STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus

Elaine F. Remmers, Robert M. Plenge, Annette T. Lee, Robert R. Graham, Geoffrey Hom, Timothy W. Behrens, Paul I W De Bakker, Julie M. Le, Hye Soon Lee, Franak Batliwalla, Wentian Li, Seth L. Masters, Matthew G. Booty, John P. Carulli, Leonid Padyukov, Lars Alfredsson, Lars Klareskog, Wei V. Chen, Christopher I. Amos, Lindsey A. CriswellMichael F Seldin, Daniel L. Kastner, Peter K. Gregersen

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Abstract

BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. METHODS: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. RESULTS: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81×10-7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87×10-9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. CONCLUSIONS: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

Original languageEnglish (US)
Pages (from-to)977-986
Number of pages10
JournalNew England Journal of Medicine
Volume357
Issue number10
DOIs
StatePublished - Sep 6 2007

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Systemic Lupus Erythematosus
Rheumatoid Arthritis
Chromosomes
Single Nucleotide Polymorphism
Alleles
Haplotypes
Odds Ratio
Disease Susceptibility
North America
Sweden
Introns
Chronic Disease
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Remmers, E. F., Plenge, R. M., Lee, A. T., Graham, R. R., Hom, G., Behrens, T. W., ... Gregersen, P. K. (2007). STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. New England Journal of Medicine, 357(10), 977-986. https://doi.org/10.1056/NEJMoa073003

STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. / Remmers, Elaine F.; Plenge, Robert M.; Lee, Annette T.; Graham, Robert R.; Hom, Geoffrey; Behrens, Timothy W.; De Bakker, Paul I W; Le, Julie M.; Lee, Hye Soon; Batliwalla, Franak; Li, Wentian; Masters, Seth L.; Booty, Matthew G.; Carulli, John P.; Padyukov, Leonid; Alfredsson, Lars; Klareskog, Lars; Chen, Wei V.; Amos, Christopher I.; Criswell, Lindsey A.; Seldin, Michael F; Kastner, Daniel L.; Gregersen, Peter K.

In: New England Journal of Medicine, Vol. 357, No. 10, 06.09.2007, p. 977-986.

Research output: Contribution to journalArticle

Remmers, EF, Plenge, RM, Lee, AT, Graham, RR, Hom, G, Behrens, TW, De Bakker, PIW, Le, JM, Lee, HS, Batliwalla, F, Li, W, Masters, SL, Booty, MG, Carulli, JP, Padyukov, L, Alfredsson, L, Klareskog, L, Chen, WV, Amos, CI, Criswell, LA, Seldin, MF, Kastner, DL & Gregersen, PK 2007, 'STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus', New England Journal of Medicine, vol. 357, no. 10, pp. 977-986. https://doi.org/10.1056/NEJMoa073003
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. New England Journal of Medicine. 2007 Sep 6;357(10):977-986. https://doi.org/10.1056/NEJMoa073003
Remmers, Elaine F. ; Plenge, Robert M. ; Lee, Annette T. ; Graham, Robert R. ; Hom, Geoffrey ; Behrens, Timothy W. ; De Bakker, Paul I W ; Le, Julie M. ; Lee, Hye Soon ; Batliwalla, Franak ; Li, Wentian ; Masters, Seth L. ; Booty, Matthew G. ; Carulli, John P. ; Padyukov, Leonid ; Alfredsson, Lars ; Klareskog, Lars ; Chen, Wei V. ; Amos, Christopher I. ; Criswell, Lindsey A. ; Seldin, Michael F ; Kastner, Daniel L. ; Gregersen, Peter K. / STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. In: New England Journal of Medicine. 2007 ; Vol. 357, No. 10. pp. 977-986.
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abstract = "BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. METHODS: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. RESULTS: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27{\%} of chromosomes of patients with established rheumatoid arthritis, as compared with 22{\%} of those of controls (for the SNP rs7574865, P=2.81×10-7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31{\%} of chromosomes of case patients and 22{\%} of those of controls (P=1.87×10-9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60{\%} increased risk for rheumatoid arthritis. CONCLUSIONS: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.",
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T1 - STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus

AU - Remmers, Elaine F.

AU - Plenge, Robert M.

AU - Lee, Annette T.

AU - Graham, Robert R.

AU - Hom, Geoffrey

AU - Behrens, Timothy W.

AU - De Bakker, Paul I W

AU - Le, Julie M.

AU - Lee, Hye Soon

AU - Batliwalla, Franak

AU - Li, Wentian

AU - Masters, Seth L.

AU - Booty, Matthew G.

AU - Carulli, John P.

AU - Padyukov, Leonid

AU - Alfredsson, Lars

AU - Klareskog, Lars

AU - Chen, Wei V.

AU - Amos, Christopher I.

AU - Criswell, Lindsey A.

AU - Seldin, Michael F

AU - Kastner, Daniel L.

AU - Gregersen, Peter K.

PY - 2007/9/6

Y1 - 2007/9/6

N2 - BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. METHODS: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. RESULTS: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81×10-7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87×10-9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. CONCLUSIONS: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

AB - BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. METHODS: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. RESULTS: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81×10-7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87×10-9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. CONCLUSIONS: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

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