Genetic Variation at the PAT loci: associations, gene-diet interactions and obesity risk.
Abstract: Currently in
the United States 66% of Americans aged twenty or greater are either overweight or
obese. However, both medical and nutritional recommendations derived from
population-based studies have had a limited impact on effective and sustained weight
loss. This intra-individual difference under similar environmental conditions has been
attributed to genetic factors, or the ... read moreinteraction of both genetic and environmental
factors. We investigated whether genetic variation in the human PAT candidate gene
family can modulate anthropometric related traits alone, or in response to dietary fat.
We identified several common SNPs modulating anthropomorphic traits. Furthermore,
several of these variants show interaction with dietary fat to modulate anthropometric
traits, the most convincing being the PLIN4 SNP rs8887. We demonstrate the minor A
allele of rs8887 created a seed site for microRNA-522. Using ex-vivo techniques we
demonstrated that rs8887 is able to modulate PLIN4 levels through this microRNA site.
Phylogenetic analysis suggests the microRNA-522 target site created by the rs8887 minor
allele is undergoing genetic drift among human populations. To determine if the effect
of rs8887 is a rare occurrence or an example of a more common form of functional SNP
that can affect miR binding, we utilized newly released SNP data from the 1000 Genomes
Project to perform a genome-wide scan of SNPs that abrogate or create microRNA
recognition element seed sites (MRESS). We estimate the percent of SNPs falling within
both validated (5%) and predicted miR seed sites (3%) and determine the number
appreciable in the human genome. We identified 87 predicted miR seed site SNPs are
listed in GWAS association studies, or in strong LD with a GWAS SNP and that may
represent the functional variants of identified GWAS SNPs. We also gather previously
published co-expression and eQTL data supporting a functional role for four of these
SNPs shown to associate with disease phenotypes. Our data provide further insight into
the link between variation in the PAT gene family and anthropometric related traits in
humans. Furthermore, with relevance to human disease we show that publicly available
resources can be used to identify a class of high priority candidate SNPs for functional
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Genetics.
Advisor: Jose Ordovas.
Committee: Gordon Huggins, Alan Kopin, and Donna Slonim.
Keyword: Genetics.read less