Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury.
The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon-intron boundaries, and 2 kb of 5' UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P<0.001), with an additional SNP associated with the ALI phenotype (P=0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P=0.002) and with ALI (P=0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P<0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5' of the MYLK gene in both European and African Americans and an additional 3' region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.
Gao
Li
L
Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.
Grant
Audrey
A
Halder
Indrani
I
Brower
Roy
R
Sevransky
Jonathan
J
Maloney
James P
JP
Moss
Marc
M
Shanholtz
Carl
C
Yates
Charles R
CR
Meduri
Gianfranco Umberto
GU
Shriver
Mark D
MD
Ingersoll
Roxann
R
Scott
Alan F
AF
Beaty
Terri H
TH
Moitra
Jaideep
J
Ma
Shwu Fan
SF
Ye
Shui Q
SQ
Barnes
Kathleen C
KC
Garcia
Joe G N
JG
D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000368:Aged; D016022:Case-Control Studies; D005091:Exons; D005260:Female; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009219:Myosin-Light-Chain Kinase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000235:genetics*; D012306:Risk; D018805:Sepsis / Q000150:complications / Q000235:genetics; D044465:White People
D020033:Protein Isoforms; D009219:Myosin-Light-Chain Kinase