Prediction of Type 1 Diabetes at Birth

Cord Blood Metabolites vs Genetic Risk Score in the Norwegian Mother, Father, and Child Cohort

German Tapia; Tommi Suvitaival; Linda Ahonen; Nicolai A. Lund-Blix; Pål R. Njølstad; Geir Joner; Torild Skrivarhaug; Cristina Legido-Quigley; Ketil Størdal; Lars C. Stene

Disclosures

J Clin Endocrinol Metab. 2021;106(10):e4062-e4071. 

In This Article

Abstract and Introduction

Abstract

Background and Aim: Genetic markers are established as predictive of type 1 diabetes, but unknown early life environment is believed to be involved. Umbilical cord blood may reflect perinatal metabolism and exposures. We studied whether selected polar metabolites in cord blood contribute to prediction of type 1 diabetes.

Methods: Using a targeted UHPLC-QQQ-MS platform, we quantified 27 low-molecular-weight metabolites (including amino acids, small organic acids, and bile acids) in 166 children, who later developed type 1 diabetes, and 177 random control children in the Norwegian Mother, Father, and Child cohort. We analyzed the data using logistic regression (estimating odds ratios per SD [adjusted odds ratio (aOR)]), area under the receiver operating characteristic curve (AUC), and k-means clustering. Metabolites were compared to a genetic risk score based on 51 established non-HLA single-nucleotide polymorphisms, and a 4-category HLA risk group.

Results: The strongest associations for metabolites were aminoadipic acid (aOR = 1.23; 95% CI, 0.97–1.55), indoxyl sulfate (aOR = 1.15; 95% CI, 0.87–1.51), and tryptophan (aOR = 0.84; 95% CI, 0.65–1.10), with other aORs close to 1.0, and none significantly associated with type 1 diabetes. K-means clustering identified 6 clusters, none of which were associated with type 1 diabetes. Cross-validated AUC showed no predictive value of metabolites (AUC 0.49), whereas the non-HLA genetic risk score AUC was 0.56 and the HLA risk group AUC was 0.78.

Conclusions: In this large study, we found no support of a predictive role of cord blood concentrations of selected bile acids and other small polar metabolites in the development of type 1 diabetes.

Introduction

Type 1 diabetes is usually preceded by a prodromal phase characterized by islet autoantibodies, often appearing in early childhood years before diagnosis.[1] HLA and other genetic factors clearly contribute to type 1 diabetes susceptibility,[1] but the increasing incidence implicate nongenetic factors.[2] The typically early seroconversion to islet autoantibodies suggests that early life is important.[3–5]

Maternal age, obesity, and birth weight are early life nongenetic risk factors relatively consistently associated with childhood-onset type 1 diabetes.[6–11] Obesity, dysglycemia, kidney function, and related traits, both in nonpregnant and in pregnant women, are associated with perturbations in small metabolites such as amino acids, creatinine, and bile acids,[12–15] many of which have also been associated with birth weight.[12] Metabolites such as glucose, lipids, amino acids, and bile acids can cross the placenta, often bidirectionally, via free diffusion and placentally expressed transmembrane transporters.[16–18] Many small metabolites in cord blood are thus correlated with maternal levels during the third trimester.[12] For example, plasma creatinine, a marker of kidney function, largely reflects maternal levels when measured in cord blood,[19] but has been linked to birth weight.[20,21] Maternal circulating bile acids, which may be influenced by maternal gut microbiota, may program offspring metabolism, or influence their microbiome, and have been linked to insulin resistance.[14,22,23] Yet, there is only 1 small study (15 cases and 24 controls) in cord blood[24] and 1 study using dried blood spots[25] to date on nonlipid metabolites and later type 1 diabetes. The authors are not aware of any previous study investigating maternal or newborn plasma bile acids and subsequent type 1 diabetes risk.

The aim of the study was to test if selected small metabolites in cord blood, or combinations of these, could predict future risk of offspring type 1 diabetes in the Norwegian Mother, Father, and Child Cohort Study (MoBa), 1 of the largest pregnancy cohorts in the world. To ensure robust quantification, and to minimize multiple testing problems, we chose a targeted metabolomics approach focusing on small metabolites (molar mass ranging from 75 to ~500 g/mol) with previous evidence for association with metabolic traits.[13] In addition, we investigated established genetic susceptibility markers for comparison of predictive values among biomarkers present at birth.

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