A genome-wide perspective of genetic variation in human metabolism

Illig, Thomas; Gieger, Christian; Zhai, Guangju; Römisch-Margl, Werner; Wang-Sattler, Rui; Prehn, Cornelia; Altmaier, Elisabeth; Kastenmüller, Gabi; Kato, Bernet; Mewes, Hans‐Werner; Meitinger, Thomas; Angelis, Martin Hrabé de; Kronenberg, Florian; Soranzo, Nicole; Wichmann, H‐Erich; Spector, Tim D.; Adamski, Jerzy; Suhre, Karsten

doi:10.1038/ng.507

Cited by 612 publications

(688 citation statements)

References 25 publications

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“…Genome-wide association studies have shown a strong association of genetic SPTLC3 variants with alterations in lipid metabolism [29] and increased risk for myocardial infarction [30]. Therefore, lower C 16 SO levels might be directly or indirectly related to the increased risk of diabetic patients for developing cardiovascular complications.…”

Section: Discussionmentioning

confidence: 99%

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

et al. 2011

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Aims/hypothesis Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C 12 to C 18 ) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes.Methods We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n=25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. Results Deoxysphingolipids (dSLs) were significantly elevated (p ¼ 5 Â 10 À6 ) in patients with the metabolic syndrome (0.11±0.04 μmol/l) compared with controls (0.06±0.02 μmol/l) but did not differ between the metabolic A. Othman and M. F. Rütti contributed equally to this study. Diabetologia (2012) 55:421-431 DOI 10.1007/s00125-011-2384 syndrome and diabetes groups. Levels of C 16 -sphingosinebased sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p=0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. Conclusions/interpretation We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

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Section: Discussionmentioning

confidence: 99%

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

et al. 2011

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“…Notably, the strength of the observed associations is so great that they easily overcome the multiple-testing corrections necessitated by the large number of parallel GWASs inherent in metabolome-wide studies. Ceramide synthesis and transport Gieger et al 2008;Illig et al 2010;Nicholson et al 2011;Suhre et al 2011Genes Nutr (2013 A comparison of these recent studies to those on favism and lactose intolerance discussed above indicates how dramatically gene-metabolism research has changed over the past decade and a half. In the past, linking variations in metabolism to a specific gene was often the endpoint of extensive mechanistic and epidemiological studies.…”

Section: Holistic Metabolomics Phenotypes In Gwasmentioning

confidence: 99%

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

et al. 2012

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Genome-wide association studies (GWASs) have become a very important tool to address the genetic origin of phenotypic variability, in particular associated with diseases. Nevertheless, these types of studies provide limited information about disease etiology and the molecular mechanisms involved. Recently, the incorporation of metabolomics into the analysis has offered novel opportunities for a better understanding of disease-related metabolic deregulation. The pattern emerging from this work is that gene-driven changes in metabolism are prevalent and that common genetic variations can have a profound impact on the homeostatic concentrations of specific metabolites. A particularly interesting aspect of this work takes into account interactions of environment and lifestyle with the genome and how this interaction translates into changes in the metabolome. For instance, the role of PY-ROXD2 in trimethylamine metabolism points to an interaction between host and microbiome genomes (host/ microbiota). Often, these findings reveal metabolic deregulations, which could eventually be tuned with a nutritional intervention. Here we review the development of gene-metabolism association studies from a single-gene/ single-metabolite to a genome-wide/metabolome-wide approach and highlight the conceptual changes associated with this ongoing transition. Moreover, we report some of our recent GWAS results on a cohort of 265 individuals from an ethnically diverse population that validate and refine previous findings on gene-urine metabolism interactions. Specifically, our results confirm the effect of PYROXD2 polymorphisms on trimethylamine metabolism and suggest that a previously reported association of N-acetylated compounds with the ALMS1/NAT8 locus is driven by SNPs in the ALMS1 gene.

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“…A number of genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the chromosome 6 region that includes ELOVL2 to be strongly associated with plasma fatty acid proportions (Aulchenko et al 2009;Sabatti et al 2009;Tanaka et al 2009;Illig et al 2010). A subsequent meta-analysis confirmed a number of minor allele associations with higher EPA and DPA and lower DHA proportions (Lemaitre et al 2011).…”

Section: Introductionmentioning

confidence: 99%

ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement

et al. 2013

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Fish oil supplementation provides an inconsistent degree of protection from cardiovascular disease (CVD), which may be attributed to genetic variation. Single nucleotide polymorphisms (SNPs) in the elongation-ofvery-long-chain-fatty-acids-2 (ELOVL2) gene have been strongly associated with plasma proportions of n-3 longchain polyunsaturated fatty acids (LC-PUFA). We investigated the effect of genotype interaction with fish oil dosage on plasma n-3 LC-PUFA proportions in a parallel doubleblind controlled trial, involving 367 subjects randomised to treatment with 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1.51:1) or olive oil placebo for 6 months. We genotyped 310 subjects for ELOVL2 gene SNPs rs3734398, rs2236212 and rs953413. At baseline, carriers of all minor alleles had lower proportions of plasma DHA than non-carriers (P = 0.021-0.030). Interaction between genotype and treatment was a significant determinant of plasma EPA (P \ 0.0001) and DHA (P = 0.004-0.032). After the 1.8 g/day dose, carriers of ELOVL2 SNP minor alleles had approximately 30 % higher proportions of EPA (P = 0.002-0.004) and 9 % higher DHA (P = 0.013-0.017) than non-carriers. Minor allele carriers could therefore particularly benefit from a high intake of EPA and DHA in maintaining high levels of plasma n-3 PUFA conducive to protection from CVD.

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A genome-wide perspective of genetic variation in human metabolism

Cited by 612 publications

References 25 publications

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement

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