This page contains a Flash digital edition of a book.
Eisenbarth_edit_Cardiology_book_temp 23/12/2009 12:34 Page 81
Type 1 Diabetes—Pathogenesis, Prediction, and Prevention
approximately 80% of children with FOXP3 mutations develop type 1
Figure 2: Genetic Risk of Siblings of Patents with
diabetes with onset as early as the first days of life.
36
The
Type 1 Diabetes
AIRE gene
controls expression of peripheral antigens such as insulin in the thymus
and it is hypothesized that lack of multiple peripheral antigens in the % autoantibody-positive % with diabetes
thymus of individuals with mutations of the AIRE gene contribute to their
100 100
widespread autoimmunity.
37
Other diseases contributing to the 80 80
n=29
knowledge of diabetes pathogenesis include autoimmune diseases
60 60
known to be associated with type 1 diabetes, e.g. Addison’s disease,
celiac disease, pernicious anemia, and thyroiditis.
38
These polygenic
40 40
conditions reflect the immunogenetics behind common forms of
20 20
n=19
autoimmune diabetes. Approximately one-third of children with new-
0
0
onset type 1 diabetes have associated organ-specific autoimmunity (e.g.
0510 15 20 0 5 10 15 20
Age (years) Age (years)
thyroid peroxidase, transglutaminase, 21-hydroxylase autoantibodies).
Share 2 MHC haplotypes: 29 (16 cases) Share 2 MHC haplotypes: 29 (11 cases)
Share 0 or 1: 19 (3 cases) Share 0 or 1: 19 (1 case)
p=0.03 p=0.04
The MHC class II region on chromosome 6 has long been linked to diabetes
HR 3.4, 95% CI (1.1–7.0) HR 6.1, 95% CI (1.04–11.81)
susceptibility. Effects of high-risk alleles in this region are consistent across
Siblings at high risk (Share 2)
different ethnicities despite large differences in allele frequencies.
39
There
Siblings at low risk (Share 0 or 1)
is also significant homology between species, with defined genes and
regions of risk in man, NOD mice, and susceptible rat strains.
23,40–43 DR3/4 (a high-risk genotype in type 1 diabetes) confers extreme genetic risk for siblings of
patients with type 1 diabetes if they have inherited both HLA-DR3 and DR4 identical by descent.
The extremely high-risk genotype DR3/4–DQ2/DQ8 (DR3–DQA1* By contrast, the DR3/4 genotype of siblings confers much lower risk if either the DR3 or the
40,44
501–DQB1*201; DR4–DQA1*301–DQB1*302) occurs in 2.4% of Denver
DR4 haplotype was not the same haplotype found in the proband sibling.
HR = hazard ratio; MHC = major histocompatibility complex; CI = confidence interval.
newborns, and 30–40% of all type 1 diabetes patients carry this
heterozygous genotype. Children with this genotype have an absolute
risk of one in 15 versus one in 300 in the general population.
24,25
In long-
Table 1: DRB1*04 Subtypes Conferring Varying Degrees of
Risk in Patients with Diabetes
term follow-up studies of 30,000 newborns (selected for either high-
risk HLA or a first-degree relative with type 1 diabetes), we find that
HLA-DRB1*04 HLA-DQB1 Odds Ratio (OR)
41% of DR3/4 siblings, as well as 16% of offspring of type 1 diabetes
0405 0302 11.4
patients, expressed islet autoantibodies by seven years of age.
0401 0302 8.4
Furthermore, in siblings identical by descent for both DR3/4
0402 0302 3.6
haplotypes, 63% had positive autoantibodies by seven years of age
0404 0302 1.6
and 85% were positive by 15 years of age (see Figure 2). This is in 0403 0302 0.27
contrast to only 20% developing autoantibodies in DR3/4 siblings 0401 0301 0.35
sharing no or one haplotype identical by descent.
44
Within the general Note the extreme risk of DRB1*0405 and DRB1*0401 allele and the protective nature of
40
population, the DR3/4 genotype combined with analysis of DP alleles
DRB1*0403.
(absence of protective DPB1*0402) and DR4 (absence of DRB1*0403)
confers a 20% risk of developing islet autoimmunity.
45
and B8 are all associated as well, with HLA-B39 conferring higher risk in
three different populations and HLA-B8 being lower-risk when linked with
While 2.4% of the population of Denver carry the DR3/4 heterozygous the DR3 allele in the well-known extended haplotype with DR3, HLA-B8,
genotype, over 30% of patients with diabetes have this genotype.
27
and HLA-A1.
50,51
HLA-C3, C8, and C16 have been reported to increase
Interestingly, either DR3 or DR4 haplotypes in homozygous form susceptibility.
51
Extensive long-range linkage dysequilibrium between
(DR3/DR3 or DR4/DR4) are lower-risk compared with the DR3/4 genotype. alleles of genes of the MHC make it difficult to pinpoint specific genes
The mechanism for the increased heterozygote risk is not completely contributing to risk. One of the most common extended haplotypes
delineated, but it has been hypothesized that the DQA1*0501 allele of consists of DR3–B8–A1 alleles, termed the 8.1 haplotype (containing
DR3 haplotype and the DQB1*0302 allele of DR4 haplotype combine, DRB1*0303–DQA1*0501–DQB1*0201–HLA-B8–HLA-A1). This is the most
creating a ‘chimeric’ molecule (DQA1*0501, DQB1*0302) for antigen common extended haplotype in the Caucasian population, with over 99%
presentation that increases the risk of diabetes.
40
There are also MHC identity across the MHC by single nucleotide polymorphism (SNP)
class II alleles that are protective (see Table 1): DQB1*0602 is present in analysis. Interestingly, it is increased in type 1 diabetes individuals (18%,
20% of the population but only 1% of children with type 1 diabetes. versus 9% of Caucasian controls)
52
due presumably to the DR3 and DQ2
Other protective alleles include DRB1*0403 (even when DQB1*0302 is alleles and not as much to the HLA-B8 and HLA-A1 portion of the
present) and DRB1*1401.
40,46
Even within DRB1*04 alleles there are haplotype. The DR3–B8–A1 haplotype confers less risk than other
variations conferring greater and lesser risk.
47,48
DR3 haplotypes. Higher risk was found in the less common DR3–B18–A30
haplotype (Basque haplotype) as well as other non-B8 DR3-positive
MHC class I loci (HLA-A, B, and C) play a lesser role in diabetes individuals.
53,54
This would point to susceptibility loci telomeric to class II
susceptibility. A24 is associated with a younger age at presentation and alleles. For several years, interest has turned to regions outside the MHC
A30 is associated with higher risk; A1 is lower-risk than other HLA-A region for susceptibility to type 1 diabetes. Because there is a known
alleles when associated with the DR3–B8 haplotype.
49
HLA-B18, B39, B44, correlation between development of diabetes and anti-insulin antibodies
US ENDOCRINOLOGY 81
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124
Produced with Yudu - www.yudu.com