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subjects with type 1 diabetes were from the australian type 1 diabetes dna repository ( 11,12 ) .
they had been diagnosed by a specialist physician on the basis of hyperglycemia requiring immediate and ongoing insulin therapy .
all subjects were of european descent and lived in metropolitan melbourne or the wider state of victoria .
they were recruited in an unselected manner from diabetes clinics , including the royal children 's hospital , which until recently followed up the majority of children and teenagers with type 1 diabetes in victoria .
virtually all individuals with type 1 diabetes in victoria attend diabetes clinics or are seen by specialists with attachments to these clinics .
subjects ( n = 462 ) diagnosed before 18 years of age between 1950 and 2005 ( 91% after 1975 ) were typed for hla - drb1 alleles .
hla - drb1 genotyping was performed by pcr - based sequence - specific oligonucleotide hybridization , modified from the 11th international histocompatibility workshop protocol to accommodate subsequently described sequence polymorphisms ( 13 ) .
briefly , pcr primers were designed to provide either generic or allele - specific amplification of exon 2 of the drb1 allele .
the pcr - amplified dna was rendered single stranded by exposure to sodium hydroxide , immobilized onto nylon membranes , and hybridized with biotinylated oligonucleotide probes designed to detect sequence polymorphisms between drb1 alleles .
stringent washing was performed in the presence of 3 mol / l tetramethylammonium chloride and the hybridized product detected using a streptavidin / alkaline phosphatase conjugate and chemiluminescent substrate cdp - star ( roche diagnostics , castle hill , nsw , australia ) .
allele assignments were made by comparing patterns of hybridization to those predicted from published sequences .
subjects were grouped by decade of birth or diagnosis ( 19501969 , combined due to small numbers ; 19701979 ; 19801989 ; 19901999 ; and 20002005 ) and from the highest ( dr3,4 ) to intermediate ( dr3,3 or dr4,4 ; dr4,x or dr3,x ) to the lowest ( drx , x , where x denotes a non-3 or non-4 allele ) hla genotypes for type 1 diabetes risk .
statistics were performed with graphpad prism version 3.0 software ( la jolla , ca ) .
hla - drb1 genotyping was performed by pcr - based sequence - specific oligonucleotide hybridization , modified from the 11th international histocompatibility workshop protocol to accommodate subsequently described sequence polymorphisms ( 13 ) .
briefly , pcr primers were designed to provide either generic or allele - specific amplification of exon 2 of the drb1 allele .
the pcr - amplified dna was rendered single stranded by exposure to sodium hydroxide , immobilized onto nylon membranes , and hybridized with biotinylated oligonucleotide probes designed to detect sequence polymorphisms between drb1 alleles .
stringent washing was performed in the presence of 3 mol / l tetramethylammonium chloride and the hybridized product detected using a streptavidin / alkaline phosphatase conjugate and chemiluminescent substrate cdp - star ( roche diagnostics , castle hill , nsw , australia ) .
allele assignments were made by comparing patterns of hybridization to those predicted from published sequences .
subjects were grouped by decade of birth or diagnosis ( 19501969 , combined due to small numbers ; 19701979 ; 19801989 ; 19901999 ; and 20002005 ) and from the highest ( dr3,4 ) to intermediate ( dr3,3 or dr4,4 ; dr4,x or dr3,x ) to the lowest ( drx , x , where x denotes a non-3 or non-4 allele ) hla genotypes for type 1 diabetes risk .
statistics were performed with graphpad prism version 3.0 software ( la jolla , ca ) .
the mean age at diagnosis of the total cohort of type 1 diabetes subjects was ( means  sd ) 8.5  4.5 years , and this did not differ across decades of diagnosis ( p = 0.54 , anova ) .
the proportion of the highest - risk genotype , dr3,4 , decreased significantly over time from 79% in 19501969 to 28% in 20002005 ( p < 0.0001 ) ( table 1 ) ( fig .
on the other hand , the proportion of the heterozygous intermediate - risk genotypes , dr4,x and dr3,x , increased significantly over this period ( table 1 ) ; taken together , they increased from 20 to 48% ( p = 0.0002 ) ( fig .
homozygosity for dr4 , but not dr3 , increased over time , and the lowest - risk genotype , drx , x , was consistently low ( 3% ) ( table 1 ) . matched for drb1 genotype and decade of birth ,
there was no change across time in age at diagnosis for the high - risk dr3,4 genotype , but for the intermediate risk genotypes ( dr4,4 ; dr3,3 ; dr4,x ; and dr3,x ) age at diagnosis decreased over time ( fig .
the incidence of childhood - onset type 1 diabetes in australia has doubled in the last 20 years , from 11.3 cases per 100,000 person - years in 1985 to 23.2 in 2002 ( 14 ) . on the assumption that the drb1 genotype frequencies were representative of the total population of individuals with type 1 diabetes , the contribution of drb1 genotypes to the increasing incidence of type 1 diabetes was examined .
the numbers of incident cases ( rev . in 14 ) were related to specific drb1 genotype proportions .
as shown in table 2 , the population incidence of type 1 diabetes in subjects with the highest - risk genotype ( dr3,4 ) has remained unchanged .
in contrast , the number of cases with intermediate - risk genotypes ( dr3,3 or dr4,4 and dr3,x or dr4,x ) has increased , accounting for the increase in disease incidence .
hla class ii profiling demonstrates that the genetic contribution in individuals diagnosed with type 1 diabetes has changed over the last five decades . the contemporary increase in disease incidence
is accounted for by individuals with lower - risk hla class ii genotypes who , in previous eras , would not have developed diabetes in childhood .
it would appear , therefore , that changing environmental conditions have increased the penetrance of these lower - risk genotypes .
our findings are similar to those reported in the northern hemisphere ( 6,7 ) but are more likely to be free of selection bias based on survival , as 91% of our subjects were diagnosed after 1975 .
subjects were unselected and predominantly of european anglo - celtic origin , with no change over the decades to suggest dilution by immigrants of other ethnic backgrounds .
nevertheless , the possibility that they were not entirely representative of the total population of individuals with type 1 diabetes across the decades remains a potential limitation . with this caveat , environmental conditions operating in both hemispheres therefore appear to be permissive for the increasing incidence of type 1 diabetes among individuals without the classic high - risk dr3,4 genotype .
furthermore , the mean age at diagnosis has decreased in children with lower - risk genotypes , representing further evidence for the impact of environment .
the temporal change in the genetic contribution to type 1 diabetes raises several points for discussion .
first , studies of type 1 diabetes may need to consider stratification by year of birth and diagnosis to dissect the relative influences of genes and environment .
this concept is also more broadly relevant to other human diseases in which polygenetic susceptibility and environment interact .
second , the hla profile of classic , childhood - onset type 1 diabetes has shifted and is now similar to that of adults with autoimmune diabetes , who are characterized as having lower - risk hla genes ( 15,16 ) .
however , adults diagnosed today with autoimmune diabetes were born > 30 years ago when the contribution of environment was presumably much less .
third , it appears that the shift in the distribution of hla genotypes began in the 1980s .
a variety of environmental factors including infectious exposure in early life , the quantity and composition of food intake , and the amount of exercise and sleep ( with concomitant obesity ) have been implicated in promoting the rising incidence of type 1 diabetes . since the 1980s , the incidence of type 1 diabetes in australia has more then doubled ( 14 ) .
a change in individuals diagnosed in the 1980s could reflect the impact of environmental factors acting in early life in the 1970s .
two candidate factors may be worthy of comment . first , up until the mid-1970s newborns in victorian hospitals were housed together in nurseries for up to a week , but this practice ceased when the high prevalence of diarrhea associated with rotavirus infection was found to be significantly reduced by  rooming - in  with the mother ( 17 )
. the possibility that rotavirus infection in the neonate could protect against type 1 diabetes is supported by findings in the nonobese diabetic ( nod ) mouse model of the disease ( 18 ) ; interestingly , though , rotavirus infection postweaning in the nod mouse did not protect but rather increased disease incidence ( 18 ) .
the latter result is consistent with our finding in children followed longitudinally in whom rotavirus infection was positively associated with evidence of islet autoimmunity ( 19 ) .
second , the prevalence of obesity , and presumably insulin resistance , in australian children began to accelerate in the 1970s ( 20 ) .
we have shown that insulin resistance is an independent risk factor for development of type 1 diabetes in children with islet autoimmunity ( 21 ) .
therefore , insulin resistance promoted by changing environmental conditions may contribute to the pathogenesis and rising incidence of type 1 , as well as type 2 , diabetes .
the stable incidence of dr3,4 across time suggests that this genotype is resistant to the influence of environment .
one interpretation is that adaptive t - cell  mediated immunity responsible for -cell destruction is optimal with dr3,4 but not with lower - risk genotypes .
however , the latter can be complemented by innate immunity promoted ( together with insulin resistance ) by a proinflammatory environment ( 22 ) .
our findings illustrate that the contribution of hla genes to type 1 diabetes has changed but not lessened over time . indeed , genetic susceptibility to type 1 diabetes is no less relevant as more individuals fall under the shadow of a
objective  the rising incidence of type 1 diabetes has been attributed to environment , implying a lesser role for genetic susceptibility . 
 however , the rise could be accounted for by either more cases with classic high - risk genes or by cases with other risk genes . separately , for any degree of genetic susceptibility , age at presentation may decrease in a permissive environment . to examine these possibilities , human leukocyte antigen ( hla ) class ii drb1 genes known to confer risk for type 1 
 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades.research design and methods  caucasoid subjects ( n = 462 ) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were drb1 genotyped.resultsmean  sd age at diagnosis , 8.5  4.5 years , did not differ across decades . 
 recent diagnosis was associated with a lower proportion but unchanged incidence of the highest - risk drb1 genotype dr3,4 ( 20002005 , 28% vs. 19501969 , 79% ; p < 0.0001 ) and a higher proportion of lower - risk genotypes dr4,x and dr3,x ( 20002005 , 48% vs. 19501969 , 20% ; p = 0.0002 ) . 
 the frequency of the drx , x genotype was low ( 3% ) across decades . 
 recent birth was associated with a lower age at diagnosis for lower risk dr3,3 and dr4,4 ( p < 0.0001 ) and dr4,x ( p 
 < 0.0001 ) and dr3,x ( p = 0.015 ) genotypes but not for dr3,4.conclusions  the rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower - risk hla class ii genes , who previously would not have developed type 1 diabetes in childhood .