Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent

Authors: HASLAM, DANIELLE - Harvard Medical School; LIANG, LIMING - Harvard School Of Public Health; WANG, DONG - Harvard Medical School; KELLY, RACHEL - Harvard Medical School; WITTENBECHER, CLEMENS - Harvard School Of Public Health; PEREZ, CYNTHIA - University Of Puerto Rico; MARTINEZ, MARIJULIE - University Of Puerto Rico; LEE, CHIH-HAO - Harvard School Of Public Health; CLISH, CLARY - Broad Institute Of Mit/harvard; WONG, DAVID - University Of California (UCLA); Parnell, Laurence; Lai, Chao Qiang; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MANSON, JOANN - Harvard Medical School; HU, FRANK - Harvard Medical School; STAMPFER, MEIR - Harvard Medical School; TUCKER, KATHERINE - University Of Massachusetts; JOSHIPURA, KAUMUDI - Harvard School Of Public Health; BHUPATHIRAJU, SHILPA - Harvard Medical School

Submitted to: BMJ Open Diabetes Research & Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2021
Publication Date: 8/19/2021
Citation: Haslam, D.E., Liang, L., Wang, D.D., Kelly, R.S., Wittenbecher, C., Perez, C.M., Martinez, M., Lee, C., Clish, C., Wong, D., Parnell, L.D., Lai, C., Ordovas, J.M., Manson, J.E., Hu, F.B., Stampfer, M.J., Tucker, K.L., Joshipura, K., Bhupathiraju, S.N. 2021. Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent. BMJ Open Diabetes Research & Care. https://doi.org/10.1136/bmjdrc-2021-002298.
DOI: https://doi.org/10.1136/bmjdrc-2021-002298

Interpretive Summary: Racial and ethnic minorities have a higher burden of type 2 diabetes. Specifically, among Hispanics, the prevalence, progression, and death rate from diabetes are much higher than for non-Hispanic whites. The basis of this problem is a combination of risk factors, including genetics, lack of access to health care, socioeconomic status, cultural attitudes, and behaviors, such as poor diet, obesity, and sedentary life. The biological mechanisms induced by this combination of biological and social differences resulting in a higher risk of diabetes and its consequences are mostly unknown. To gain a better understanding at the molecular level, we conducted a deep analysis of circulating metabolites (>700) in the blood of participants in two Hispanic Studies (the Boston PR Health Study and the San Juan Overweight Adult Longitudinal Study) totaling 1158 individuals. Our results show a distinct pattern of lipid-related molecules associated with diabetes and point to specific molecular mechanisms at the cellular level that may be disrupted in people with diabetes, providing clues about dietary approaches for disease prevention in this vulnerable population.

Technical Abstract: Introduction: We investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults. Research design and methods: We used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40-75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates. Results: Six metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS. Conclusions: Among Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.