Genotype x adiposity interaction linkage analyses reveal a locus on chromosome 1 for lipoprotein-associated phospholipase A2, a marker of inflammation and oxidative stress.
Because obesity leads to a state of chronic, low-grade inflammation and oxidative stress, we hypothesized that the contribution of genes to variation in a biomarker of these two processes may be influenced by the degree of adiposity. We tested this hypothesis using samples from the San Antonio Family Heart Study that were assayed for activity of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a marker of inflammation and oxidative stress. Using an approach to model discrete genotypexenvironment (GxE) interaction, we assigned individuals to one of two discrete diagnostic states (or "adiposity environments"): nonobese or obese, according to criteria suggested by the World Health Organization. We found a genomewide maximum LOD of 3.39 at 153 cM on chromosome 1 for Lp-PLA(2). Significant GxE interaction for Lp-PLA(2) at the genomewide maximum (P=1.16 x 10(-4)) was also found. Microarray gene-expression data were analyzed within the 1-LOD interval of the linkage signal on chromosome 1. We found two transcripts--namely, for Fc gamma receptor IIA and heat-shock protein (70 kDa)--that were significantly associated with Lp-PLA(2) (P<.001 for both) and showed evidence of cis-regulation with nominal LOD scores of 2.75 and 13.82, respectively. It would seem that there is a significant genetic response to the adiposity environment in this marker of inflammation and oxidative stress. Additionally, we conclude that GxE interaction analyses can improve our ability to identify and localize quantitative-trait loci.
Diego
Vincent P
VP
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, 78245-0549, USA. vdiego@darwin.sfbr.org
Rainwater
David L
DL
Wang
Xing-Li
XL
Cole
Shelley A
SA
Curran
Joanne E
JE
Johnson
Matthew P
MP
Jowett
Jeremy B M
JB
Dyer
Thomas D
TD
Williams
Jeff T
JT
Moses
Eric K
EK
Comuzzie
Anthony G
AG
Maccluer
Jean W
JW
Mahaney
Michael C
MC
Blangero
John
J
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000502:physiology; D050154:Adiposity / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008126:Lod Score; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D054467:Phospholipases A2; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D018840:HSP70 Heat-Shock Proteins; D017452:Receptors, IgG; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase