Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus

Silvia N. Kariuki, Beverly S. Franek, Akaash A. Kumar, Jasmine Arrington, Rachel A. Mikolaitis, Tammy O. Utset, Meenakshi Jolly, Mary K. Crow, Andrew D. Skol, Timothy B. Niewold

Research output: Contribution to journalArticle

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Abstract

Introduction: Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE.Methods: We undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2).Results: SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10-4). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10-6 and P = 2.6 × 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE.Conclusions: This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE.

Original languageEnglish (US)
Article numberR151
JournalArthritis Research and Therapy
Volume12
Issue number4
DOIs
StatePublished - Jul 26 2010
Externally publishedYes

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Genome-Wide Association Study
Systemic Lupus Erythematosus
Cytokines
Phenotype
Interferon-alpha
Single Nucleotide Polymorphism
Class 2 Receptor-Like Protein Tyrosine Phosphatases
Serum
Lysophosphatidic Acid Receptors
Leucine
Autoantibodies
Ephrin-A5
Ankyrin Repeat
Protein Phosphatase 1
Serology
Autoimmune Diseases
Odds Ratio
Databases

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. / Kariuki, Silvia N.; Franek, Beverly S.; Kumar, Akaash A.; Arrington, Jasmine; Mikolaitis, Rachel A.; Utset, Tammy O.; Jolly, Meenakshi; Crow, Mary K.; Skol, Andrew D.; Niewold, Timothy B.

In: Arthritis Research and Therapy, Vol. 12, No. 4, R151, 26.07.2010.

Research output: Contribution to journalArticle

Kariuki, SN, Franek, BS, Kumar, AA, Arrington, J, Mikolaitis, RA, Utset, TO, Jolly, M, Crow, MK, Skol, AD & Niewold, TB 2010, 'Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus', Arthritis Research and Therapy, vol. 12, no. 4, R151. https://doi.org/10.1186/ar3101
Kariuki, Silvia N. ; Franek, Beverly S. ; Kumar, Akaash A. ; Arrington, Jasmine ; Mikolaitis, Rachel A. ; Utset, Tammy O. ; Jolly, Meenakshi ; Crow, Mary K. ; Skol, Andrew D. ; Niewold, Timothy B. / Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. In: Arthritis Research and Therapy. 2010 ; Vol. 12, No. 4.
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AU - Kariuki, Silvia N.

AU - Franek, Beverly S.

AU - Kumar, Akaash A.

AU - Arrington, Jasmine

AU - Mikolaitis, Rachel A.

AU - Utset, Tammy O.

AU - Jolly, Meenakshi

AU - Crow, Mary K.

AU - Skol, Andrew D.

AU - Niewold, Timothy B.

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N2 - Introduction: Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE.Methods: We undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2).Results: SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10-4). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10-6 and P = 2.6 × 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE.Conclusions: This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE.

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