Maria J Redondo1, Andrea K Steck2, Jay Sosenko3, Mark Anderson4, Peter Antinozzi5, Aaron Michels2, John M Wentworth6, Mark A Atkinson7, Alberto Pugliese3, Susan Geyer8. 1. Baylor College of Medicine, Texas Children's Hospital, Houston, TX redondo@bcm.edu. 2. Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO. 3. University of Miami, Miami, FL. 4. University of California San Francisco, San Francisco, CA. 5. Wake Forest School of Medicine, Winston-Salem, NC. 6. Walter and Eliza Hall Institute and Royal Melbourne Hospital, Parkville, Australia. 7. University of Florida, Gainesville, FL. 8. University of South Florida, Tampa, FL.
Abstract
OBJECTIVE: The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. RESULTS: During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. CONCLUSIONS: The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.
OBJECTIVE: The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. RESULTS: During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obeseparticipants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. CONCLUSIONS: The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.
Authors: Jeffrey P Krischer; Kristian F Lynch; Desmond A Schatz; Jorma Ilonen; Åke Lernmark; William A Hagopian; Marian J Rewers; Jin-Xiong She; Olli G Simell; Jorma Toppari; Anette-G Ziegler; Beena Akolkar; Ezio Bonifacio Journal: Diabetologia Date: 2015-02-10 Impact factor: 10.122
Authors: Jay S Skyler; Carla J Greenbaum; John M Lachin; Ellen Leschek; Lisa Rafkin-Mervis; Peter Savage; Lisa Spain Journal: Ann N Y Acad Sci Date: 2008-12 Impact factor: 5.691
Authors: Maria J Redondo; Jesse Muniz; Luisa M Rodriguez; Dinakar Iyer; Fariba Vaziri-Sani; Morey W Haymond; Christiane S Hampe; Michael L Metzker; Struan F A Grant; Ashok Balasubramanyam Journal: BMJ Open Diabetes Res Care Date: 2014-04-06
Authors: Christine Therese Ferrara; Susan Michelle Geyer; Yuk-Fun Liu; Carmella Evans-Molina; Ingrid M Libman; Rachel Besser; Dorothy J Becker; Henry Rodriguez; Antoinette Moran; Stephen E Gitelman; Maria J Redondo Journal: Diabetes Care Date: 2017-02-15 Impact factor: 19.112
Authors: Jay S Skyler; George L Bakris; Ezio Bonifacio; Tamara Darsow; Robert H Eckel; Leif Groop; Per-Henrik Groop; Yehuda Handelsman; Richard A Insel; Chantal Mathieu; Allison T McElvaine; Jerry P Palmer; Alberto Pugliese; Desmond A Schatz; Jay M Sosenko; John P H Wilding; Robert E Ratner Journal: Diabetes Date: 2016-12-15 Impact factor: 9.461
Authors: Nicholas J Timpson; Cecilia M Lindgren; Michael N Weedon; Joshua Randall; Willem H Ouwehand; David P Strachan; N William Rayner; Mark Walker; Graham A Hitman; Alex S F Doney; Colin N A Palmer; Andrew D Morris; Andrew T Hattersley; Eleftheria Zeggini; Timothy M Frayling; Mark I McCarthy Journal: Diabetes Date: 2008-12-03 Impact factor: 9.461
Authors: Maria J Redondo; Susan Geyer; Andrea K Steck; Jay Sosenko; Mark Anderson; Peter Antinozzi; Aaron Michels; John Wentworth; Ping Xu; Alberto Pugliese Journal: Diabetes Care Date: 2017-10-12 Impact factor: 19.112
Authors: Manuela Battaglia; Simi Ahmed; Mark S Anderson; Mark A Atkinson; Dorothy Becker; Polly J Bingley; Emanuele Bosi; Todd M Brusko; Linda A DiMeglio; Carmella Evans-Molina; Stephen E Gitelman; Carla J Greenbaum; Peter A Gottlieb; Kevan C Herold; Martin J Hessner; Mikael Knip; Laura Jacobsen; Jeffrey P Krischer; S Alice Long; Markus Lundgren; Eoin F McKinney; Noel G Morgan; Richard A Oram; Tomi Pastinen; Michael C Peters; Alessandra Petrelli; Xiaoning Qian; Maria J Redondo; Bart O Roep; Desmond Schatz; David Skibinski; Mark Peakman Journal: Diabetes Care Date: 2019-11-21 Impact factor: 19.112
Authors: Christine Ferrara-Cook; Susan Michelle Geyer; Carmella Evans-Molina; Ingrid M Libman; Dorothy J Becker; Stephen E Gitelman; Maria Jose Redondo Journal: Diabetes Care Date: 2020-01-14 Impact factor: 19.112
Authors: Maria J Redondo; Carmella Evans-Molina; Andrea K Steck; Mark A Atkinson; Jay Sosenko Journal: Diabetes Care Date: 2019-06-04 Impact factor: 19.112
Authors: William T Cefalu; Dana K Andersen; Guillermo Arreaza-Rubín; Christopher L Pin; Sheryl Sato; C Bruce Verchere; Minna Woo; Norman D Rosenblum Journal: Diabetes Care Date: 2022-01-01 Impact factor: 17.152
Authors: Maria J Redondo; Brandon M Nathan; Laura M Jacobsen; Emily Sims; Laura E Bocchino; Alberto Pugliese; Desmond A Schatz; Mark A Atkinson; Jay Skyler; Jerry Palmer; Susan Geyer; Jay M Sosenko Journal: Diabetologia Date: 2021-01-26 Impact factor: 10.122