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Comparative Study
. 2014 Jun;34(6):1307-13.
doi: 10.1161/ATVBAHA.114.303252. Epub 2014 Mar 27.

Comparative Genome-Wide Association Studies in Mice and Humans for Trimethylamine N-oxide, a Proatherogenic Metabolite of Choline and L-carnitine

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Free PMC article
Comparative Study

Comparative Genome-Wide Association Studies in Mice and Humans for Trimethylamine N-oxide, a Proatherogenic Metabolite of Choline and L-carnitine

Jaana Hartiala et al. Arterioscler Thromb Vasc Biol. .
Free PMC article

Abstract

Objective: Elevated levels of plasma trimethylamine N-oxide (TMAO), the product of gut microbiome and hepatic-mediated metabolism of dietary choline and L-carnitine, have recently been identified as a novel risk factor for the development of atherosclerosis in mice and humans. The goal of this study was to identify the genetic factors associated with plasma TMAO levels.

Approach and results: We used comparative genome-wide association study approaches to discover loci for plasma TMAO levels in mice and humans. A genome-wide association study in the hybrid mouse diversity panel identified a locus for TMAO levels on chromosome 3 (P=2.37 × 10(-6)) that colocalized with a highly significant (P=1.07 × 10(-20)) cis-expression quantitative trait locus for solute carrier family 30 member 7. This zinc transporter could thus represent 1 positional candidate gene responsible for the association signal at this locus in mice. A genome-wide association study for plasma TMAO levels in 1973 humans identified 2 loci with suggestive evidence of association (P=3.0 × 10(-7)) on chromosomes 1q23.3 and 2p12. However, genotyping of the lead variants at these loci in 1892 additional subjects failed to replicate their association with plasma TMAO levels.

Conclusions: The results of these limited observational studies indicate that, at least in humans, genes play a marginal role in determining TMAO levels and that any genetic effects are relatively weak and complex. Variation in diet or the repertoire of gut microbiota may be more important determinants of plasma TMAO levels in mice and humans, which should be investigated in future studies.

Keywords: atherosclerosis; genetics; humans; mice; trimethylamine N-oxide.

Figures

Figure 1
Figure 1. Association of the FMO locus with FMO3 mRNA levels, plasma TMAO levels, and risk of CAD in humans
Using a publicly available eQTL liver dataset, 57 SNPs were tested for association with hepatic FMO3 mRNA levels, one of which (rs2075988) yielded a significant p-value (4.5×10−4) after Bonferroni correction for multiple testing (A). In the GeneBank cohort, none of the 471 SNPs tested in the FMO locus yielded significant association with plasma TMAO levels (B). Evaluation of the FMO locus with risk of CAD using 388 SNPs available from the results of the CARDIoGRAM consortium did not reveal any significant associations (C). The same genomic interval spanning ~451kb across the FMO cluster on chromosome 1q24.3 is shown for all three plots and the variant most strongly associated with FMO3 mRNA levels is given as the reference SNP (rs2075988).
Figure 2
Figure 2. Manhattan plot for GWAS of plasma TMAO levels in mice
A GWAS for plasma TMAO levels in the HMDP identifies a significant locus over the Slc30a7 gene (red dot) at 110–115Mb on chromosome 3 and a suggestive locus on chromosome 1 ~40kb away from the Lbr gene (A). A regional plot for chromosome 3 shows the location and transcriptional orientation of Slc30a7 (indicated by red arrow) in relation to the peak SNPs in this region (B). Of the genes in this locus, a highly significant (p=1.07×10−20) cis-acting eQTL is observed for Slc30a7 (C). The red line indicates the genome-wide threshold for significance in the HMDP (p=4.1×10−6). Plasma TMAO and hepatic mRNA levels were quantitated in male mice from ~100 HMDP strains (n=3–8 mice per strain) and analyzed for association with ~107,000 SNPs, after correcting for population structure using the EMMA algorithm.
Figure 3
Figure 3. Results of a GWAS for plasma TMAO levels in humans
The Q-Q plot of the GWAS results for plasma TMAO levels in humans (n=1973) shows slight deviation of the observed p-values from the expected distribution under the null hypothesis of no association (A). The observed genomic control factor in these analyses was 1.007, indicating that the results are not confounded by underlying population stratification. A GWAS analysis in humans identifies two loci on chromosomes 1 and 2 exhibiting suggestive evidence of association with plasma TMAO levels but no locus that exceeds the genome-wide threshold for significance (indicated by the horizontal red line) (B).

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