Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

Objective: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life.

Research Design and Methods: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoproteinsubclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, others) measured at age 8y, 16y, 18y, and 25y. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent
sample of 24,925 adults.

Results: At age 8y, associations were most evident for type 2 diabetes liability (per SDhigher) with lower lipids in high-density lipoprotein (HDL) subtypes, e.g. -0.03 SD (95% CI=-0.06, -0.003) for total lipids in very-large HDL. At 16y, associations were stronger with pre-glycemic traits including citrate and with glycoprotein acetyls (0.05 SD, 95% CI=0.01, 0.08), and at 18y, associations were stronger with branched chain amino acids. At 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability.

Conclusions: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8y, decades before the clinical onset of disease.