Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans

Author:

Chen Zsu-Zsu12ORCID,Pacheco Julian Avila3,Gao Yan4,Deng Shuliang5,Peterson Bennet5,Shi Xu5,Zheng Shuning5,Tahir Usman A.25,Katz Daniel H.5,Cruz Daniel E.25,Ngo Debby26,Benson Mark D.25,Robbins Jeremy M.25,Guo Xiuqing7,del Rocio Sevilla Gonzalez Magdalena238,Manning Alisa238,Correa Adolfo4,Meigs James B.238,Taylor Kent D.7,Rich Stephen S.9ORCID,Goodarzi Mark O.10ORCID,Rotter Jerome I.7,Wilson James G.5,Clish Clary B.3ORCID,Gerszten Robert E.235ORCID

Affiliation:

1. 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA

2. 2Harvard School of Medicine, Boston, MA

3. 3Broad Institute of MIT and Harvard, Boston, MA

4. 4University of Mississippi Medical Center, Jacksonville, MS

5. 5Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA

6. 6Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA

7. 7The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA

8. 8Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA

9. 9University of Virginia School of Medicine, Charlottesville, VA

10. 10Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA

Abstract

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or “known” and 2,342 nontargeted or “unknown” compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)—a community cohort of self-identified African Americans—who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose. Of these, 144 and 68 associations, respectively, replicated in a multiethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ = 0.29), and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference49 articles.

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5. Diseases of liporegulation: new perspective on obesity and related disorders;Unger;FASEB J,2001

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