Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus

Elena Sanchez, Ajay Nadig, Bruce C. Richardson, Barry I. Freedman, Kenneth M. Kaufman, Jennifer A. Kelly, Timothy B. Niewold, Diane L. Kamen, Gary S. Gilkeson, Julie T. Ziegler, Carl D. Langefeld, Graciela S. Alarcón, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, Elizabeth E. Brown, Robert P. Kimberly, John D. Reveille, Luis M. Vilá, Joan T. MerrillJuan Manuel Anaya, Judith A. James, Bernardo A. Pons-Estel, Javier Martin, So Yeon Park, So Young Bang, Sang Cheol Bae, Kathy L. Moser, Timothy J. Vyse, Lindsey A. Criswell, Patrick M. Gaffney, Betty P. Tsao, Chaim O. Jacob, John B. Harley, Marta E. Alarcón-Riquelme, Amr H. Sawalha

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Objective: Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods: 4001 European-derived, 547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results: Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10-6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion: Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

Original languageEnglish (US)
Pages (from-to)1752-1757
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume70
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

Fingerprint

Genetic Loci
Genetic Predisposition to Disease
Systemic Lupus Erythematosus
Alleles
Exanthema
Oral Ulcer
Hispanic Americans
African Americans
Autoimmune Diseases
Genes
Kidney
Testing
interleukin-21

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Sanchez, E., Nadig, A., Richardson, B. C., Freedman, B. I., Kaufman, K. M., Kelly, J. A., ... Sawalha, A. H. (2011). Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 70(10), 1752-1757. https://doi.org/10.1136/ard.2011.154104

Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. / Sanchez, Elena; Nadig, Ajay; Richardson, Bruce C.; Freedman, Barry I.; Kaufman, Kenneth M.; Kelly, Jennifer A.; Niewold, Timothy B.; Kamen, Diane L.; Gilkeson, Gary S.; Ziegler, Julie T.; Langefeld, Carl D.; Alarcón, Graciela S.; Edberg, Jeffrey C.; Ramsey-Goldman, Rosalind; Petri, Michelle; Brown, Elizabeth E.; Kimberly, Robert P.; Reveille, John D.; Vilá, Luis M.; Merrill, Joan T.; Anaya, Juan Manuel; James, Judith A.; Pons-Estel, Bernardo A.; Martin, Javier; Park, So Yeon; Bang, So Young; Bae, Sang Cheol; Moser, Kathy L.; Vyse, Timothy J.; Criswell, Lindsey A.; Gaffney, Patrick M.; Tsao, Betty P.; Jacob, Chaim O.; Harley, John B.; Alarcón-Riquelme, Marta E.; Sawalha, Amr H.

In: Annals of the Rheumatic Diseases, Vol. 70, No. 10, 10.2011, p. 1752-1757.

Research output: Contribution to journalArticle

Sanchez, E, Nadig, A, Richardson, BC, Freedman, BI, Kaufman, KM, Kelly, JA, Niewold, TB, Kamen, DL, Gilkeson, GS, Ziegler, JT, Langefeld, CD, Alarcón, GS, Edberg, JC, Ramsey-Goldman, R, Petri, M, Brown, EE, Kimberly, RP, Reveille, JD, Vilá, LM, Merrill, JT, Anaya, JM, James, JA, Pons-Estel, BA, Martin, J, Park, SY, Bang, SY, Bae, SC, Moser, KL, Vyse, TJ, Criswell, LA, Gaffney, PM, Tsao, BP, Jacob, CO, Harley, JB, Alarcón-Riquelme, ME & Sawalha, AH 2011, 'Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus', Annals of the Rheumatic Diseases, vol. 70, no. 10, pp. 1752-1757. https://doi.org/10.1136/ard.2011.154104
Sanchez E, Nadig A, Richardson BC, Freedman BI, Kaufman KM, Kelly JA et al. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Annals of the Rheumatic Diseases. 2011 Oct;70(10):1752-1757. https://doi.org/10.1136/ard.2011.154104
Sanchez, Elena ; Nadig, Ajay ; Richardson, Bruce C. ; Freedman, Barry I. ; Kaufman, Kenneth M. ; Kelly, Jennifer A. ; Niewold, Timothy B. ; Kamen, Diane L. ; Gilkeson, Gary S. ; Ziegler, Julie T. ; Langefeld, Carl D. ; Alarcón, Graciela S. ; Edberg, Jeffrey C. ; Ramsey-Goldman, Rosalind ; Petri, Michelle ; Brown, Elizabeth E. ; Kimberly, Robert P. ; Reveille, John D. ; Vilá, Luis M. ; Merrill, Joan T. ; Anaya, Juan Manuel ; James, Judith A. ; Pons-Estel, Bernardo A. ; Martin, Javier ; Park, So Yeon ; Bang, So Young ; Bae, Sang Cheol ; Moser, Kathy L. ; Vyse, Timothy J. ; Criswell, Lindsey A. ; Gaffney, Patrick M. ; Tsao, Betty P. ; Jacob, Chaim O. ; Harley, John B. ; Alarcón-Riquelme, Marta E. ; Sawalha, Amr H. / Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. In: Annals of the Rheumatic Diseases. 2011 ; Vol. 70, No. 10. pp. 1752-1757.
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title = "Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus",
abstract = "Objective: Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods: 4001 European-derived, 547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results: Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10-6, OR 1.25, 95{\%} CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95{\%} CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95{\%} CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95{\%} CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95{\%} CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95{\%} CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion: Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.",
author = "Elena Sanchez and Ajay Nadig and Richardson, {Bruce C.} and Freedman, {Barry I.} and Kaufman, {Kenneth M.} and Kelly, {Jennifer A.} and Niewold, {Timothy B.} and Kamen, {Diane L.} and Gilkeson, {Gary S.} and Ziegler, {Julie T.} and Langefeld, {Carl D.} and Alarc{\'o}n, {Graciela S.} and Edberg, {Jeffrey C.} and Rosalind Ramsey-Goldman and Michelle Petri and Brown, {Elizabeth E.} and Kimberly, {Robert P.} and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Merrill, {Joan T.} and Anaya, {Juan Manuel} and James, {Judith A.} and Pons-Estel, {Bernardo A.} and Javier Martin and Park, {So Yeon} and Bang, {So Young} and Bae, {Sang Cheol} and Moser, {Kathy L.} and Vyse, {Timothy J.} and Criswell, {Lindsey A.} and Gaffney, {Patrick M.} and Tsao, {Betty P.} and Jacob, {Chaim O.} and Harley, {John B.} and Alarc{\'o}n-Riquelme, {Marta E.} and Sawalha, {Amr H.}",
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TY - JOUR

T1 - Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus

AU - Sanchez, Elena

AU - Nadig, Ajay

AU - Richardson, Bruce C.

AU - Freedman, Barry I.

AU - Kaufman, Kenneth M.

AU - Kelly, Jennifer A.

AU - Niewold, Timothy B.

AU - Kamen, Diane L.

AU - Gilkeson, Gary S.

AU - Ziegler, Julie T.

AU - Langefeld, Carl D.

AU - Alarcón, Graciela S.

AU - Edberg, Jeffrey C.

AU - Ramsey-Goldman, Rosalind

AU - Petri, Michelle

AU - Brown, Elizabeth E.

AU - Kimberly, Robert P.

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Merrill, Joan T.

AU - Anaya, Juan Manuel

AU - James, Judith A.

AU - Pons-Estel, Bernardo A.

AU - Martin, Javier

AU - Park, So Yeon

AU - Bang, So Young

AU - Bae, Sang Cheol

AU - Moser, Kathy L.

AU - Vyse, Timothy J.

AU - Criswell, Lindsey A.

AU - Gaffney, Patrick M.

AU - Tsao, Betty P.

AU - Jacob, Chaim O.

AU - Harley, John B.

AU - Alarcón-Riquelme, Marta E.

AU - Sawalha, Amr H.

PY - 2011/10

Y1 - 2011/10

N2 - Objective: Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods: 4001 European-derived, 547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results: Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10-6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion: Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

AB - Objective: Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods: 4001 European-derived, 547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results: Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10-6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion: Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

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