The Prediction of Type 1 Diabetes in discordant and concordant families: 16 years of follow-up. Focus on the future

For 40 years, research continues to improve the forecasting methods and the development of effective and safe methods of preventing type 1 diabetes mellitus (T1DM).
Аim.
Prediction of the early preclinical stage of T1DM.
Materials and methods.
We studied the predisposing and protective haplotypes (HLA-DRB1, gene DQ) together with immunological markers (ICA, GADA, IAA) in 224 discordant/concordant families.
Results.
At the Endocrinology Research Centre, population and family risks of the development of T1DM in Russia were calculated on the basis of population genetic approaches. The analysis of the prevalence of HLA genotypes among T1DM patients revealed that the high-risk haplotypes in the structure of genotype(s) DQ2 and/or DQ8 in combination with the others were 78%: of these genotypes DQ2/DQ8, DQ2/DQ2, and DQ8/DQ8 accounted for 35%; DQ2/X* and DQ8/X* accounted for 43%; and the low-risk genotype Х*/Х* accounted for 22%. The genotype Х/Х consisted of weaker predisposing haplotypes that were specific to the Russian population in combination with neutral haplotypes or those consisting of neutral haplotypes only. The analysis of patients with T1DM genotypes revealed that high-risk genotypes (DQ2/DQ8) were more common in ill children up to the age of 5 (33% of cases) than in T1DM children over 10 years (23%) (p=0.05). Conversely, the low-risk genotypes were significantly less likely to be found in children with manifestations of diabetes up to 5 years than in sick people over 10 years [5% and 13%, respectively (p <0.05)]. This is consistent with hereditary load of diabetes manifestations in young children and with the earlier data. The 16-year prospective surveillance showed that the manifestation of the disease occurred in 8.4% of siblings. The analysis of the frequency of autoantibodies revealed that autoantibodies were identified the most reliably prior to the manifestation of the disease compared with T1DM patients in the initial period and healthy siblings (eldest siblings without the disease during the whole monitoring period): 90%, 48.6% and 31%, respectively, p <0.05.
Conclusion.
The 16-year prospective surveillance in families with T1DM showed that the frequency of recurring diabetes cases was 8.4%, which exceeds the siblings? rate of risk of 6.4% that had been empirically calculated 20 years ago. This may be due to an increase in the incidence of T1DM in the population and different methodological approaches (one-time screening versus long-term monitoring).

type 1 diabetes, genetic susceptibility, HLA-haplotypes, genotypes, phenotypes, autoantibodies to betbeta-cells

1. Дедов ИИ. Инновационные технологии в лечении и профилактике сахарного диабета и его осложнений. Сахарный диабет. 2013;(3):4–10. [Dedov II. Novel technologies for the treatment and prevention of diabetes mellitus and its complications. Diabetes mellitus. 2013;(3):4-10.] doi: 10.14341/2072-0351-811

2. IDF Diabetes Atlas. 6-th edition. 2013. Available from: http://www.idf.org/diabetesatlas

3. Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész 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

4. Dabelea D. The accelerating epidemic of childhood diabetes. Lancet. 2009;373(9680):1999-2000. doi: 10.1016/S0140-6736(09)60874-6

5. Atkinson MA. The Pathogenesis and Natural History of Type 1 Diabetes. ColdSpringHarbPerspectMed 2012;2(11):1-19. doi: 10.1101/cshperspect.a007641

6. Кураева ТЛ, Титович ЕВ, Прокофьев СА, Петеркова ВА. Генетические и иммунологические технологии определения риска развития сахарного диабета 1 типа. Перспективы предупреждения болезни. Пособие для врачей. Под редакцией академика РАН и РАМН И.И.Дедова. Москва 2011. 24 с. [Kuraeva TL, Titovich EV, Prokof'ev SA, Peterkova VA. Geneticheskie i immunologicheskie tekhnologii opredeleniya riska razvitiya sakharnogo diabeta 1 tipa. Perspektivy preduprezhdeniya bolezni. Posobie dlya vrachey. Edited by I.I.Dedov. Moscow; 2011. 24 p.]

7. Chern MM, Anderson VE, Barbosa J. Empirical risk for insulin-dependent diabetes (IDD) in sibs. Further definition of genetic heterogeneity. Diabetes. 1982;31(12):1115-1118.

8. Дедов ИИ, Кураева ТЛ, Титович ЕВ. Медико-генетическое консультирование и профилактика сахарного диабета 1 типа. Глава в книге: Сахарный диабет: диагностика, лечение, профилактика. Под редакцией Дедова ИИ, Шестаковой МВ. Москва: Медицинское информационное агентство; 2011. С. 281-307. [Dedov II, Kuraeva TL, Titovich EV. Mediko-geneticheskoe konsul'tirovanie i profilaktika sakharnogo diabeta 1 tipa. In: Dedov II, Shestakova MV, editors. Sakharnyy diabet: diagnostika, lechenie, profilaktika. Moscow: Medical news agency; 2011. P. 281-307.]

9. Fakhfakh R. Genetic Markers, Serological Auto Antibodies and Prediction of Type 1 Diabetes. In: Edited by Wagner D. Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy. InTech; 2011. doi: 10.5772/23889

10. Morran MP, Omenn GS, Pietropaolo M. Immunology and genetics of type 1 diabetes. Mt Sinai J Med. 2008;75(4):314-327. doi: 10.1002/msj.20052

11. Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK, et al. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure? Diabetologia. 2003;46(3):420-425. PMid:12687342

12. Fourlanos S, Harrison LC, Colman PG. The accelerator hypothesis and increasing incidence of type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2008;15(4):321-325. doi: 10.1097/MED.0b013e3283073a5a

13. Leslie RD. Predicting adult-onset autoimmune diabetes: clarity from complexity. Diabetes. 2010;59(2):330-331. doi: 10.2337/db09-1620