Genome-Wide DNA Methylation Study in Lupus in an Admixed Mexican Population

Maria Teruel¹, Patrick Coit², Mikhail Dozmorov³, Mario Cardiel⁴, Ignacio Garcia-De La Torre⁵, Marco A Maradiaga-Ceceña Sr.⁶, José Francisco Moctezuma⁷, Maria Teresa Tusié-Luna⁸, Marta Alarcón-Riquelme^9,10 and Amr H Sawalha², ¹GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain, ²Division of Rheumatology, University of Michigan, Ann Arbor, MI, ³Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, ⁴Centro de Investigación Clínica de Morelia SC, Morelia, Mexico, ⁵Immunology & Rheumatology, Centro de Est. de Invest. Bas. y Clin., S.C., Guadalajara, JAL, Mexico, ⁶Hospital General de Culiacán, Culiacán, Mexico, ⁷Servicio de Reumatología, Hospital General de Mexico, Ciudad de Mexico, Mexico, ⁸Medicina Genómica y Toxicología Ambiental, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico, ⁹Uppsala University, Uppsala, Sweden, ¹⁰Centro de Genomica e Investigación Oncológica, Pfizer-University of Granada-Junta de Andalucía, Granada, Spain

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Epigenetics, Ethnic studies, Genetic Biomarkers, methylation and systemic lupus erythematosus (SLE)

Session Information

Date: Sunday, November 5, 2017

Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Our knowledge about the pivotal role DNA methylation plays in the pathogenesis of SLE has significantly increased in the last few years. However, we still have a relatively poor idea about the role of this epigenetic mark in the development of SLE in admixed populations. In addition, we do not yet understand the role of DNA methylation in explaining the higher prevalence and severity of SLE in these populations. To achieve these goals, we have conducted a genome-wide DNA methylation case-control study on individuals with different degrees of Amerindian ancestry.

Methods: Whole blood DNA from 60 females SLE patients and 59 female healthy individuals from Mexico were included in the study. The Native American ancestry was estimated using STRUCTURE and a set of ancestry informative markers (AIMs), and data from 1000 Genomes populations and a set of individuals of Nahua population were used as reference panel. In order to minimize the effect of other minor ancestries, all individuals were selected to have less than 10 % of Asian and African ancestries. DNA methylation data were generated using the Infinium MethylationEPIC BeadChip (Illumina). Differential methylation between groups was estimated by beta regression after adjusting for age, technical variables and estimated cell type composition. SLE patients were stratified according to clinical manifestations. Functional annotations were performed using DAVID/Panther.

Results: Differential DNA methylation pattern was observed among individuals with different degrees of native Amerindian ancestry. The probe cg03693186 located in DAPK1 gene had the most significant signal detected (p-value =3.0 E^-19). In a case-control association analysis, an overall hypomethylation in lupus was observed, especially in genes involved in the type I interferon response and regulation such as IFIH1, IF44, IF44L, MX1 and NLRC5, consistent with findings in other populations. When comparing DNA methylation changes associated with lupus nephritis, a significant enrichment in the canonical WNT/β-catenin signaling pathway (p-value adjusted= 1.1 E^-7) was found among hypomethylated genes. Hypermethylated genes in lupus nephritis show a significant enrichment in Angiotensin II-stimulated signaling through G proteins and beta-arrestin (p-value adjusted= 0.0034).

Conclusion: Differential methylation of interferon-regulated genes is associated with SLE in an admixed Amerindian population from Mexico, consistent with the epigenetic interferon signature observed in other ethnicities. The Amerindian association found for DAPK1 gene, a positive mediator of gamma-interferon induced programmed cell death, might provide clues to explain the higher SLE prevalence and severity observed in these populations. In addition, our results also identify other biological pathways associated with lupus nephritis that might help to clarify the high prevalence and severity of lupus nephritis in admixed populations.

Disclosure: M. Teruel, None; P. Coit, None; M. Dozmorov, None; M. Cardiel, None; I. Garcia-De La Torre, None; M. A. Maradiaga-Ceceña Sr., None; J. F. Moctezuma, None; M. T. Tusié-Luna, None; M. Alarcón-Riquelme, Genzyme/Sanofi Corporation, 2; A. H. Sawalha, None.

To cite this abstract in AMA style:

Teruel M, Coit P, Dozmorov M, Cardiel M, Garcia-De La Torre I, Maradiaga-Ceceña MA Sr., Moctezuma JF, Tusié-Luna MT, Alarcón-Riquelme M, Sawalha AH. Genome-Wide DNA Methylation Study in Lupus in an Admixed Mexican Population [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-methylation-study-in-lupus-in-an-admixed-mexican-population/. Accessed .

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