PMID- 28763444
OWN - NLM
STAT- MEDLINE
DCOM- 20170817
LR  - 20220311
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 14
IP  - 8
DP  - 2017 Aug
TI  - Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study.
PG  - e1002362
LID - 10.1371/journal.pmed.1002362 [doi]
LID - e1002362
AB  - BACKGROUND: The incidence of type 1 diabetes (T1D) is increasing globally. One 
      hypothesis is that increasing childhood obesity rates may explain part of this 
      increase, but, as T1D is rare, intervention studies are challenging to perform. 
      The aim of this study was to assess this hypothesis with a Mendelian 
      randomization approach that uses genetic variants as instrumental variables to 
      test for causal associations. METHODS AND FINDINGS: We created a genetic 
      instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood 
      adiposity in children aged 2-10 years. Summary-level association results for 
      these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a 
      meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 
      reference samples. Using inverse-variance weighted Mendelian randomization 
      analysis, we found support for an effect of childhood adiposity on T1D risk (odds 
      ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index 
      [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy 
      bias (p = 0.04) diluting the estimates towards the null. We therefore applied 
      Egger regression and multivariable Mendelian randomization methods to control for 
      this type of bias and found evidence in support of a role of childhood adiposity 
      in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of 
      our study include that underlying genes and their mechanisms for most of the 
      genetic variants included in the score are not known. Mendelian randomization 
      requires large sample sizes, and power was limited to provide precise estimates. 
      This research has been conducted using data from the Early Growth Genetics (EGG) 
      Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) 
      Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science 
      Genetic Association Consortium (SSGAC), as well as meta-analysis results from a 
      T1D genome-wide association study. CONCLUSIONS: This study provides genetic 
      support for a link between childhood adiposity and T1D risk. Together with 
      evidence from observational studies, our findings further emphasize the 
      importance of measures to reduce the global epidemic of childhood obesity and 
      encourage mechanistic studies.
FAU - Censin, J C
AU  - Censin JC
AUID- ORCID: 0000-0001-6625-6074
AD  - Department of Medical Sciences, Molecular Epidemiology and Science for Life 
      Laboratory, Uppsala University, Uppsala, Sweden.
FAU - Nowak, Christoph
AU  - Nowak C
AUID- ORCID: 0000-0001-8435-3978
AD  - Department of Medical Sciences, Molecular Epidemiology and Science for Life 
      Laboratory, Uppsala University, Uppsala, Sweden.
FAU - Cooper, Nicholas
AU  - Cooper N
AUID- ORCID: 0000-0003-0049-2204
AD  - Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation 
      Laboratory, Department of Medical Genetics, Cambridge Institute for Medical 
      Research, National Institute for Health Research Cambridge Biomedical Research 
      Centre, University of Cambridge, Cambridge, United Kingdom.
FAU - Bergsten, Peter
AU  - Bergsten P
AUID- ORCID: 0000-0002-4937-8464
AD  - Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
FAU - Todd, John A
AU  - Todd JA
AD  - Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation 
      Laboratory, Department of Medical Genetics, Cambridge Institute for Medical 
      Research, National Institute for Health Research Cambridge Biomedical Research 
      Centre, University of Cambridge, Cambridge, United Kingdom.
AD  - JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre 
      for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical 
      Research Centre, University of Oxford, Oxford, United Kingdom.
FAU - Fall, Tove
AU  - Fall T
AUID- ORCID: 0000-0003-2071-5866
AD  - Department of Medical Sciences, Molecular Epidemiology and Science for Life 
      Laboratory, Uppsala University, Uppsala, Sweden.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - U01 DK062418/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20170801
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
SB  - IM
MH  - Adiposity
MH  - Child
MH  - Child, Preschool
MH  - Diabetes Mellitus, Type 1/*epidemiology/*etiology/genetics
MH  - Europe/epidemiology
MH  - Female
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Male
MH  - *Mendelian Randomization Analysis
MH  - Odds Ratio
MH  - Pediatric Obesity/*complications/*epidemiology/genetics
MH  - Polymorphism, Single Nucleotide
MH  - Risk Factors
PMC - PMC5538636
COIS- The authors have declared that no competing interests exist.
EDAT- 2017/08/02 06:00
MHDA- 2017/08/18 06:00
PMCR- 2017/08/01
CRDT- 2017/08/02 06:00
PHST- 2016/11/30 00:00 [received]
PHST- 2017/06/19 00:00 [accepted]
PHST- 2017/08/02 06:00 [entrez]
PHST- 2017/08/02 06:00 [pubmed]
PHST- 2017/08/18 06:00 [medline]
PHST- 2017/08/01 00:00 [pmc-release]
AID - PMEDICINE-D-16-03850 [pii]
AID - 10.1371/journal.pmed.1002362 [doi]
PST - epublish
SO  - PLoS Med. 2017 Aug 1;14(8):e1002362. doi: 10.1371/journal.pmed.1002362. 
      eCollection 2017 Aug.