Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes

Danièle Pacaud, Anita M Nucci, David Cuthbertson, Dorothy J Becker, Suvi M Virtanen, Johnny Ludvigsson, Jorma Ilonen, Mikael Knip, TRIGR investigators, Danièle Pacaud, Anita M Nucci, David Cuthbertson, Dorothy J Becker, Suvi M Virtanen, Johnny Ludvigsson, Jorma Ilonen, Mikael Knip, TRIGR investigators

Abstract

Aims/hypothesis: The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.

Methods: In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.

Results: Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity.

Conclusions/interpretation: The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.

Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract.

Keywords: Beta cell autoimmunity; Birthweight; Familial risk; Father; Genetic risk; Linear growth; Mother; Proband; Type 1 diabetes.

Figures

Fig. 1
Fig. 1
Time to presence of autoantibodies by family history (mother vs father vs sibling): multiple autoantibodies defined as two or more antibodies (logrank χ2 16.2, p < 0.001) (a); GADA as first antibody (logrank χ2 4.8, p = 0.090) (b); IAA as first antibody (logrank χ2 5.5, p = 0.064) (c); IA-2A as first antibody (logrank χ2 0.55, p = 0.761) (d); ZnT8A as first antibody (logrank χ2 0.6, p = 0.73) (e); and ICA as first antibody (logrank χ2 1.2, p = 0.55) (f)

References

    1. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care. 2000;23(10):1516–1526. doi: 10.2337/diacare.23.10.1516.
    1. Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G, EURODIAB Study Group Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027–2033. doi: 10.1016/S0140-6736(09)60568-7.
    1. Gale EAM. The rise of childhood type 1 diabetes in the 20th century. Diabetes. 2002;51(12):3353–3361. doi: 10.2337/diabetes.51.12.3353.
    1. Chen YL, Huang YC, Qiao YC, et al. Climates on incidence of childhood type 1 diabetes mellitus in 72 countries. Sci Rep. 2017;7(1):12810. doi: 10.1038/s41598-017-12954-8.
    1. Ludvigsson J. Increasing Incidence but decreasing awareness of type 1 diabetes in Sweden. Diabetes Care. 2017;40(10):e143–e144. doi: 10.2337/dc17-1175.
    1. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449–2462. doi: 10.1016/S0140-6736(18)31320-5.
    1. Gale EA, Gillespie KM. Diabetes and gender. Diabetologia. 2001;44(1):3–15. doi: 10.1007/s001250051573.
    1. Cardwell CR, Stene LC, Joner G, et al. Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data. Diabetologia. 2010;53(4):641–651. doi: 10.1007/s00125-009-1648-5.
    1. Stene LC, Magnus P, Lie RT, Sovik O, Joner G, Norwegian childhood Diabetes Study Group Birth weight and childhood onset type 1 diabetes: population based cohort study. BMJ. 2001;322(7291):889–892. doi: 10.1136/bmj.322.7291.889.
    1. Larsson HE, Lynch K, Lernmark B, et al. Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia. 2005;48(8):1484–1491. doi: 10.1007/s00125-005-1813-4.
    1. Couper JJ, Beresford S, Hirte C, et al. Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care. 2009;32(1):94–99. doi: 10.2337/dc08-0821.
    1. Lamb MM, Yin X, Zerbe GO, et al. Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia. 2009;52(10):2064–2071. doi: 10.1007/s00125-009-1428-2.
    1. Larsson HE, Hansson G, Carlsson A, et al. Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes. Diabetologia. 2008;51(9):1623–1630. doi: 10.1007/s00125-008-1074-0.
    1. Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK, Childhood Diabetes in Finland Study Group Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care. 2000;23(12):1755–1760. doi: 10.2337/diacare.23.12.1755.
    1. Krischer JP, Liu X, Lernmark A, et al. The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history on the progression from multiple autoantibodies to type 1 diabetes: a TEDDY study report. Diabetes. 2017;66(12):3122–3129. doi: 10.2337/db17-0261.
    1. Elding Larsson H, Vehik K, Haller MJ, et al. Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: The Environmental Determinants of Diabetes in the Young Study. Diabetes. 2016;65(7):1988–1995. doi: 10.2337/db15-1180.
    1. Krischer JP, Lynch KF, Lernmark A, et al. Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: The TEDDY study. Diabetes Care. 2017;40(9):1194–1202. doi: 10.2337/dc17-0238.
    1. TRIGR Study Group Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) Pediatr Diabetes. 2007;8(3):117–137. doi: 10.1111/j.1399-5448.2007.00239.x.
    1. Knip M, Akerblom HK, Becker D, et al. Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311(22):2279–2287. doi: 10.1001/jama.2014.5610.
    1. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC Growth charts for the United States: methods and development. Vital Health Stat. 2002;11(246):1–190.
    1. Knip M, Virtanen SM, Seppa K, et al. Dietary intervention in infancy and later signs of β-cell autoimmunity. N Engl J Med. 2010;363(20):1900–1908. doi: 10.1056/NEJMoa1004809.
    1. Turtinen M, Harkonen T, Parkkola A, Ilonen J, Knip M, Finnish Pediatric Diabetes Register Sex as a determinant of type 1 diabetes at diagnosis. Pediatr Diabetes. 2018;19(7):1221–1228. doi: 10.1111/pedi.12697.
    1. Yu L, Chase HP, Falorni A, Rewers M, Lernmark A, Eisenbarth GS. Sexual dimorphism in transmission of expression of islet autoantibodies to offspring. Diabetologia. 1995;38(11):1353–1357. doi: 10.1007/bf00401769.
    1. Hippich M, Beyerlein A, Hagopian WA, et al. Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families. Diabetes. 2019;68(4):847–857. doi: 10.2337/db18-0882.
    1. Bonifacio E, Pfluger M, Marienfeld S, Winkler C, Hummel M, Ziegler AG. Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c) Diabetologia. 2008;51(7):1245–1252. doi: 10.1007/s00125-008-1022-z.
    1. Roll U, Christie MR, Fuchtenbusch M, Payton MA, Hawkes CJ, Ziegler AG. Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes. 1996;45(7):967–973. doi: 10.2337/diab.45.7.967.
    1. Ilonen J, Hammais A, Laine AP, et al. Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life. Diabetes. 2013;62(10):3636–3640. doi: 10.2337/db13-0300.
    1. Wilkin TJ (2001) The accelerator hypothesis: weight gain as the missing link between type 1 and type 11 diabetes. Diabetologia 44:914–922
    1. Johansson C, Samuelsson U, Ludvigsson J. A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1994;37(1):91–94. doi: 10.1007/BF00428783.
    1. Liu X, Vehik K, Huang Y, et al. Distinct growth phases in early life associated with the risk of type 1 diabetes: the TEDDY study. Diabetes Care. 2020;43(3):556–562. doi: 10.2337/dc19-1670.
    1. Nucci AM, Becker DJ, Virtanen SM, et al. Growth differences between North American and European children at risk for type 1 diabetes. Pediatr Diabetes. 2012;13(5):425–431. doi: 10.1111/j.1399-5448.2011.00840.x.
    1. Writing Group for the TRIGR Study Group. Knip M, Akerblom HK, et al. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. JAMA. 2018;319(1):38–48. doi: 10.1001/jama.2017.19826.
    1. Krischer JP, Liu X, Vehik K, et al. Predicting islet cell autoimmunity and type 1 diabetes: an 8-year TEDDY study progress report. Diabetes Care. 2019;42(6):1051–1060. doi: 10.2337/dc18-2282.

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