Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.
J Autoimmun
; 89: 90-100, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29310926
ABSTRACT
Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody one known region near SH2B3 (HRâ¯=â¯1.35, pâ¯=â¯3.58â¯×â¯10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HRâ¯=â¯1.46, pâ¯=â¯2.17â¯×â¯10-6) and one novel region near PPIL2 (HRâ¯=â¯2.47, pâ¯=â¯9.64â¯×â¯10-7) with suggestive evidence (pâ¯<â¯10-5). Two known regions (PTPN22 pâ¯=â¯2.25â¯×â¯10-6, INS; pâ¯=â¯1.32â¯×â¯10-7) and one novel region (PXK/PDHB pâ¯=â¯8.99â¯×â¯10-6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS pâ¯=â¯5.67â¯×â¯10-6 and TTC34/PRDM16 6.45â¯×â¯10-6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1 pâ¯=â¯8.02â¯×â¯10-6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS pâ¯=â¯3.13â¯×â¯10-7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42â¯×â¯10-6â¯>â¯pâ¯>â¯2.31â¯×â¯10-6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Islotes Pancreáticos
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Diabetes Mellitus Tipo 1
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Genotipo
Tipo de estudio:
Diagnostic_studies
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
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Prognostic_studies
/
Risk_factors_studies
Límite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
/
Newborn
Idioma:
En
Revista:
J Autoimmun
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos