A family-specific linkage analysis of blood lipid response to fenofibrate in the Genetics of Lipid Lowering Drug and Diet Network

Abstract

Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-C on chromosome 7 (peak LOD score=4.76) in the full sample (n=821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N=19), we observed a peak LOD score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

“…In support of our findings are the reports of higher cholesterol levels in partially (55) or completely CD36-deficient individuals (9) and the higher LDL levels and abnormal cholesterol absorption of CD36-null mice (24,56). In addition, a recent linkage analysis of LDL particle response to fenofibrate treatment in GOLDN reported a peak encompassing the CD36 locus (57). Thus, the LDL associations we identified and their potential relationship to disease risk warrant further investigation.…”

Genome-wide linkage scan for loci influencing plasma triglyceride levels

“…Hidalgo et al [ 6 ] reported no linkage in their analysis of TG levels, using a different approach than the one we followed here. They relied primarily on MERLIN to both estimate IBD matrices and conduct linkage analyses.…”

“…Second, and possibly more important, it limited the number of loci that Hidalgo et al were able to use for IBD inference. Only 10 sets of approximately 3000 SNPs each were used to perform “linkage analyses in independent overlapping intervals of the genome” [ 6 ] from 729,490 SNPs that were available to them for analysis. By using IBDLD [ 7 ] we were able to leverage the information contained in more than 375,632 SNPs to derive our MIBD estimates at the 3561 loci that were used in our linkage analyses.…”

“…GOLDN data were collected at 4 time points (2 before the fenofibrate intervention and 2 after it) providing an opportunity to investigate the genetic effects associated with the response to fenofibrate administration. Hidalgo et al [ 6 ] found, using GOLDN data, a strong linkage signal for changes in low-density lipoprotein cholesterol (LDL-C) near 7:108 cM (LOD = 5.17) and for changes in high-density lipoprotein cholesterol (HDL-C) near 10:37 cM (LOD = 4.75), but reported no evidence of linkage to either total cholesterol or triglyceride levels.…”

“…In this study, we conduct genome-wide linkage scans to map loci that influence fasting triglyceride levels in plasma before and after fenofibrate was administered to GOLDN participants. To do so, we follow a different approach than the one used by Hidalgo et al [ 6 ]. We used IBDLD [ 7 ] to estimate multipoint identity by descent and empirical kinship information from genome-wide single-nucleotide polymorphism (SNP) association data, followed by linkage analysis using the variance-component framework built into SOLAR (Sequential Oligogenic Linkage Analysis Routines) [ 8 ].…”