PMID- 31125083
OWN - NLM
STAT- MEDLINE
DCOM- 20200527
LR  - 20210109
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 104
IP  - 10
DP  - 2019 Oct 1
TI  - Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation 
      to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.
PG  - 4815-4826
LID - 10.1210/jc.2019-00183 [doi]
AB  - OBJECTIVE: We investigated potential interactions between body mass index (BMI) 
      and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and 
      FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults 
      (LADA) and type 2 diabetes. METHODS: We pooled data from two population-based 
      studies: (i) a Swedish study with incident cases of LADA [positive for glutamic 
      acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative 
      for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a 
      prospective Norwegian study that included incident cases of LADA (n = 131) and 
      type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were 
      adjusted for age, sex, physical activity, and smoking. Interaction between 
      overweight (BMI >/= 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed 
      by attributable proportion due to interaction (AP). RESULTS: The combination of 
      overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with 
      pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 
      1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared 
      with normal-weight individuals with low/intermediate genetic risk. There was a 
      significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 
      0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 
      to 0.61). The highest risk of LADA was seen in overweight individuals homozygous 
      for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 
      to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in 
      relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction 
      was observed with high-risk genotypes of HLA or FTO. CONCLUSIONS: Overweight 
      interacts with HLA high-risk genotypes but also with genes associated with type 2 
      diabetes in the promotion of LADA.
CI  - Copyright (c) 2019 Endocrine Society.
FAU - Hjort, Rebecka
AU  - Hjort R
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Lofvenborg, Josefin E
AU  - Lofvenborg JE
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Ahlqvist, Emma
AU  - Ahlqvist E
AD  - Department of Clinical Sciences in Malmo, Clinical Research Centre, Lund 
      University, Malmo, Sweden.
FAU - Alfredsson, Lars
AU  - Alfredsson L
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Andersson, Tomas
AU  - Andersson T
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
AD  - Center for Occupational and Environmental Medicine, Stockholm County Council, 
      Stockholm, Sweden.
FAU - Grill, Valdemar
AU  - Grill V
AD  - Department of Clinical and Molecular Medicine, NTNU, Norwegian University of 
      Science and Technology, Trondheim, Norway.
FAU - Groop, Leif
AU  - Groop L
AD  - Department of Clinical Sciences in Malmo, Clinical Research Centre, Lund 
      University, Malmo, Sweden.
AD  - Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland.
FAU - Sorgjerd, Elin P
AU  - Sorgjerd EP
AD  - HUNT Research Centre, Department of Public Health and Nursing, Norwegian 
      University of Science and Technology, Trondheim, Norway.
FAU - Tuomi, Tiinamaija
AU  - Tuomi T
AD  - Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland.
AD  - Division of Endocrinology, Abdominal Center, Helsinki University Hospital, 
      Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, 
      Finland.
AD  - Folkhalsan Research Center, Helsinki, Finland.
FAU - Asvold, Bjorn Olav
AU  - Asvold BO
AD  - Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, 
      Trondheim, Norway.
AD  - K.G. Jebsen Center for Genetic Epidemiology, NTNU, Department of Public Health 
      and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
FAU - Carlsson, Sofia
AU  - Carlsson S
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (HLA Antigens)
RN  - 0 (TCF7L2 protein, human)
RN  - 0 (Transcription Factor 7-Like 2 Protein)
RN  - EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
RN  - EC 1.14.11.33 (FTO protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics
MH  - Case-Control Studies
MH  - Diabetes Mellitus, Type 2/complications/epidemiology/*genetics
MH  - Female
MH  - Genetic Association Studies
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - HLA Antigens/*genetics
MH  - Humans
MH  - Incidence
MH  - Latent Autoimmune Diabetes in Adults/complications/epidemiology/*genetics
MH  - Male
MH  - Middle Aged
MH  - Norway/epidemiology
MH  - Overweight/complications/epidemiology/*genetics
MH  - Polymorphism, Single Nucleotide
MH  - Risk Factors
MH  - Sweden/epidemiology
MH  - Transcription Factor 7-Like 2 Protein/*genetics
PMC - PMC6735731
COIS- Author Contributions: All authors contributed to the interpretation of the 
      results and critically revised and approved the final version of the manuscript. 
      Contributions to the data collection was made by S.C., R.H., J.E.L. and T.A. 
      (ESTRID), L.A. (EIRA), L.G., E.A., T.T. (ANDIS), E.P.S., V.G. and B.O.A. (HUNT). 
      J.E.L. contributed to the data analysis. T.A. contributed with statistical 
      expertise. S.C. was responsible for the conceptualized research objectives and 
      designed the study and thoroughly revised the manuscript. R.H. developed the 
      objectives of the study and was responsible for drafting of the manuscript and 
      analyzing the data and takes full accountability for the accuracy of the analyses 
      and the work as a whole. The authors have nothing to disclose. Data 
      Availability: Restrictions apply to the availability of data generated or 
      analyzed during this study to preserve patient confidentiality or because they 
      were used under license. The corresponding author will on request detail the 
      restrictions and any conditions under which access to some data may be provided.
EDAT- 2019/05/28 06:00
MHDA- 2020/05/28 06:00
PMCR- 2020/05/24
CRDT- 2019/05/25 06:00
PHST- 2019/01/24 00:00 [received]
PHST- 2019/05/20 00:00 [accepted]
PHST- 2019/05/28 06:00 [pubmed]
PHST- 2020/05/28 06:00 [medline]
PHST- 2019/05/25 06:00 [entrez]
PHST- 2020/05/24 00:00 [pmc-release]
AID - 5497101 [pii]
AID - 201900183 [pii]
AID - 10.1210/jc.2019-00183 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2019 Oct 1;104(10):4815-4826. doi: 
      10.1210/jc.2019-00183.