RT, Lessard, CJ, Li, H, Edberg, JC, Zidovetzki, R, Criswell, LA, Gaffney, PM, Graham, DC, Graham, RR, Kelly, JA, Kaufman, KM, Brown, EE, Alarcõn, GS, Petri, MA, Reveille, JD, McGwin, G, Vilá, LM, Ramsey-Goldman, R, Jacob, CO, Vyse, TJ, Tsao, BP, Harley, JB, Kimberly, RP, Alarcõn-Riquelme, ME, Langefeld, CD & Moser, KL 2011, 'Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus', Arthritis and rheumatism, vol. 63, no. 7, pp. 2049-2057. https://doi.org/10.1002/art.30356

@article{d45d366b7b694ba5afc4b4d2ccd44b79,

title = "Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus",

abstract = "Objective The overexpression of interferon (IFN)-inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN-responsive genes in SLE. Methods We systematically evaluated association of SLE with a total of 1,754 IFN pathway-related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3-stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons. Results A total of 15,166 single-nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 {\~A} - 10-12), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 {\~A} - 10-4), the heat-shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 {\~A} - 10 -3), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 {\~A} - 10-2). Conclusion This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.",

author = "Ramos, {Paula S.} and Williams, {Adrienne H.} and Ziegler, {Julie T.} and Comeau, {Mary E.} and Guy, {Richard T.} and Lessard, {Christopher J.} and He Li and Edberg, {Jeffrey C.} and Raphael Zidovetzki and Criswell, {Lindsey A.} and Gaffney, {Patrick M.} and Graham, {Deborah Cunninghame} and Graham, {Robert R.} and Kelly, {Jennifer A.} and Kaufman, {Kenneth M.} and Brown, {Elizabeth E.} and Alarc{\~o}n, {Graciela S.} and Petri, {Michelle A.} and Reveille, {John D.} and Gerald McGwin and Vil{\'a}, {Luis M.} and Rosalind Ramsey-Goldman and Jacob, {Chaim O.} and Vyse, {Timothy J.} and Tsao, {Betty P.} and Harley, {John B.} and Kimberly, {Robert P.} and Alarc{\~o}n-Riquelme, {Marta E.} and Langefeld, {Carl D.} and Moser, {Kathy L.}",

year = "2011",

month = jul,

doi = "10.1002/art.30356",

language = "English (US)",

volume = "63",

pages = "2049--2057",

journal = "Arthritis and rheumatism",

issn = "0004-3591",

publisher = "John Wiley and Sons Ltd",

number = "7",

}

TY - JOUR

T1 - Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus

AU - Ramos, Paula S.

AU - Williams, Adrienne H.

AU - Ziegler, Julie T.

AU - Comeau, Mary E.

AU - Guy, Richard T.

AU - Lessard, Christopher J.

AU - Li, He

AU - Edberg, Jeffrey C.

AU - Zidovetzki, Raphael

AU - Criswell, Lindsey A.

AU - Gaffney, Patrick M.

AU - Graham, Deborah Cunninghame

AU - Graham, Robert R.

AU - Kelly, Jennifer A.

AU - Kaufman, Kenneth M.

AU - Brown, Elizabeth E.

AU - Alarcõn, Graciela S.

AU - Petri, Michelle A.

AU - Reveille, John D.

AU - McGwin, Gerald

AU - Vilá, Luis M.

AU - Ramsey-Goldman, Rosalind

AU - Jacob, Chaim O.

AU - Vyse, Timothy J.

AU - Tsao, Betty P.

AU - Harley, John B.

AU - Kimberly, Robert P.

AU - Alarcõn-Riquelme, Marta E.

AU - Langefeld, Carl D.

AU - Moser, Kathy L.

PY - 2011/7

Y1 - 2011/7

N2 - Objective The overexpression of interferon (IFN)-inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN-responsive genes in SLE. Methods We systematically evaluated association of SLE with a total of 1,754 IFN pathway-related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3-stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons. Results A total of 15,166 single-nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 Ã - 10-12), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 Ã - 10-4), the heat-shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 Ã - 10 -3), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 Ã - 10-2). Conclusion This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.

AB - Objective The overexpression of interferon (IFN)-inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN-responsive genes in SLE. Methods We systematically evaluated association of SLE with a total of 1,754 IFN pathway-related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3-stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons. Results A total of 15,166 single-nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 Ã - 10-12), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 Ã - 10-4), the heat-shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 Ã - 10 -3), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 Ã - 10-2). Conclusion This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.

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JO - Arthritis and rheumatism

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Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus

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