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

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 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.

Figure 1.

Lp-PLA₂ linkage on chromosome 1. Comparison of the G×A interaction model under the WHO definition of adiposity status with the standard linkage model. The solid line indicates LOD plot under the G×A interaction model and the dashed line indicates LOD plot under the standard linkage model.

Figure 2.

Multipoint genome scan of Lp-PLA₂

Figure 3.

G×A interaction effects. The solid line with unblackened diamonds indicates genetic SD (gsd), the solid line with blackened circles indicates QTL SD (qsd), and the dashed line with blackened triangles indicates environmental SD (esd).

Figure 4.

Transcripts under the linkage signal; transcripts within the 1-LOD interval of the linkage peak at 153 cM. Top, Negative logarithm (base 10) of the Q values for the test of association between the transcript and Lp-PLA₂ plotted against chromosomal location. The dashed line corresponds to the Q value threshold of .05 for the beta coefficients. Bottom, Negative logarithm (base 10) of the Q values computed from the pointwise LOD scores plotted against chromosomal location. The grid line at 2.0 corresponds to the Q value threshold of .01 for the pointwise LOD scores. Location is expressed in terms of megabases along the ordinate, for better separation. To plot all values on a scale at which the Q value threshold could be easily discerned, the three highest −log Q values for MGC31963, HSP70, and ATF6 were arbitrarily given a −log Q value of 3.0. Their real corresponding Q values are in table 3 (HSPA6=HSP70).