A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients
Patrick Coit, … , Kathleen Maksimowicz-McKinnon, Amr H. Sawalha
Patrick Coit, … , Kathleen Maksimowicz-McKinnon, Amr H. Sawalha
Published October 27, 2020
Citation Information: JCI Insight. 2020;5(22):e143654. https://doi.org/10.1172/jci.insight.143654.
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Research Article

A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients

Abstract

Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow-up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in 2 CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African American and European American lupus patients include type I IFN–response genes such as IRF7 and IFI44, and genes related to the NF-κB pathway. TREML4, which plays a vital role in TLR signaling, was hypomethylated in African American patients and demonstrated a strong cis–methylation quantitative trait loci (cis-meQTL) effect among 8855 cis-meQTL associations identified in our study.

Authors

Patrick Coit, Lourdes Ortiz-Fernandez, Emily E. Lewis, W. Joseph McCune, Kathleen Maksimowicz-McKinnon, Amr H. Sawalha

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Figure 4

meQTL involving the SNP rs9369265 within TREML4 in lupus patients.

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meQTL involving the SNP rs9369265 within TREML4 in lupus patients. (A) R...
(A) Rs9369265 is significantly associated with the methylation status of cg25555787 (FDR-adjusted P value = 1.22 × 10–16). Mean β for genotype TT = 23% (25th percentile = 21.2%, 75th percentile = 25.0%, n = 4), mean β for genotype CT = 52.0% (25th percentile = 48.3%, 75th percentile = 55.2%, n = 25), and mean β for genotype CC = 85.6% (25th percentile = 84.2%, 75th percentile = 87.3%, n = 24). Whiskers extend to the maximum value within 1.5 times the IQR on either end of the group. Points beyond the whiskers are outliers. The minor allele frequency of rs9369265 significantly differed between European American (n = 32) and African American (n = 21) lupus patients (P = 1.45 × 10–3), with the T allele associated with lower DNA methylation. Comparing allelic proportions between ancestry groups was done using a 2-proportion z test. All P values were 2 tailed, and a significance threshold of P < 0.05 was used. (B) Rs9369265 is an exonic SNP in TREML4 and is significantly associated with the methylation status of 2 CpG sites upstream of the transcription start site of TREML4 (cg25555787 and cg03849834) (hg19). This region has epigenetic marks including DNase hypersensitivity (DNase HS), histone 3 lysine 4 mono- (H3K4me1) and –tri-methylation (H3K4me3) and is labeled as an enhancer region for TREML4 (Flanking Active TSS; orange bar) in primary human neutrophils. Data for B were generated using the WashU Epigenome Browser (https://epigenomegateway.wustl.edu/) using ENCODE and Epigenome Roadmap ChromHMM data tracks from peripheral primary human neutrophils (E030).