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Type 1 Diabetes
Figure 3: Non-human Leukocyte Antigen Loci Found to
wide association studies have also been performed on type 1 diabetes
Have an Association with Diabetes
patients in hopes of finding other loci of interest. High-density SNP
analysis (over 300,000 per individual) and follow-up meta-analyses have
Odds ratio
added to the list of regions involved in type 1 diabetes. Several signals
7
of interest include confirmation of the MHC, PTPN22, cytotoxic
T-lymphocyte antigen 4 (CTLA4), and insulin gene loci. Other genes of
6
interest include those encoding CD25/interleukin-2 receptor alpha
5
(IL2RA) and interferon-induced helicase C domain-containing protein 1
(IFIH1); the strongest signal from the latter three genes was in
4
CD25/IL2RA, with more than one SNP associated with risk. CTLA4,
despite an odds ratio of 1.1–1.2, has been implicated in multiple studies
3
and is known to be strongly involved in T-cell signaling.
61–67
More than
2
40 loci are now firmly associated with risk of type 1 diabetes, with the
strongest signals by far associated with the MHC (see Figure 3).
68
1
INS
IFIH1CD25 CD25
12q24 CTLA4
PTPN22
Serological Markers
HLA class II
Autoantibody development and insulitis are the end result of loss ofERBB3 (12q13)PTPN2 (18p11)
KIAA0350 (16p13)
self-tolerance and a component of the heightened immune response
Over 40 non-human leukocyte antigen (HLA) loci have been found to have an association with
that results in destruction of beta cells in the pancreatic islets.
diabetes via genome-wide association. Here, some of the highest are listed. Note that the scale
Numerous antibodies are generated from a very early age in type 1
starts with an odds ratio of 1. The HLA region is by far the most important, with an odds ratio of
68
over 6.5, while most others do not exceed an odds ratio of 2.
diabetes-susceptible patients. The most important autoantibodies
include (in typical order of appearance chronologically) anti-insulin, anti-
Figure 4: Results of the DAISY Study
GAD65, anti-IA-2, and anti-ZnT8 antibodies.
69–71
Presence of multiple islet
autoantibodies is the most important predictor of progression to
% autoantibody-positive % with diabetes
disease in type 1 diabetes.
72
Development of autoantibodies can begin
30 30
as early as four to 12 months of age, with earlier development
25 25
correlating with greater risk of progression to overt disease (type 1
20 20
diabetes).
73
For some patients with pre-diabetes, autoantibodies do not
15 15
appear before 50 years of age. Insulin autoantibodies, often the first to
10 10
appear, can be a predictor of severity as their levels are inversely related
5 5
to age at disease onset.
74
Furthermore, if two or more of the above
0 0 antibodies are elevated (with each assay set at positivity ≥99 percentile
052.5 7.5 10 12.5 052.5 7.5 10 12.5
of normal populations), both relatives and individuals in the general
Age (years) Age (years)
population will ‘inevitably’ develop overt disease (>90%) versus
High risk: 262 (19 cases) High risk: 262 (8 cases)
Low risk: 96 (1 case) Low risk: 96 (0 cases)
individuals with only one antibody (20%).
44,75,76
p=0.02 p=0.08
High risk (no protective allele)
In the DAISY Study, the development of autoantibodies in DR3/4 general
Low risk (DPB*0402)
population individuals is influenced by DP alleles (see Figure 4). The rate
(see below), the insulin gene has been of particular interest. There is a of progression to diabetes increases in direct proportion with
variable number tandem repeat sequence (VNTR) at the 5´ end of the autoantibody positivity, with autoantibody development often preceding
insulin gene that has been known for over two decades to be associated disease onset.
77
Individuals can express autoantibodies for decades
with risk in type 1 diabetes. Longer repeats are protective and are prior to hyperglycemia. Despite a percentage of false or transiently
associated with increased insulin expression in the thymus.
55,56
positive individuals, people deemed ‘high-risk’ via genotyping can be
Differences in expression of the insulin 2 versus insulin 1 gene in NOD followed with a reasonable prediction of disease progression such that
mouse thymus presumably relate to the same mechanism (see above). prevention trials are under way.
78
These individuals, found in studies
such as DAISY, can also then be followed with glucose tolerance testing
PTPN22 is located on 1p13 and encodes for protein tyrosine and glycated hemoglobin (HbA
1c
) to diagnose hyperglycemia early, and
phosphatase non-receptor type 22 (PTPN22)/lymphoid phosphatase often they can be started on insulin therapy without hospitalization or
(LyP). Position 1858 contains a non-synonymous SNP that changes the development of ketoacidosis.
79,80
arginine to tryptophan at position 620. This polymorphism results in a
gain of function that increases inhibition of TCR signaling. Many groups Disease Modification in Type 1 Diabetes
have confirmed its presence in type 1 diabetes patients in many For the last few decades standards of management for type 1 diabetes
different populations, with an odds ratio of 3.4 in its homozygous have centered on glucose monitoring and insulin replacement therapy.
form.
57–59
It is hypothesized that this SNP decreases T-cell signaling, While the technology has greatly improved with regard to insulin pumps
thereby decreasing negative selection in the thymus. This risk allele and continuous glucose monitoring to simulate as best as possible
is therefore associated with many autoimmune diseases.
60
Genome- physiological pancreatic beta-cell function, it is by no means a perfect
82 US ENDOCRINOLOGY
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