Abstract MP31: DNA Methylation Patterns are Associated with Genetic Variation and Systemic Inflammation
Authors: Aslibekyan Stella , Frazier-Wood Alexis C , Absher Devin M , Sha Jin , Zhi Degui , Kabagambe Edmond K , Straka Robert J , Tiwari Hemant K , Tsai Michael Y , Hopkins Paul N , Borecki Ingrid B , Ordovas Jose M , Arnett Donna K 
Published: July 2021

Introduction:
Chronic systemic inflammation is a complex trait characterized by moderate to high heritability and important implications for cardiovascular health. Previously identified genetic polymorphisms explain only a modest fraction of variability in circulating inflammatory marker concentrations.

Hypothesis:
We hypothesized that variation in DNA methylation patterns contributes to the missing heritability of inflammatory traits, and that such associations may in turn be influenced by environmental factors (smoking, alcohol, and obesity) as well as common genetic variants.

Methods:
Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 593), we assayed the methylation status of approximately 450,000 sites across the genome and measured serum concentrations of high-sensitivity C-reactive protein (hsCRP), soluble interleukin-2 receptor alpha (sIL2Ra), interleukin-6 (IL6), tumor necrosis factor alpha (TNFa), and monocyte chemoattractant protein 1 (MCP1). To investigate and validate the associations between DNA methylation patterns and systemic inflammation, we split the GOLDN data set into discovery (n= 451) and replication (n= 142) data sets. During the discovery stage, we modeled continuous methylation scores at each site on inflammatory markers, adjusted for age, sex, study site, and T-cell purity as fixed effects and family structure as a random effect.

Results:
After correcting for multiple comparisons, the strongest signal was obtained from an intergenic CpG island on chromosome 20 and levels of hsCRP (P=5×10-10) and sILR2a (P=6×10-6). Our findings are consistent with previous linkage studies that have identified a quantitative trait locus for inflammation in an adjacent region of chromosome 20. Moreover, the association with sIL2Ra but not hsCRP was observed in replication analyses (P=0.008). Models adjusting for current smoking status, alcohol consumption, or body mass index did not appreciably change the estimates of association. Finally, we performed a genome-wide analysis to identify quantitative trait loci for methylation of the CpG site on chromosome 20. We found a genome-wide significant (P=3×10×-8) association with rs11223480 on chromosome 11 in OPCML, which encodes a tumor suppressor, and suggestive (P<4×10-6) associations with a cluster of 9 variants located on chromosome 20 in MACROD2, a gene previously reported to be associated with systemic inflammation.

Conclusions:
We have conducted the first integrated study of epigenetic variation, genotype, and circulating inflammatory marker concentrations. In conclusion, our findings suggest that differential methylation of an intergenic region on chromosome 20, likely in conjunction with the underlying genotype, is associated with systemic inflammation and merits further evaluation as a cardiovascular risk factor.