The Influence of Parental Type 1 Diabetes (T1D) on the Progression to T1D in Autoantibody-Positive Offspring
Authors: ISMAIL HEBA M. , SIMS EMILY K. , GEYER SUSAN , REDONDO MARIA J. , EVANS-MOLINA CARMELLA , LIBMAN INGRID , DIMEGLIO LINDA , BECKER DOROTHY J. , PALMER JERRY P. , SKYLER JAY S. , KRISCHER JEFFREY , SCHATZ DESMOND , PUGLIESE ALBERTO , SOSENKO JAY 
Published: June 2018

Studies have suggested that autoantibody positivity (Ab+) and T1D occur less commonly in maternal offspring (MO) than paternal offspring (PO) of T1D patients. However, there is little information on the impact of parental T1D on progression to T1D once Ab+ occurs in the offspring. We have thus compared MO vs. PO for progression to T1D in the Ab+ cohort of the TrialNet Pathway to Prevention study using data from 33,382 screened subjects whose parents had T1D. Cox regression with adjustments for age, sex, ethnicity, Abs, and Index60 (a composite measure of C-peptide and glucose) was used to compare T1D progression. The prevalence of Ab+ was lower for MO than for PO [3.1% (549/17,652) vs. 4.5% (726/16,027), p&lt;0.001]. However, among those Ab+ participants, progression to T1D was greater in MO [HR=1.46 (95% CI: 1.13-1.90), p=0.004]. Although progression from single Ab+ to multiple (M)Ab+ did not differ significantly between MO (n=208) and PO (n=267) [HR=0.76 (0.48-1.19), p=0.23], progression from MAb+ to T1D was significantly higher in MO (n=341) than PO (n=459) [HR=1.45 (1.10-1.90), p&lt;0.01]. We assessed whether in utero exposure might explain the greater risk for progression from MAb+ to T1D in MO. In a comparison of mothers and fathers diagnosed with T1D before the birth of offspring, MO (n=224) were at more risk for T1D than PO (n=357) [HR=1.40 (1.02-1.93), p=0.035]. However, among parents diagnosed with T1D after the birth of offspring, the risk for T1D among MO (n=75) and PO (n=69) was similar [HR=1.15 (0.60-2.22), p=0.67]. The risk for MO of mothers who were diagnosed before their birth vs. MO of mothers who were diagnosed after their birth was not significantly different [HR=1.37 (0.75-2.5), p=0.31].
In conclusion, as observed previously, MO had a lower prevalence of Ab+ than PO. However, when Ab+ was present, MO were at higher risk for T1D. Moreover, the overall findings suggest that in utero exposure could possibly contribute to the increased risk from MAb+ to T1D in MO.

Disclosure
H.M. Ismail: None. E.K. Sims: None. S. Geyer: None. M.J. Redondo: None. C. Evans-Molina: None. I. Libman: Consultant; Self; Novo Nordisk A/S. L. DiMeglio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Medtronic, Sanofi, Caladrius Biosciences, Inc., Janssen Research & Development, Xeris Pharmaceuticals, Inc., Sanofi. D.J. Becker: None. J.P. Palmer: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Abvance. Consultant; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Dance Biopharm. Consultant; Self; Diavacs, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Ideal Life Inc., ImmunoMolecular Therapeutics, Intrexon, Merck & Co., Inc.. Advisory Panel; Self; Orgenesis Inc.. Consultant; Self; Sanofi, Servier, VTV Therapeutics, Valeritas, Inc., Viacyte, Inc.. Board Member; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Board Member; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. Board Member; Self; Moerae Matrix. Stock/Shareholder; Self; Moerae Matrix, Dance Biopharm, Ideal Life Inc., Intrexon, VasoPrep Surgical. J. Krischer: None. D. Schatz: None. A. Pugliese: None. J. Sosenko: None.