Genome-Wide Association Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci

Laura A McIntosh¹, Miranda C Marion², Marc Sudman¹, Mary E Comeau², Sampath Prahalad³, John F. Bohnsack⁴, Johannes P Haas⁵, Carol A Wallace⁶, Daniel J Lovell⁷, Thomas A Griffin⁸, Mara L Becker⁹, Peter A Nigrovic^10,11, Marilynn Punaro¹², Carlos D Rosé¹³, Carol A Wise¹⁴, Halima Moncrieffe¹⁵, Timothy D Howard¹⁶, Carl D Langefeld¹⁷, Susan D Thompson^15,18 and Boston Children’s JIA Registry, JIA gene expression studies, NIAMS JIA genetic registry, TREAT study, Understanding TNF Therapy in JIA Project, ¹Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²Biostatistical Sciences and Center for Public Health Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, ³Pediatrics, Emory Children's Center, Atlanta, GA, ⁴Division of Allergy, Immunology and Pediatric Rheumatology, University of Utah, Salt Lake City, UT, ⁵German Centre for Rheumatology in Children and Young People, Garmisch-Partenkirchen, Germany, ⁶Pediatrics, Seattle Children's Hospital, Seattle, WA, ⁷Rheumatology, PRCSG Cincinnati Children's Hospital Medical Center, Cinncinnati, OH, ⁸Levine Children’s Hospital at Carolinas Medical Center, Charlotte, NC, ⁹Rheumatology, Children's Mercy Kansas City, Kansas City, MO, ¹⁰Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, ¹¹Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, ¹²Pediatric Rheumatology, Texas Scottish Rite Hospital for Children, Dallas, TX, ¹³Pediatrics, Division of Rheumatology, Nemours/A.I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE, ¹⁴Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, ¹⁵Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ¹⁶Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, ¹⁷Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, ¹⁸Center for Autoimmune Disease Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: genetics, Genomics and juvenile idiopathic arthritis (JIA)

Session Information

Date: Monday, November 14, 2016

Title: Genetics, Genomics and Proteomics I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease, affecting approximately 1 in 1,000 children. JIA is a complex genetic trait and encompasses a wide spectrum of clinical heterogeneity. To date, genetic association studies in JIA had limited sample sizes, used heterogeneous patient populations containing all disease subtypes, or included only candidate regions (e.g. Immunochip). In this study, we focused on oligoarticular and rheumatoid factor negative (RF^–) polyarticular subtypes of JIA because they are clinically similar and the most prevalent forms of disease. This study employed large cohorts and imputed SNP data in a genome-wide association study (GWAS) to catalog novel genetic risk factors.

Methods: Three cohorts totaling 2,751 oligoarticular or RF^– polyarticular JIA cases and 15,864 controls, all of European ancestry, were genotyped using two platforms. Cohort 1 (814 cases and 3,055 controls) and cohort 2 (1,057 cases and 11,824 controls) were genotyped on the Affymetrix Genome-Wide Human SNP 6.0 Array, while cohort 3 (880 cases and 985 controls) was genotyped on the Illumina HumanCoreExome-12+ Array. Imputation was performed using 1000 Genomes Project data, followed by a meta-analysis of all 3 cohorts.

Results: Meta-analysis resulted in suggestive evidence of association (P<1×10^-6) at 10 regions along the genome: JAK1 (rs10889504: OR=0.78, P=4.18×10^-7), PRR9_LOR (rs873234: OR=1.43, P=5.12×10^-8), PTH1R (rs1138518: OR=1.23, P=1.87×10^-7), ILDR1_CD86 (rs1138518: OR=1.45, P=6.73×10^-8), FLJ41649 (rs10807228: OR=1.42, P=5.80×10^-7), AHI1_LINC00271 (rs9321502: OR=1.18, P=3.48×10^-7), HBP1 (rs111865019: OR=0.84, P=7.29×10^-7), ASAP1 (rs34962169: OR=1.43, P=6.36×10^-7), WDFY4 (rs1904603: OR=1.27, P=1.79×10^-7), and RNF215 (rs5753109: OR=1.19, P=3.09×10^-7). Among these regions, association studies in other autoimmune diseases provided additional evidence of support for JAK1 (Celiac Disease: rs12409333 – r²=0.898, P=3.80×10^-5, Multiple Sclerosis: rs12409333 – r²=0.898, P=2.70×10^-4), ILDR1_CD86 (Celiac Disease: rs2061197 – r²=0.407, P=8.55×10^-6), AHI1_LINC00271 (Autoimmune Thyroid Disease: rs2179781 – r²=0.757, P=4.84×10^-4, Celiac Disease: rs12206850 – r²=0.701, P=6.89×10^-4, Multiple Sclerosis: rs11154801 – r²=0.740, P=1.00×10^-13, Type 1 Diabetes: rs11154801 -r²=0.740, P=2.55×10^-5) and WDFY4 (Systemic Lupus Erythematosus: rs877819 – r²=0.473, P=8.00×10^-9). Furthermore, cis expression quantitative trait loci were shown for PTH1R (rs2242116), AHI1 (rs2614276), HBP1 (rs7790080, rs2301801, and rs2237659), WDFY4 (rs2940707), and RNF215 (rs2242116). Histone modifications of JAK1 (rs6588107: H3K4Me1, H3K27Ac and rs72922282: H3K4Me3, H3K27Ac), AHI_LINC00271 (rs6935146: H3K4Me1), and ASAP1 (rs67434056: H3K4Me1) showed additional regulation of gene expression.

Conclusion: These genome-wide genetic association results are supported by findings in other autoimmune diseases and/or relate to gene expression levels. Thus, they are likely to represent novel regions potentially contributing to the disease pathology of oligoarticular and RF^– polyarticular JIA.

Disclosure: L. A. McIntosh, None; M. C. Marion, None; M. Sudman, None; M. E. Comeau, None; S. Prahalad, None; J. F. Bohnsack, None; J. P. Haas, None; C. A. Wallace, None; D. J. Lovell, None; T. A. Griffin, None; M. L. Becker, None; P. A. Nigrovic, None; M. Punaro, None; C. D. Rosé, None; C. A. Wise, None; H. Moncrieffe, None; T. D. Howard, None; C. D. Langefeld, None; S. D. Thompson, None.

To cite this abstract in AMA style:

McIntosh LA, Marion MC, Sudman M, Comeau ME, Prahalad S, Bohnsack JF, Haas JP, Wallace CA, Lovell DJ, Griffin TA, Becker ML, Nigrovic PA, Punaro M, Rosé CD, Wise CA, Moncrieffe H, Howard TD, Langefeld CD, Thompson SD. Genome-Wide Association Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/genome-wide-association-analysis-reveals-novel-juvenile-idiopathic-arthritis-susceptibility-loci/. Accessed .

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