Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes

被引：87

作者：

Fall, Tove ^{[1
,2
]}

Salihovic, Samira ^{[1
,2
]}

Brandmaier, Stefan ^{[3
,4
]}

Nowak, Christoph ^{[1
,2
]}

Ganna, Andrea ^{[1
,2
,5
,6
,7
,8
]}

Gustafsson, Stefan ^{[1
,2
]}

Broeckling, Corey D. ^{[9
]}

Prenni, Jessica E. ^{[9
,10
]}

Kastenmueller, Gabi ^{[11
]}

Peters, Annette ^{[4
,12
,13
]}

Magnusson, Patrik K. ^{[8
]}

Wang-Sattler, Rui ^{[3
,13
]}

Giedraitis, Vilmantas ^{[14
]}

Berne, Christian ^{[15
]}

Gieger, Christian ^{[3
,4
,13
]}

Pedersen, Nancy L. ^{[8
]}

Ingelsson, Erik ^{[1
,2
,16
]}

Lind, Lars ^{[15
]}

机构：

[1] Uppsala Univ, Dept Med Sci, Mol Epidemiol, Box 1115, S-75141 Uppsala, Sweden

[2] Uppsala Univ, Sci Life Lab, Uppsala, Sweden

[3] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[4] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany

[5] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[6] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[7] Harvard Med Sch, Boston, MA USA

[8] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[9] Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA

[10] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA

[11] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, Neuherberg, Germany

[12] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[13] German Ctr Diabet Res DZD, Munich, Germany

[14] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden

[15] Uppsala Univ, Dept Med Sci, Uppsala, Sweden

[16] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA

来源：

DIABETOLOGIA | 2016年 / 59卷 / 10期

基金：

欧洲研究理事会; 瑞典研究理事会;

关键词：

Genetic; Metabolomics; Prediction; Type; 2; diabetes; GENOME-WIDE; LOCI; MELLITUS; INSIGHTS; GLUCOSE; PREDICTION; KORA; RISK;

D O I：

10.1007/s00125-016-4041-1

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims/hypothesis Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. Methods In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. Results Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. Conclusions/interpretation We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. Access to research materials Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).

引用

页码：2114 / 2124

页数：11

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