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The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes
Research Letters
The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes Kathleen M Gillespie,Steven C Bain, Anthony H Barnett, Polly J Bingley,Michael R Christie, Geoffrey V Gill, Edwin A M Gale
Lancet 2004; 364: 1699–700 See Comment page 1645
The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0·003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect. The incidence of childhood onset type 1 diabetes increased worldwide during the second half of the 20th century, with an especially rapid rise in those diagnosed when younger than 5 years.1 The major genetic contribution to susceptibility derives from a hierarchy of HLA haplotypes ranging from susceptible to protective. Age at onset is inversely related to the proportion of HLA high-risk susceptibility haplotypes, and young children with type 1 diabetes show the greatest HLA-associated genetic risk. Since the rise in incidence is too rapid to be explained by increased transmission of susceptibility haplotypes from one generation to the next, changing environmental factors are probably important. The threshold model of genetic liability2 predicts that exposure of a population with similar genetic characteristics to a more permissive environment (ie, an environment that is more conducive to the development of diabetes) will result in a progressive dilution of HLA-associated genetic susceptibility. We aimed to test this hypothesis. People who survive 50 years of diabetes in the UK can be nominated for the Nabarro medal awarded by the charity Diabetes UK. A cohort of medal winners with childhood onset diabetes formed our study group, and the comparison group was taken from a current population-based study in the Oxford region of the UK.3 The Bart’s-Oxford (BOX) Study is a prospective population-based family study, which since 1985 has recruited more than 90% of children who developed type 1 diabetes under age 21 years in the former Oxford health authority region. The Golden Years cohort4 was recruited from a nationwide register of individuals who had been awarded 50-year medals by Diabetes UK. Genetic samples were available from 194 medal-winners (52% male) diagnosed when aged younger than 15 years between 1922 and 1946. These individuals were randomly assigned three controls, matched for sex and age at diagnosis, in 1-year bands, from among 1150 BOX study probands diagnosed between 1985 and 2002. Participants in both studies gave oral or written consent for collection and analysis of genetic material, and both studies were submitted to and approved by the appropriate ethics committees. Specific consent for this study was not sought since the material was collected and analysed according to protocols for which consent www.thelancet.com Vol 364 November 6, 2004
had been given, and the data analysis was fully anonymised. HLA class II typing for DRB1, DQA1, and DQB1 was undertaken on DNA from blood or mouth swab samples.4,5 Haplotypes in diabetic probands were subdivided according to age at onset, and conditional logistic regression was done to account for matching in examination of differences in genotype frequencies between the two cohorts. Of the Golden Years cohort, 47% were positive for the highest risk HLA genotype DR3-DQ2/DR4-DQ8 compared with 35% of those in the BOX cohort (p=0·003; table). Of those diagnosed when younger than 5 years old, 63% of the Golden Years cohort had DR3DQ2/DR4-DQ8 compared with 42% of the BOX cohort (p=0·03). By contrast, the number of individuals negative for both high-risk haplotypes (designated X/X in the table and figure) was similar. Our findings lend support to the hypothesis that the rising incidence of type 1 diabetes in children has resulted from exposure of a genetically susceptible subgroup of the population to an environment that is
HLA genotypes
Diabetes and Metabolism, Division of Medicine, University of Bristol, Bristol, UK (K M Gillespie PhD, Prof P J Bingley MD, Prof E A M Gale MB); University of Birmingham and Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK (S C Bain MD, Prof A H Barnett MD); Department of Medicine, University of Liverpool, University Hospital Aintree, Liverpool, UK (G V Gill MD); and Department of Medicine, Guy’s, King’s, and St Thomas’ School of Medicine, London, UK (M R Christie PhD) Correspondence to: Prof E A M Gale, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, UK [email protected]
HLA genotype by age at diagnosis of proband <5
Golden Years (total number) 35 BOX (total number) 105 DRB1-DQA1-DQB1 03-0501-02/04-0301-0302 Golden Years 22 (63%) BOX 44 (42%) 04-0301-0302/04-0301-0302 Golden Years 0 (0%) BOX 7 (7%) 04-0301-0302/X Golden Years 6 (17%) BOX 26 (24%) 03-0501-02/03-0501-02 Golden Years 2 (6%) BOX 8 (8%) 03-0501-02/X Golden Years 2 (6%) BOX 15 (14%) X/X Golden Years 3 (8%) BOX 5 (5%)
5–9
10–14
Overall 0–15
68 204
91 273
194 582
30 (45%) 74 (36%)
40 (44%) 88 (32%)
92 (47%) 206 (35%)
4 (6%) 17 (9%)
6 (7%) 27 (10%)
10 (5%) 51 (9%)
15 (22%) 50 (25%)
20 (22%) 62 (23%)
41 (21%) 138 (24%)
5 (7%) 13 (6%)
8 (9%) 19 (7%)
15 (8%) 40 (7%)
10 (14%) 31 (15%)
7 (8%) 45 (16%)
19 (10%) 91 (15%)
4 (4%) 19 (9%)
10 (10%) 32 (12%)
17 (9%) 56 (10%)
Table: HLA class II genotypes in Golden Years and BOX cohorts, subdivided according to age at onset
1699
Research Letters
70
Golden Years cohort BOX cohort
60
Carriers (%)
50 40 30 20 10
DQ
X
DR
3-
X/
2/
X DR
4-
DQ
8/
8 DQ 4DR DR
3-
DQ
2/
X
0
HLA genotype
Figure: Distribution of HLA class II haplotypes in Golden Years and BOX cohorts
increasingly conducive to diabetes development. A consequence will be to accelerate disease onset, thus diluting the concentration of high-risk HLA susceptibility haplotypes in the youngest and most genetically high-risk subgroup of the diabetic population. A Finnish study has also reported a higher concentration of highrisk haplotypes in 367 individuals who developed type 1 diabetes between 1939 and 1965 than in 736 individuals who contracted the disease between 1990 and 2001. The analysis showed a heightened proportion of individuals with the protective haplotype DR15-DQB2*0602 in the recently diagnosed population—an effect not observed in our study.6 Selection bias is a potential pitfall in our analysis, which was based on the assumption that the Golden Years cohort is representative of the genetic distribution of the childhood diabetic population 50 years ago, since only a minority of children who developed diabetes in the 1940s and 50s are likely to have survived to now. Bias would be introduced if HLA type influences longevity or susceptibility to late complications of diabetes such as diabetic nephropathy, but there is at present no evidence for this effect.7 The proportion of children with the highest risk HLA genotype is inversely related to age, and we have avoided this potential source of bias by matching for age at onset. Immigration has also affected the genetic make-up of the population, but more than 95% of children in the BOX cohort are of white European descent, so this effect should be slight.
1700
Childhood type 1 diabetes was uncommon in the first half of the 20th century, but its incidence has risen rapidly over the past 50 years.1 The overall proportion of newly diagnosed individuals carrying either, or both, of the two established susceptibility haplotypes DR4-DQ8 and DR3-DQ2 has not changed; however, there are now fewer with the highest risk DR4-DQ8/DR3-DQ2 genotype, balanced by an increase in the number of those with the lower risk DR4-DQ8/X and DR3-DQ2/X genotypes. The rising incidence of type 1 diabetes in young children has, therefore, been confined to a genetically susceptible subgroup of the population. The heightened proportion of lower risk haplotypes and decreased median age at onset of the disorder within this subgroup are consistent with a major environmental effect on diabetes development.1 Contributors K M Gillespie did the analysis presented in this paper and wrote up the manuscript; S C Bain and A H Barnett were responsible for genetic analysis of the Golden Years Cohort; P J Bingley was responsible for the Bart’s-Oxford Family Study; M R Christie coordinated collaboration between the studies; G V Gill coordinated collection of the Golden Years Cohort; E A M Gale suggested the analysis and helped draft the manuscript; and all authors participated in the discussion. Conflict of interest statement We declare that we have no conflict of interest. Acknowledgments Diabetes UK and the Wellcome Trust funded the Bart’s-Oxford study and Diabetes UK funded the Golden Years study. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. References 1 Gale EAM. The rise of childhood type 1 diabetes in the twentieth century. Diabetes 2002; 51: 3353–61. 2 Falconer DS. Introduction to quantitative genetics. New York: Ronal Press, 1964: 301–11. 3 Gardner SG, Bingley PJ, Sawtell, P, Weeks S, Gale EAM. Rapid increase in the incidence of type 1 (insulin-dependent) diabetes in children under five years of age in the Oxford region. BMJ 1997; 315: 713–17. 4 Bain SC, Gill GV, Dyer PH, et al. Characteristics of type 1 diabetes of over 50 years duration (the Golden Years cohort). Diabet Med 2003; 20: 808–11. 5 Gillespie KM, Valovin SJ, Saunby J, et al. HLA class II typing of whole genome amplified mouth swab DNA. Tissue Antigens 2000; 56: 530–38. 6 Hermann R, Knip M, Veijola R, 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: 420–25. 7 Chowdhury TA, Dyer PH, Mijovic CH, et al. Human leucocyte antigen and insulin gene regions and nephropathy in type 1 diabetes. Diabetologia 1999; 42: 1017–20.
www.thelancet.com Vol 364 November 6, 2004
The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes Kathleen M Gillespie,Steven C Bain, Anthony H Barnett, Polly J Bingley,Michael R Christie, Geoffrey V Gill, Edwin A M Gale
Lancet 2004; 364: 1699–700 See Comment page 1645
The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0·003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect. The incidence of childhood onset type 1 diabetes increased worldwide during the second half of the 20th century, with an especially rapid rise in those diagnosed when younger than 5 years.1 The major genetic contribution to susceptibility derives from a hierarchy of HLA haplotypes ranging from susceptible to protective. Age at onset is inversely related to the proportion of HLA high-risk susceptibility haplotypes, and young children with type 1 diabetes show the greatest HLA-associated genetic risk. Since the rise in incidence is too rapid to be explained by increased transmission of susceptibility haplotypes from one generation to the next, changing environmental factors are probably important. The threshold model of genetic liability2 predicts that exposure of a population with similar genetic characteristics to a more permissive environment (ie, an environment that is more conducive to the development of diabetes) will result in a progressive dilution of HLA-associated genetic susceptibility. We aimed to test this hypothesis. People who survive 50 years of diabetes in the UK can be nominated for the Nabarro medal awarded by the charity Diabetes UK. A cohort of medal winners with childhood onset diabetes formed our study group, and the comparison group was taken from a current population-based study in the Oxford region of the UK.3 The Bart’s-Oxford (BOX) Study is a prospective population-based family study, which since 1985 has recruited more than 90% of children who developed type 1 diabetes under age 21 years in the former Oxford health authority region. The Golden Years cohort4 was recruited from a nationwide register of individuals who had been awarded 50-year medals by Diabetes UK. Genetic samples were available from 194 medal-winners (52% male) diagnosed when aged younger than 15 years between 1922 and 1946. These individuals were randomly assigned three controls, matched for sex and age at diagnosis, in 1-year bands, from among 1150 BOX study probands diagnosed between 1985 and 2002. Participants in both studies gave oral or written consent for collection and analysis of genetic material, and both studies were submitted to and approved by the appropriate ethics committees. Specific consent for this study was not sought since the material was collected and analysed according to protocols for which consent www.thelancet.com Vol 364 November 6, 2004
had been given, and the data analysis was fully anonymised. HLA class II typing for DRB1, DQA1, and DQB1 was undertaken on DNA from blood or mouth swab samples.4,5 Haplotypes in diabetic probands were subdivided according to age at onset, and conditional logistic regression was done to account for matching in examination of differences in genotype frequencies between the two cohorts. Of the Golden Years cohort, 47% were positive for the highest risk HLA genotype DR3-DQ2/DR4-DQ8 compared with 35% of those in the BOX cohort (p=0·003; table). Of those diagnosed when younger than 5 years old, 63% of the Golden Years cohort had DR3DQ2/DR4-DQ8 compared with 42% of the BOX cohort (p=0·03). By contrast, the number of individuals negative for both high-risk haplotypes (designated X/X in the table and figure) was similar. Our findings lend support to the hypothesis that the rising incidence of type 1 diabetes in children has resulted from exposure of a genetically susceptible subgroup of the population to an environment that is
HLA genotypes
Diabetes and Metabolism, Division of Medicine, University of Bristol, Bristol, UK (K M Gillespie PhD, Prof P J Bingley MD, Prof E A M Gale MB); University of Birmingham and Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK (S C Bain MD, Prof A H Barnett MD); Department of Medicine, University of Liverpool, University Hospital Aintree, Liverpool, UK (G V Gill MD); and Department of Medicine, Guy’s, King’s, and St Thomas’ School of Medicine, London, UK (M R Christie PhD) Correspondence to: Prof E A M Gale, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, UK [email protected]
HLA genotype by age at diagnosis of proband <5
Golden Years (total number) 35 BOX (total number) 105 DRB1-DQA1-DQB1 03-0501-02/04-0301-0302 Golden Years 22 (63%) BOX 44 (42%) 04-0301-0302/04-0301-0302 Golden Years 0 (0%) BOX 7 (7%) 04-0301-0302/X Golden Years 6 (17%) BOX 26 (24%) 03-0501-02/03-0501-02 Golden Years 2 (6%) BOX 8 (8%) 03-0501-02/X Golden Years 2 (6%) BOX 15 (14%) X/X Golden Years 3 (8%) BOX 5 (5%)
5–9
10–14
Overall 0–15
68 204
91 273
194 582
30 (45%) 74 (36%)
40 (44%) 88 (32%)
92 (47%) 206 (35%)
4 (6%) 17 (9%)
6 (7%) 27 (10%)
10 (5%) 51 (9%)
15 (22%) 50 (25%)
20 (22%) 62 (23%)
41 (21%) 138 (24%)
5 (7%) 13 (6%)
8 (9%) 19 (7%)
15 (8%) 40 (7%)
10 (14%) 31 (15%)
7 (8%) 45 (16%)
19 (10%) 91 (15%)
4 (4%) 19 (9%)
10 (10%) 32 (12%)
17 (9%) 56 (10%)
Table: HLA class II genotypes in Golden Years and BOX cohorts, subdivided according to age at onset
1699
Research Letters
70
Golden Years cohort BOX cohort
60
Carriers (%)
50 40 30 20 10
DQ
X
DR
3-
X/
2/
X DR
4-
DQ
8/
8 DQ 4DR DR
3-
DQ
2/
X
0
HLA genotype
Figure: Distribution of HLA class II haplotypes in Golden Years and BOX cohorts
increasingly conducive to diabetes development. A consequence will be to accelerate disease onset, thus diluting the concentration of high-risk HLA susceptibility haplotypes in the youngest and most genetically high-risk subgroup of the diabetic population. A Finnish study has also reported a higher concentration of highrisk haplotypes in 367 individuals who developed type 1 diabetes between 1939 and 1965 than in 736 individuals who contracted the disease between 1990 and 2001. The analysis showed a heightened proportion of individuals with the protective haplotype DR15-DQB2*0602 in the recently diagnosed population—an effect not observed in our study.6 Selection bias is a potential pitfall in our analysis, which was based on the assumption that the Golden Years cohort is representative of the genetic distribution of the childhood diabetic population 50 years ago, since only a minority of children who developed diabetes in the 1940s and 50s are likely to have survived to now. Bias would be introduced if HLA type influences longevity or susceptibility to late complications of diabetes such as diabetic nephropathy, but there is at present no evidence for this effect.7 The proportion of children with the highest risk HLA genotype is inversely related to age, and we have avoided this potential source of bias by matching for age at onset. Immigration has also affected the genetic make-up of the population, but more than 95% of children in the BOX cohort are of white European descent, so this effect should be slight.
1700
Childhood type 1 diabetes was uncommon in the first half of the 20th century, but its incidence has risen rapidly over the past 50 years.1 The overall proportion of newly diagnosed individuals carrying either, or both, of the two established susceptibility haplotypes DR4-DQ8 and DR3-DQ2 has not changed; however, there are now fewer with the highest risk DR4-DQ8/DR3-DQ2 genotype, balanced by an increase in the number of those with the lower risk DR4-DQ8/X and DR3-DQ2/X genotypes. The rising incidence of type 1 diabetes in young children has, therefore, been confined to a genetically susceptible subgroup of the population. The heightened proportion of lower risk haplotypes and decreased median age at onset of the disorder within this subgroup are consistent with a major environmental effect on diabetes development.1 Contributors K M Gillespie did the analysis presented in this paper and wrote up the manuscript; S C Bain and A H Barnett were responsible for genetic analysis of the Golden Years Cohort; P J Bingley was responsible for the Bart’s-Oxford Family Study; M R Christie coordinated collaboration between the studies; G V Gill coordinated collection of the Golden Years Cohort; E A M Gale suggested the analysis and helped draft the manuscript; and all authors participated in the discussion. Conflict of interest statement We declare that we have no conflict of interest. Acknowledgments Diabetes UK and the Wellcome Trust funded the Bart’s-Oxford study and Diabetes UK funded the Golden Years study. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. References 1 Gale EAM. The rise of childhood type 1 diabetes in the twentieth century. Diabetes 2002; 51: 3353–61. 2 Falconer DS. Introduction to quantitative genetics. New York: Ronal Press, 1964: 301–11. 3 Gardner SG, Bingley PJ, Sawtell, P, Weeks S, Gale EAM. Rapid increase in the incidence of type 1 (insulin-dependent) diabetes in children under five years of age in the Oxford region. BMJ 1997; 315: 713–17. 4 Bain SC, Gill GV, Dyer PH, et al. Characteristics of type 1 diabetes of over 50 years duration (the Golden Years cohort). Diabet Med 2003; 20: 808–11. 5 Gillespie KM, Valovin SJ, Saunby J, et al. HLA class II typing of whole genome amplified mouth swab DNA. Tissue Antigens 2000; 56: 530–38. 6 Hermann R, Knip M, Veijola R, 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: 420–25. 7 Chowdhury TA, Dyer PH, Mijovic CH, et al. Human leucocyte antigen and insulin gene regions and nephropathy in type 1 diabetes. Diabetologia 1999; 42: 1017–20.
www.thelancet.com Vol 364 November 6, 2004