title: Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome.
abstract: Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (∼30%-40%). Health disparities exist with African descent (AD) subjects exhibiting greater mortality than European descent (ED) individuals. Myosin light chain kinase is encoded by MYLK, whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, that is, cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK cytosine-guanine dinucleotides (CpGs) between ARDS patients and intensive care unit (ICU) controls overall and by ethnicity in a nested case-control study of 39 ARDS cases and 75 non-ARDS ICU controls. Two MYLK CpG sites (cg03892735 and cg23344121) were differentially modified between ARDS subjects and controls (P < 0.05; q < 0.25) in a logistic regression model, where no effect modification by ethnicity or age was found. One CpG site was associated with ARDS in patients aged <58 years, cg19611163 (intron 19, 20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2, 3) and CpG (cg16212219, intron 31, 32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting modified cytosine quantitative trait loci (mQTL) were identified using linear regression between local genetic variants and modification levels for 2 ARDS-associated CpGs (cg23344121 and cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS.
authors.affiliation: Laboratory Animal Resource Center, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Keely L
authors.initials: KL
authors.lastname: Szilágyi
authors.affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: University of Arizona Health Sciences, University of Arizona, Tucson, Ariz.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Biological Resources Laboratory, University of Illinois at Chicago, Chicago, Ill.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Fortman
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address: wei.zhang1@northwestern.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Arizona Health Sciences, University of Arizona, Tucson, Ariz.
authors.forename: Joe G N
authors.initials: JGN
authors.lastname: Garcia
mesh_terms: D002874:Chromosome Mapping; D015897:Comorbidity; D018899:CpG Islands / Q000235:genetics; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009219:Myosin-Light-Chain Kinase / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000235:genetics*; D012307:Risk Factors
chemical_list: D009219:Myosin-Light-Chain Kinase