CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients.

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, P = 0.002) and the CLEC16A AA genotype (rs12708716, P = 0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (P = 0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (P = 0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups.

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives.

AIMS/HYPOTHESIS: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. METHODS: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression. RESULTS: In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan-Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. CONCLUSIONS/INTERPRETATION: In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes.

The effect of parental rejection on the emotional eating behaviour of youngsters: A laboratory-based study.

Results from survey studies demonstrate a relationship between parental rejection and self-reported emotional eating of youngsters. The aim of the current study was to build on this research by examining the relationship between parental rejection and actual emotional eating, using an experimental laboratory paradigm. Participants were 46 youngsters between the ages of 10 and 17 years old. Participants first completed online questionnaires at home, measuring parental rejection and emotional eating style. At the laboratory, participants were randomly assigned to a neutral condition or negative mood condition, followed by a multi-item snack buffet. The interaction effect maternal rejection × condition on energy intake from savoury food was significant. More maternal rejection predicted more energy intake from savoury food in the negative mood condition, but not in the neutral condition. The results highlight the importance of assessing, and if mandatory, improving the emotional bond between parent and child in the prevention and intervention of emotional eating.

Observation of parental functioning at mealtime using a sibling design.

This study investigates whether parental feeding practices are part of the shared environment or responsive to characteristics of different children from the same family. Thirty-six mothers with two children (4-12 y) of which 10 sibling-pairs were discordant for weight status (healthy weight-overweight), were invited to the lab for a standard meal. Maternal responsive and controlling behaviour was observed and coded. Children's weight status and eating behaviour was assessed. Results indicated that in general, mothers show similar levels of responsiveness and controlling behaviour within families. However, the use of mothers' authoritarian and permissive behaviour and her expressions of involvement at mealtime were consequently related to children's amount of food eaten and their restraining eating style. Thus, the amount of food children eat, both observed and assessed by questionnaire, seems related to more maladaptive parenting practices in mothers. This pleads for more tailor-made guidelines when advising parents of children with eating- and weight problems.

The Daily Relation between Parental Rejection and Emotional Eating in Youngsters: A Diary Study.

KEY POINTS  Cross-sectional survey studies have demonstrated significant associations between parental rejection and peer rejection on the one hand and disturbed eating in youngsters, like emotional eating, on the other hand. In this study, we wanted to expand our knowledge on these relationships by investigating the daily fluctuations in these variables. Youngsters completed a 7-day diary to assess daily parental rejection, peer rejection and emotional eating. Using multilevel analyses, our results showed that daily variations in parental rejection were related to daily variations in emotional eating of the youngsters. This highlights the importance of addressing the parent-child relationship in interventions for emotional eating in youngsters. Background: This study investigated the daily relation between parental rejection and peer rejection on the one hand and emotional eating in youngsters on the other hand. Methods: Participants (N = 55) between the ages of 11 and 15 years completed a 7-day diary. A multilevel design was used to examine day-to-day within-person relationships between parental and peer rejection (measured by CHS) and emotional eating (measured by DEBQ-C) of youngsters. Results: The results showed that daily variations in parental rejection were related to daily variations in emotional eating of the youngsters. Daily peer rejection was only marginally significantly related to the emotional eating of the youngsters. Conclusions: These results indicate that especially parental rejection, and to a lesser extent peer rejection, are associated with the emotional eating of youngsters. The findings highlight the importance of addressing the parent-child relationship in interventions for emotional eating in youngsters.

Can we link emotional eating with the emotion regulation skills of adolescents?

OBJECTIVE: A recent cross-sectional study showed that maternal rejection is associated with emotional eating of obese youngsters seeking treatment, and that this relation is mediated by maladaptive emotion regulation (ER) of the youngsters. We wanted to build on this study and investigate the relation between parental rejection, maladaptive ER and emotional eating in a community sample using longitudinal data. DESIGN: Participants were 81 youngsters between the ages of 10 and 16 years. Participants completed questionnaires assessing maternal and paternal rejection, ER strategies and emotional eating, at two time moments (M = 71 days between time moments). Latent change models were used to estimate level and change of each variable. RESULTS: Results showed that the levels of maternal rejection, maladaptive ER and emotional eating were related. The indirect effect of the level of maternal rejection on the level of emotional eating through the level of maladaptive ER was marginally significant. On average, maternal rejection showed no change over time, whereas the other variables decreased. The changes in the variables were not related. CONCLUSION: The findings highlight the importance of assessing the emotional bond between mother and youngster and the ER of youngsters with an emotional eating style.