Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland

Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.Väitöstyön tarkoituksena oli tutkia tyypin 1 diabeteksen (T1D) sekä diabeettisen nefropatian (DN) kasautumista perheissä. Ensimmäisen osatyön tavoitteena oli tutkia monotsygoottisten että ditsygoottisten kaksosten konkordanssia T1D:n suhteen sekä määrittää geneettisten tekijöiden ja ympäristötekijöiden suhteellista osuutta T1D:n synnyssä. Toisen osatyön tarkoitus oli määrittää T1D:sta sairastavien sisarusten kumulatiivinen sairastumisriski T1D:een pitkän seuranta-ajan kuluessa. Tavoitteena oli myös selvittää riskiin vaikuttavia tekijöitä, erityisesti indeksipotilaan (probandin) sairastumisiän vaikutusta sekä eri syntymäkohorttien välisiä eroja. Kolmannen osatyön päämääränä oli tutkia, onko perheen toisella diabeetikkosisaruksella kohonnut riski sairastua diabeettiseen nefropatiaan, jos aiemmin sairastuneella sisaruksella on jo todettu tämä tauti. Tarkoituksena oli myös selvittää, vaikuttaako diabeettisen nefropatian vaikeusaste (dialyysi ja munuaisensiirto) sisarusriskiin sekä sitä, onko diabetekseen sairastumisiällä vaikutusta nefropatiariskiin. Viimeisessä osatyön tarkoitus oli tutkia T1D:ta sairastavien henkilöiden lasten diabetesriskiä longitudinaalisesti ja sitä, eroaako diabeetikkomiesten ja -naisten lasten diabetesriski. Lisäksi tutkittiin, vaikuttaako diabeetikkovanhemman sairastumisikä lapsen riskiin ja erityisesti, onko sairastumisiän vaikutus samanlainen sekä diabeetikkomiesten että diabeetikkonaisten lapsilla. Myös lasten syntymäkohortin vaikutusta tutkittiin. Kolme laajaa, väestöpohjaista aineistoa oli käytössä. Ensimmäinen aineisto sisälsi kaikki Suomessa vuosina 1958-86 syntyneet kaksosparit (nuorten kaksosten kohortti, n=22646 paria)). Toinen aineisto koostui vuosina 1965-79 T1D:een alle 18-vuotiaina sairastuneista diabeetikoista (n=5144) ja heidän sisaruksistaan (n=10168) ja kolmas aineisto koostui em. diabeetikoista ja heidän lapsistaan (n=5291). Monotsygoottisista kaksospareista 27.3 % oli konkordantteja T1D:n suhteen (molemmilla T1D), kun taas ditsygoottisista kaksospareista vain 3.8 %. Rakenneyhtälömallituksessa parhaiten sopiva malli selitti sairastumiseen liittyvää vaihtelua sekä geneettisin että yksilöllisin ympäristötekijöin ja heritabiliteetin estimaatiksi saatiin 88 %. Identtiset kaksoset sairastuivat hyvin samanikäisinä. Pisin sairastumisväli identtisillä konkordanteilla pareilla oli 6.9 vuotta. Identtisten kaksosparien sairastumisiän korrelaatio oli 0.95, kun se epäidenttisillä kaksospareilla oli 0.43. Diabeetikkojen sisarusten pitkä seuranta osoitti, että T1D:n kumulatiivinen riski 50 ikävuoteen mennessä oli 6.9 %. Riskiin vaikutti kuitenkin hyvin voimakkaasti probandin sairastumisikä. Jos probandi oli sairastunut 0-4, 5-9, 10-14 tai yli 15-vuotiaana, 40 ikävuoden kumulatiivinen riski sisaruksilla oli vastaavasti 13.2, 7.8, 4.7 ja 3.4 %. Mitä myöhäisempään syntymäkohorttiin sisarus kuului, sitä suurempi oli kumulatiivinen riski. Kuitenkin, sisarusten ja taustaväestön ilmaantuvuuksien välinen standardisoitu ilmaantuvuussuhde (SIR) oli noin 12 koko seurantajakson ajan. Perheessä myöhemmin T1D:een sairastuneella sisaruksella oli 2.3-kertainen riski sairastua DN:aan, jos ensiksi T1D:een sairastuneella oli DN. Jos probandilla oli loppuvaiheen munuaistauti (dialyysi, munuaissiirre), riski kasvoi kolminkertaiseksi. Diabetekseen sairastumisikä vaikutti riskiin siten, että suurin riski oli henkilöillä, jotka olivat sairastuneet murrosiässä tai joitakin vuosia ennen murrosikää. T1D:ta sairastavien miesten lasten kumulatiivinen riski sairastua T1D:een oli 20 ikävuoteen mennessä 7.8 %, kun taas diabeetikkonaisten lasten riski oli 5.3 %. Kaiken kaikkiaan diabeetikkomiesten lasten sairastumisriski oli 1.7-kertainen diabeetikkonaisten lasten riskiin verrattuna. Kun miesdiabeetikkojen lasten riski kasvoi sitä suuremmaksi, mitä nuorempana miesdiabeetikko oli diagnosoitu, naisdiabeetikkojen sairastumisiällä ei ollut vaikutusta lasten sairastumisriskiin. Lasten ja taustaväestön ilmaantuvuuksien välinen SIR oli noin 10 koko seurantajakson ajan, mutta kumulatiivinen riski oli sitä suurempi, mitä nuorempi syntymäkohortti oli kyseessä

Tyypin 1 diabetes ja muut autoimmuunisairaudet

Vertaisarvioitu.Joka viidennellä tyypin 1 diabetesta sairastavalla on vähintään toinen muu autoimmuunisairaus, ja sairastuvuus autoimmuunitauteihin on moninkertainen muuhun väestöön verrattuna. Lapsuusiän jälkeen tyypin 1 diabetekseen sairastuneiden, naispuolisten ja iäkkäiden kilpirauhasen vajaatoiminnan riski on suurin, kun taas keliakia puhkeaa diabetekseen sairastuneille useammin alle kymmenvuotiaana. Syitä autoimmuunisairauksien kasautumisesta samoille yksilöille ei tunneta riittävästi. Kyseessä on monisyinen tapahtumaketju, johon liittyvät perimä, puolustusjärjestelmän toiminta ja ulkoiset tekijät. Uudet solubiologian tutkimusmenetelmät yhdessä kliinisten ja epidemiologisten tutkimusten kanssa lisäävät tietoa, jota tarvitaan autoimmuunisairauksien ennustamiseen, taudinkuvan lievittymiseen tai parhaimmillaan sairastumisen ehkäisemiseen. Sitä odotellessa on tarpeen seuloa autoimmuunisairauksia Diabeteksen Käypä hoito -suosituksen mukaisesti ja kliinisten oireiden perusteella.Peer reviewe

Exercise and nutrition in type 1 diabetes : Insights from the FinnDiane cohort

Type 1 diabetes is a challenging disease, characterized by dynamic changes in the insulin need during life periods, seasons of the year, but also by everyday situations. In particular, changes in insulin need are evident before, during and after exercise and having meals. In the midst of different life demands, it can be very burdensome to achieve tight glycemic control to prevent late diabetes complications, and at the same time, to avoid hypoglycemia. Consequently, many individuals with type 1 diabetes are faced with diabetes distress, decreasing profoundly their quality of life. Today, the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study, launched in 1997, has gathered data from more than 8,000 well-characterized individuals with type 1 diabetes, recruited from 93 centers all over Finland and has established its position as the world's leading project on studying complications in individuals with type 1 diabetes. Studying risk factors and mechanisms of diabetes complications is inconceivable without trying to understand the effects of exercise and nutrition on glycemic control and the development of diabetes complications. Therefore, in this paper we provide findings regarding food and exercise, accumulated during the 25 years of studying lives of Finnish people with type 1 diabetes.Peer reviewe

Long-term population-based trends in the incidence of cardiovascular disease in individuals with type 1 diabetes from Finland : a retrospective, nationwide, cohort study

Background Cardiovascular disease is the main determinant of premature mortality in patients with type 1 diabetes. However, time trends regarding different types of cardiovascular disease in childhood-onset type 1 diabetes with a long timespan from the diagnosis of diabetes are not well established. This study aimed to investigate the cumulative incidence of cardiovascular disease in individuals with type 1 diabetes in a population-based cohort in Finland, the country with the world's highest incidence of type 1 diabetes. Methods In this retrospective, nationwide registry-based, cohort study, all patients who were diagnosed between Jan 1, 1965, and Dec 31, 1999 with type 1 diabetes when they were younger than 15 years old in Finland were followed up and monitored for the occurrence of cardiovascular disease (including coronary artery disease, stroke, peripheral artery disease, and heart failure) until the end of 2016 and for cardiovascular disease mortality until 2017. Cumulative incidences of cardiovascular disease were calculated by the Fine and Gray method according to the year of diabetes diagnosis using six diagnosis cohorts: 1965-69, 1970-74, 1975-1979, 1980-84, 1985-89, 1990-94, and 1990-95. Trends in cardiovascular disease event rates were analysed by Fine and Gray competing risks regression models using year of diabetes diagnosis as continuous variable. In addition, non-linearity in trends was assessed with restricted cubic splines. The excess risk of coronary artery disease and stroke was estimated by comparison with the risk in the Finnish general population by calculating standardised incidence ratios (SIRs) and their time trends. The data for Finnish general population were drawn from the Cardiovascular Disease Register of the National Institute of Health and Welfare. The SIRs were calculated as ratios of observed and expected number of events in individuals with type 1 diabetes during 1991-2014. Findings 11 766 individuals were included in this study. During 361 033 person-years of follow-up and a median of 29.6 years (IQR 22.3-37.9) follow-up, a total of 1761 individuals had single or multiple types of cardiovascular disease events. 2686 events (864 [32.2%] coronary artery disease events, of which 663 were acute myocardial infarctions; 497 [18.5%] strokes; 854 [31.8%] peripheral artery diseases, of which 498 were lower extremity amputations; and 471 [17.5%] heart failure events) were reported until Dec 31, 2016, and 1467 deaths until Dec 31, 2017. Cardiovascular disease risk decreased linearly by 3.8% (hazard ratio [HR] 0.96 [95% CI 0.96-0.97]; p Interpretation The risk of cardiovascular disease has decreased over time in Finland in individuals with childhood onset type 1 diabetes. However, there is still considerable excess cardiovascular disease risk in individuals with type 1 diabetes compared with the general population. These results highlight the need for studies on the mechanisms of atherosclerosis from the time of diagnosis of type 1 diabetes to facilitate early and effective prevention of cardiovascular disease in these individuals. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Peer reviewe

Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study

Objective To examine short and long term time trends in mortality among patients with early onset (age 0-14 years) and late onset (15-29 years) type 1 diabetes and causes of deaths over time

The Association of Severe Diabetic Retinopathy With Cardiovascular Outcomes in Long-standing Type 1 Diabetes : A Longitudinal Follow-up. Diabetes Care 2018;41:2487-2494 Response

Non peer reviewe

Perceived Stress and Adherence to the Dietary Recommendations and Blood Glucose Levels in Type 1 Diabetes

Stress may negatively impact self-management of diabetes and thereby deteriorate glycaemic control. Eating is the most frequently reported stress-release method. In this study, we investigated the association between perceived stress (PS), dietary adherence, and glycaemic control. Data from participants in the FinnDiane Study with type 1 diabetes who had completed a diet questionnaire and Cohen's perceived stress scale (PSS) were included. In addition to using a continuous PSS score, participants were divided into three groups based on the PSS scores: the first PSS quartile, low levels of PS; second and third quartiles, moderate levels of PS; and fourth quartile, high levels of PS. A diet score reflecting the level of adherence to dietary recommendations was calculated. Analyses were conducted in the whole sample and in subgroups divided by body mass index (BMI = 25 kg/m(2)). In the whole sample, high PS and continuous stress score were negatively associated with the diet score and with adherence to fish, fresh vegetable, low-fat liquid milk product, and vegetable oil-based cooking fat recommendations. The stress score was negatively associated with the diet score both in lean and in those overweight or obese. However, fish and fresh vegetable recommendations were only affected in those with corpulence. PS was not associated with mean blood glucose concentrations in the whole sample. When divided by BMI status, worse glycaemic control was observed in lean subjects reporting stress. In individuals with overweight or obesity, instead, high glucose concentrations were observed regardless of the level of perceived stress. Interventions to improve stress management could improve dietary adherence and glycaemic control and could thereby have the potential to improve long-term health and well-being of individuals with type 1 diabetes.Peer reviewe

Waist-Height Ratio and the Risk of Severe Diabetic Eye Disease in Type 1 Diabetes : A 15-Year Cohort Study

Context: Obesity prevalence has increased in type 1 diabetes (T1D). However, the relationship between body composition and severe diabetic eye disease (SDED) is unknown. Objective: To investigate the associations between body composition and SDED in adults with T1D. Methods: From 5401 adults with T1D in the Finnish Diabetic Nephropathy Study, we assessed 3468, and 437 underwent dual-energy X-ray absorptiometry for body composition analysis. The composite outcome was SDED, defined as proliferative retinopathy, laser treatment, antivascular endothelial growth factor treatment, diabetic maculopathy, vitreous hemorrhage, and vitrectomy. Logistic regression analysis evaluated the associations between body composition and SDED. Multivariable Cox regression analysis assessed the associations between the anthropometric measures and SDED. Subgroup analysis was performed by stages of albuminuria. The relevance ranking of each variable was based on the z statistic. Results: During a median follow-up of 14.5 (interquartile range 7.8-17.5) years, 886 SDED events occurred. Visceral/android fat ratio was associated with SDED [odds ratio (OR) 1.40, z = 3.13], as well as the percentages of visceral (OR 1.80, z = 2.45) and android fat (OR 1.28, z = 2.08) but not the total body fat percentage. Waist-height ratio (WHtR) showed the strongest association with the SDED risk [hazard ratio (HR) = 1.28, z= 3.73], followed by the waist (HR 1.01, z = 3.03), body mass index (HR 1.03, z = 2.33), and waist-hip ratio (HR 1.15, z= 2.22).The results were similar in normo- and microalbuminuria but not significant in macroalbuminuria. A WHtR >= 0.5 increased the SDED risk by 28% at the normo- and microalbuminuria stages. Conclusions: WHtR, a hallmark of central obesity, is associated with SDED in individuals with T1D.Peer reviewe