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Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE.A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed.In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR)?

SUBMITTER: Aterido A

PROVIDER: S-EPMC5471877 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

Aterido Adrià A Julià Antonio A Carreira Patricia P Blanco Ricardo R López-Longo José Javier JJ Venegas José Javier Pérez JJP Olivé Àlex À Andreu José Luís JL Aguirre-Zamorano Maria Ángeles MÁ Vela Paloma P Nolla Joan M JM Marenco-de la Fuente José Luís JL Zea Antonio A Pego José María JM Freire Mercedes M Díez Elvira E López-Lasanta María M López-Corbeto Mireia M Palau Núria N Tortosa Raül R Gelpí Josep Lluís JL Absher Devin D Myers Richard M RM Fernández-Nebro Antonio A Marsal Sara S

Arthritis research & therapy 20170615 1

<h4>Background</h4>Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE.<h4>Methods</h4>A two-stage pathway-based approach was used to identify the genetic variation associated with ...[more]

PMID: 28619073

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Project description:BACKGROUND:African Americans with systemic lupus erythematosus (SLE) have increased renal disease compared to Caucasians, but differences in other comorbidities have not been well-described. We used an electronic health record (EHR) technique to test for differences in comorbidities in African Americans compared to Caucasians with SLE. METHODS:We used a de-identified EHR with 2.8 million subjects to identify SLE cases using a validated algorithm. We performed phenome-wide association studies (PheWAS) comparing African American to Caucasian SLE cases and African American SLE cases to matched non-SLE controls. Controls were age, sex, and race matched to SLE cases. For multiple testing, a false discovery rate (FDR) p value of 0.05 was used. RESULTS:We identified 270 African Americans and 715 Caucasians with SLE and 1425 matched African American controls. Compared to Caucasians with SLE adjusting for age and sex, African Americans with SLE had more comorbidities in every organ system. The most striking included hypertension odds ratio (OR) = 4.25, FDR p = 5.49 × 10- 15; renal dialysis OR = 10.90, FDR p = 8.75 × 10- 14; and pneumonia OR = 3.57, FDR p = 2.32 × 10- 8. Compared to the African American matched controls without SLE, African Americans with SLE were more likely to have comorbidities in every organ system. The most significant codes were renal and cardiac, and included renal failure (OR = 9.55, FDR p = 2.26 × 10- 40) and hypertensive heart and renal disease (OR = 8.08, FDR p = 1.78 × 10- 22). Adjusting for race, age, and sex in a model including both African American and Caucasian SLE cases and controls, SLE was independently associated with renal, cardiovascular, and infectious diseases (all p <?0.01). CONCLUSIONS:African Americans with SLE have an increased comorbidity burden compared to Caucasians with SLE and matched controls. This increase in comorbidities in African Americans with SLE highlights the need to monitor for cardiovascular and infectious complications.

Dataset Information

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

Publications

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

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