Conserved properties of genetic architecture of renal and fat transcriptomes in rat models of insulin resistance
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Abstract
To define renal molecular mechanisms that are affected by permanent hyperglycemia and
may promote phenotypes relevant to diabetes nephropathy, we carried out linkage analysis of
genome-wide gene transcription in kidney of F2 offspring from the Goto-Kakizaki (GK) rat
model of type 2 diabetes and normoglycemic Brown Norway (BN) rats. We mapped 2526
statistically significant expression quantitative trait loci (eQTLs) in the cross. Over 40% of
eQTLs mapped in the close vicinity of the linked transcripts, underlying possible cisregulatory mechanisms of gene expression. We identified eQTL hotspots on chromosomes 5
and 9 regulating the expression of 80-165 genes, sex or cross direction effects, and enriched
metabolic and immunological processes by segregating GK alleles. Comparative analysis
with adipose tissue eQTLs in the same cross showed that 496 eQTLs, as well as top enriched
biological pathways, are conserved in the two tissues. Extensive similarities in eQTLs
mapped in the GK and in the spontaneously hypertensive rat (SHR) suggest a common
etiology of disease phenotypes common to the two strains, including insulin resistance which
is a prominent pathophysiological feature in both GK and SHR. Our data shed light on shared
and tissue specific molecular mechanisms that may underlie etiological aspects of insulin
resistance in the contexts of spontaneously occurring hyperglycemia and hypertension