Browsing by Author "Akolkar, Beena"

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    Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures
    (Springer Nature, 2024-10-26) Eurén, Anna; Lynch, Kristian; Lindfors, Katri; Parikh, Hemang; Koletzko, Sibylle; Liu, Edwin; Akolkar, Beena; Hagopian, William; Krischer, Jeffrey; Rewers, Marian; Toppari, Jorma; Ziegler, Anette; Agardh, Daniel; Kurppa, Kalle; TEDDY Study Group; Pediatrics, School of Medicine
    Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March-August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3-6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease.
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    The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study
    (Oxford University Press, 2024-05-24) Warncke, Katharina; Tamura, Roy; Schatz, Desmond A.; Veijola, Riitta; Steck, Andrea K.; Akolkar, Beena; Hagopian, William; Krischer, Jeffrey P.; Lernmark, Åke; Rewers, Marian J.; Toppari, Jorma; McIndoe, Richard; Ziegler, Anette-G.; Vehik, Kendra; Haller, Michael J.; Elding Larsson, Helena; Pediatrics, School of Medicine
    Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results: Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion: Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.