Childhood vaccination and type 1 diabetes.

Danish Epidemiology Science Centre, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
New England Journal of Medicine (Impact Factor: 54.42). 05/2004; 350(14):1398-404. DOI: 10.1056/NEJMoa032665
Source: PubMed

ABSTRACT A link between childhood vaccinations and the development of type 1 diabetes has been proposed.
We evaluated a cohort comprising all children born in Denmark from January 1, 1990, through December 31, 2000, for whom detailed information on vaccinations and type 1 diabetes was available. Using Poisson regression models, we estimated rate ratios according to vaccination status, including the trend associated with the number of doses, among all children and in a subgroup of children who had siblings with type 1 diabetes. Given recent claims of clustering of cases of diabetes two to four years after vaccination, we also estimated rate ratios during the period after vaccination.
Type 1 diabetes was diagnosed in 681 children during 4,720,517 person-years of follow-up. The rate ratio for type 1 diabetes among children who received at least one dose of vaccine, as compared with unvaccinated children, was 0.91 (95 percent confidence interval, 0.74 to 1.12) for Haemophilus influenzae type b vaccine; 1.02 (95 percent confidence interval, 0.75 to 1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine; 0.96 (95 percent confidence interval, 0.71 to 1.30) for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine; 1.06 (95 percent confidence interval, 0.80 to 1.40) for whole-cell pertussis vaccine; 1.14 (95 percent confidence interval, 0.90 to 1.45) for measles, mumps, and rubella vaccine; and 1.08 (95 percent confidence interval, 0.74 to 1.57) for oral poliovirus vaccine. The development of type 1 diabetes in genetically predisposed children (defined as those who had siblings with type 1 diabetes) was not significantly associated with vaccination. Furthermore, there was no evidence of any clustering of cases two to four years after vaccination with any vaccine.
These results do not support a causal relation between childhood vaccination and type 1 diabetes.

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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. 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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.