Autoantibodies against ATP4A are a feature of the abundant autoimmunity that develops in first-degree relatives of patients with type 1 diabetes

Objective: Type 1 diabetes is associated with autoantibodies to different organs that include the gut. The objective of the study was to determine the risk of developing gastric parietal cell autoimmunity in relation to other autoimmunity in individuals with a family history of type 1 diabetes. Methods: Autoantibodies to the parietal cell autoantigen, H+/K+ ATPase subunit A (ATP4A) was measured in 2218 first-degree relatives of patients with type 1 diabetes, who were prospectively followed from birth for a median of 14.5 years. All were also tested regularly for the development of islet autoantibodies, transglutaminase autoantibodies, and thyroid peroxidase autoantibodies. Results: The cumulative risk to develop ATP4A autoantibodies was 8.1% (95% CI, 6.6–9.6) by age 20 years with a maximum incidence observed at age 2 years. Risk was increased in females (HR, 1.9; 95% CI, 1.3–2.8; p = 0.0004), relatives with the HLA DR4-DQ8/DR4-DQ8 genotype (HR, 3.4; 95% CI, 1.9–5.9; p < 0.0001) and in participants who also had thyroid peroxidase autoantibodies (HR, 3.7; 95% CI, 2.5– 5.5; p < 0.0001). Risk for at least one of ATP4A-, islet-, transglutaminase-, or thyroid peroxidase-autoantibodies was 24.7% (95% CI, 22.6–26.7) by age 20 years and was 47.3% (95% CI, 41.3–53.3) in relatives who had an HLA DR3/DR4-DQ8, DR4-DQ8/ DR4-DQ8, or DR3/DR3 genotype (p < 0.0001 vs. other genotypes). Conclusions: Relatives of patients with type 1 diabetes who have risk genotypes are at very high risk for the development of autoimmunity against gastric and other organs

Vitamin D insufficiency in infants with increased risk of developing type 1 diabetes: a secondary analysis of the POInT Study

Background Vitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines.Methods In the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4–7 months at high genetic risk of developing β-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4–7 months) until 3 years, with an interval of 2 months (first three visits) or 4–6 months (visits 4–8). The protocol actively promotes vitamin D sufficiency to optimise immune tolerance. VDI was defined as a concentration below 30 ng/mL and was treated according to local guidelines of participating centres. Recovery from VDI was defined as a concentration above or equal to 30 ng/mL on the subsequent visit after VDI.Results 1050 infants were included, of which 5937 vitamin D levels were available for analyses. VDI was observed in 1464 (24.7%) visits and 507 (46.1%) of these were not resolved at the next visit. The risk of having VDI was independently associated with season (higher in winter), weight (higher with increased weight), age (higher with increased age) and country (higher in England). The risk of not recovering from VDI was independently associated with the season of the previously determined VDI, which was higher if VDI was identified in winter.Conclusions VDI is frequent in infants with increased risk of developing T1D. Treatment guidelines for VDI do not seem effective. Increasing supplementation dosages in this patient population seems warranted, especially during winter, and increasing dosages more aggressively after VDI should be considered

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.status: publishe