SNPs affecting serum metabolomic traits may regulate gene transcription and lipid accumulation in the liver.
OBJECTIVE
Circulatory metabolites are important biomarkers for many diseases, especially metabolic disorders. The biological mechanism regulating circulatory levels of metabolites remains incompletely understood. Focusing on the liver as the central organ controlling metabolic homeostasis, we investigated the potential function of nine polymorphisms associated with serum metabolomic traits in a recent GWAS.


METHODS
The mRNA levels of the associated genes were measured by real-time PCR and correlated with genotypes in normal liver tissue (n=42). Genotype and mRNA data were also correlated with total hepatic lipid content (HLC). Our findings were also compared with the previously published gene expression quantitative traits loci (eQTL) data in the liver.


RESULTS
We found that seven out of nine genes were highly expressed in hepatic tissue, while expression of four genes was significantly or marginally associated with genotypes (SPTLC3 vs rs168622, P=.002; ACADS vs rs2014355, P=.016; PLEKHH1 vs rs7156144, P=.076; ACADL vs rs2286963, P=.068). The SNP rs168622 at the SPTLC3 locus was also significantly correlated with HLC (P=.02). HLC was significantly correlated with FADS1 (r=-0.45; P=.003) and ETFDH (r=0.33; P=.037) expression. When compared with published eQTL data, SNPs in SPTLC3, ACADS, ELOVL2 and FADS1 were also in strong linkage disequilibrium (R(2)≥0.41, D'≥0.96) with eQTLs significantly affecting expression of these genes (P≤1.74×10(-5)).


CONCLUSIONS
Our study suggests that genetic variants affecting serum metabolites levels may play a functional role in the liver. This may help elucidate the mechanism by which genetic variants are involved in metabolic diseases.
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Snezana
S
Mirkov
Jamie L
JL
Myers
Jacqueline
J
Ramírez
Wanqing
W
Liu
D000090943:Delta-5 Fatty Acid Desaturase; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D055432:Metabolomics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics*
D000090943:Delta-5 Fatty Acid Desaturase; D012333:RNA, Messenger; C000716847:FADS1 protein, human