Genotype × adiposity interaction linkage analyses reveal a locus on chromosome 1 for lipoprotein-associated phospholipase A2, a marker of inflammation and oxidative stress

Vincent P. Diego, David L. Rainwater, Xing Li Wang, Shelley A. Cole, Joanne E. Curran, Matthew P. Johnson, Jeremy B.M. Jowett, Thomas D. Dyer, Jeff T. Williams, Eric K. Moses, Anthony G. Comuzzie, Jean W. MacCluer, Michael C. Mahaney, John Blangero

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    21 Scopus citations

    Abstract

    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 A2 (Lp-PLA2), a marker of inflammation and oxidative stress. Using an approach to model discrete genotype × environment (G × E) 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 G × E interaction for Lp-PLA2 at the genomewide maximum (P = 1.16 × 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-PLA2 (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 G × E interaction analyses can improve our ability to identify and localize quantitative-trait loci.

    Original languageEnglish (US)
    Pages (from-to)168-177
    Number of pages10
    JournalAmerican Journal of Human Genetics
    Volume80
    Issue number1
    DOIs
    StatePublished - Jan 2007

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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