Randi K. Johnson, Amanda J. Ireton, Patrick M. Carry, Lauren A. Vanderlinden, Fran Dong, Alex Romero, David R. Johnson, Debashis Ghosh, Fan Yang, Brigitte Frohnert, Ivana V. Yang, Katerina Kechris, Marian Rewers, Jill M. Norris
{"title":"DLGAP2附近DNA甲基化可能介导1型糖尿病家族史与1型糖尿病风险的关系","authors":"Randi K. Johnson, Amanda J. Ireton, Patrick M. Carry, Lauren A. Vanderlinden, Fran Dong, Alex Romero, David R. Johnson, Debashis Ghosh, Fan Yang, Brigitte Frohnert, Ivana V. Yang, Katerina Kechris, Marian Rewers, Jill M. Norris","doi":"10.1155/2023/5367637","DOIUrl":null,"url":null,"abstract":"Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case–control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated ( <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\"> <mi>P</mi> <mo><</mo> <mn>0.05</mn> </math> ) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences.","PeriodicalId":19797,"journal":{"name":"Pediatric Diabetes","volume":"24 1","pages":"0"},"PeriodicalIF":3.9000,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DNA Methylation Near DLGAP2 May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk\",\"authors\":\"Randi K. Johnson, Amanda J. Ireton, Patrick M. Carry, Lauren A. Vanderlinden, Fran Dong, Alex Romero, David R. Johnson, Debashis Ghosh, Fan Yang, Brigitte Frohnert, Ivana V. Yang, Katerina Kechris, Marian Rewers, Jill M. Norris\",\"doi\":\"10.1155/2023/5367637\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case–control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated ( <math xmlns=\\\"http://www.w3.org/1998/Math/MathML\\\" id=\\\"M1\\\"> <mi>P</mi> <mo><</mo> <mn>0.05</mn> </math> ) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences.\",\"PeriodicalId\":19797,\"journal\":{\"name\":\"Pediatric Diabetes\",\"volume\":\"24 1\",\"pages\":\"0\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2023-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pediatric Diabetes\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1155/2023/5367637\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pediatric Diabetes","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1155/2023/5367637","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
DNA Methylation Near DLGAP2 May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk
Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case–control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated ( ) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences.
期刊介绍:
Pediatric Diabetes is a bi-monthly journal devoted to disseminating new knowledge relating to the epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes in childhood and adolescence. The aim of the journal is to become the leading vehicle for international dissemination of research and practice relating to diabetes in youth. Papers are considered for publication based on the rigor of scientific approach, novelty, and importance for understanding mechanisms involved in the epidemiology and etiology of this disease, especially its molecular, biochemical and physiological aspects. Work relating to the clinical presentation, course, management and outcome of diabetes, including its physical and emotional sequelae, is considered. In vitro studies using animal or human tissues, whole animal and clinical studies in humans are also considered. The journal reviews full-length papers, preliminary communications with important new information, clinical reports, and reviews of major topics. Invited editorials, commentaries, and perspectives are a regular feature. The editors, based in the USA, Europe, and Australasia, maintain regular communications to assure rapid turnaround time of submitted manuscripts.