Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes

Abstract

Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow-up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline-containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07-17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.

FIG. 1.

Global changes of umbilical cord serum lipidome as related to different T1D-associated outcomes. A: Pairwise Pearson correlation coefficients for LCs and selected clinical variables. For each pair of variables, the correlation coefficients were calculated across all available samples. Categorical variables were annotated as follows: sex (male = 0 and female = 1), HLA risk (medium = 0; high = 1), mode of delivery (vaginal = 0; cesarean delivery = 1), study group (controls = 0; 1 autoantibody = 1; 2 autoantibodies = 2; 3–4 autoantibodies = 3; T1D = 4). Relative concentrations of LC2 are shown in B for all study groups. C: Relative lipid concentrations in T1D progressors and controls across the 10 LCs. The T1D progressors were divided into two subgroups: early autoantibody-positive (age at seroconversion younger than 4 years) and late autoantibody-positive (age at seroconversion older than 4 years). *P < 0.05. Aab, autoantibody; Aab⁺, antibody-positive during the follow-up.

FIG. 2.

Feasibility of cord serum lipids to predict T1D and β-cell autoimmunity in later life. A: Model to predict T1D based on cord serum concentrations of seven lipid metabolites [SM(d18:1/24:1), SM(d18:0/20:0), PC(18:1/20:4), PC(18:0/22:4), PC(38:2), PE(38:2), TG(14:0/16:0/16:0), TG(16:0/16:0/16:0)]. Samples from all T1D progressors and their matched controls were used to develop the model and calculate its characteristics. B: Model to predict β-cell autoimmunity for single autoantibody based on cord serum concentrations of seven lipid metabolites [LPC(22:6), PC(16:0e/16:0), PC(p16:0/16:0), TG(18:0/18:1/18:1), TG(16:0/18:2/20:4), as well as two unidentified lipids from clusters 1 and 5, respectively]. Samples from the one autoantibody group and their matched controls were used to develop the model and calculate its characteristics. Aab, autoantibody.