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diabetes\u2013associated 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 (\u22652) autoantibody positivity, in relatives of patients with type 1 diabetes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>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\u201345.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried \u22651 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>During follow-up (median 5.2 years, range 0.2\u201312.6), 62% of the single autoantibody\u2013positive 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\u2013positive participants (n = 158), those who carried \u22651 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 \u22651 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>The type 2 diabetes\u2013associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity\/overweight.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc18-0861","type":"journal-article","created":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T18:04:25Z","timestamp":1538417065000},"page":"2480-2486","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":34,"title":["Transcription Factor 7-Like 2 (<i>TCF7L2<\/i>) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes"],"prefix":"10.2337","volume":"41","clinical-trial-number":[{"clinical-trial-number":"nct00097292","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-4645","authenticated-orcid":false,"given":"Maria J.","family":"Redondo","sequence":"first","affiliation":[{"name":"Baylor College of Medicine, Texas Children\u2019s Hospital, Houston, 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