ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 916

Integrative Analysis of Multi-Omics Data in an Ethnically Diverse Lupus Cohort Identifies Distinct Molecular Subtypes of SLE

Cristina Lanata1, Ishan Paranjpe2, Joanne Nitiham3, Kimberly Taylor4, Brooke Rhead5, Milena Gianfrancesco6, Lisa Barcellos7, Louise Murphy8, Patricia Katz9, Laura Trupin6, Jinoos Yazdany2, Maria Dall'Era2, Marina Sirota10 and Lindsey A. Criswell9, 1Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, 2University of California, San Francisco, San Francisco, CA, 3Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, 4University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, 5University of California, Berkeley, Berkeley, CA, 6Medicine/Rheumatology, University of California, San Francisco, San Francisco, CA, 7School of Public Health, UC Berkeley, Berkeley, CA, 8Arthritis Program, Centers for Disease Control and Prevention, Atlanta, GA, 9University of California San Francisco, San Francisco, CA, 10Pediatrics, Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Date: Sunday, October 21, 2018

Title: 3S103 ACR Abstract: Genetics, Genomics & Proteomics: Precision Medicine (916–921)

Session Type: ACR Concurrent Abstract Session

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

Background/Purpose:

Systemic Lupus Erythematous (SLE) is a chronic autoimmune disease with heterogeneous disease manifestations and outcomes. We aimed to define how molecular differences underlie this clinical heterogeneity through an integrative approach leveraging methylation, genetic, and phenotypic data from a well characterized multiethnic cohort of SLE patients.

Methods:

274 participants from diverse ethnic backgrounds were recruited as part of this study. 272 met 4 SLE ACR criteria, the rest had a diagnosis of lupus nephritis or met 3 ACR criteria and had a rheumatologist’s diagnosis. In addition to clinical characterization, molecular measurements were collected on the individuals. DNA extracted from blood was analyzed on the illumina EPIC Beadchip. Single nucleotide polymorphism (SNP) genotype data was generated on the Affymetrix LAT1 World Array. First, we defined the phenotypic patient subgroups by clustering analysis – we performed principal component analysis on the ACR clinical criteria and used the top 2 eigenvectors as input for K-means clustering. We identified three stable clusters based on a stability score >0.8 determined by a bootstrap re-sampling method. Second, we applied a multivariate linear regression model adjusting for population stratification, cell composition, sex, smoking history, and age to identify differentially methylated CpGs across the phenotypic clusters. Lastly, we investigated whether the differentially methylated CpG were under genetic control in a methylation quantitative trait loci analyses (cis-meQTLs).

Results:

We identified three stable clusters based on ACR criteria: cluster 1 was characterized by a higher proportion of participants of white ethnicity with malar rash, photosensitivity, serositis, arthritis, oral ulcers and fewer subserologies; cluster 2 was characterized by a higher proportion of lupus nephritis and anti-dsDNA antibodies; cluster 3 was characterized by higher proportion of hematologic manifestations, lupus nephritis, anti-dsDNA and anti-Sm antibodies. We identified 196 CpGs in 107 genomic regions that were differentially methylated between the clusters (FDR<0.05). Of these, pathway analysis revealed significant enrichment of genes relating to Type 1 interferon signaling and IFN-gamma (adjusted p< 1E-08). Overall, Interferon-alpha responsive genes were hypomethylated in cluster 3, hypermethylated in cluster 1, with cluster 2 presenting an intermediate signature. We then investigated whether the differentially methylated CpG were under genetic control in a cis-meQTLs analysis, which identified 542 cis-meQTL pairs (FDR<0.01) with 97 CpGs under proximal genetic control, which were enriched for IFN-alpha and IFN-gamma responsive genes (hypergeometric p <0.01).

Conclusion:

Overall, we identified three clinically relevant clusters of patients in our multiethnic SLE cohort. The three clusters could be differentiated by 196 CpGs of which 97 were under genetic control and enriched for IFN-gamma and IFN-alpha responsive genes. In this work, we were successful in applying integrative computational methods to elucidate the epigenetic and genetic mechanism behind the role of Type 1 interferon in SLE pathology.

Disclosure: C. Lanata, None; I. Paranjpe, None; J. Nitiham, None; K. Taylor, None; B. Rhead, None; M. Gianfrancesco, None; L. Barcellos, None; L. Murphy, None; P. Katz, Bristol-Myers Squibb, 2; L. Trupin, None; J. Yazdany, None; M. Dall'Era, None; M. Sirota, None; L. A. Criswell, None.

To cite this abstract in AMA style:

Lanata C, Paranjpe I, Nitiham J, Taylor K, Rhead B, Gianfrancesco M, Barcellos L, Murphy L, Katz P, Trupin L, Yazdany J, Dall'Era M, Sirota M, Criswell LA. Integrative Analysis of Multi-Omics Data in an Ethnically Diverse Lupus Cohort Identifies Distinct Molecular Subtypes of SLE [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/integrative-analysis-of-multi-omics-data-in-an-ethnically-diverse-lupus-cohort-identifies-distinct-molecular-subtypes-of-sle/. Accessed .

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