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PII: S0303-7207(18)30188-6
DOI: 10.1016/j.mce.2018.06.002
Reference: MCE 10253
Please cite this article as: Nyaga, D.M., Vickers, M.H., Jefferies, C., Perry, J.K., O'Sullivan, J.M., The
genetic architecture of type 1 diabetes mellitus, Molecular and Cellular Endocrinology (2018), doi:
10.1016/j.mce.2018.06.002.
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The genetic architecture of type 1 diabetes mellitus
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The Liggins Institute, The University of Auckland, New Zealand
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Starship Children’s Health, Auckland, New Zealand
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Corresponding author: Justin M. O’Sullivan, The Liggins Institute, The University of
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Abstract
resulting in insulin deficiency and hyperglycaemia. T1D is most common among children
and young adults, and the incidence is on the rise across the world. The aetiology of T1D is
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hypothesised to involve genetic and environmental factors that result in the T-cell mediated
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destruction of pancreatic beta cells. There is a strong genetic risk to T1D; with genome-wide
association studies (GWAS) identifying over 60 susceptibility regions within the human
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genome which are marked by single nucleotide polymorphisms (SNPs). Here, we review
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what is currently known about the genetics of T1D. We argue that advancing our
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understanding of the aetiology and pathogenesis of T1D will require the integration of
genome biology (omics-data) with GWAS data, thereby making it possible to elucidate the
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putative gene regulatory networks modulated by disease-associated SNPs. This approach has
(SNPs), genome-wide association studies (GWAS), human leukocyte antigen (HLA), genome
organisation
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1. Introduction
Globally, diabetes affects more than 400 million people (World Health Organization, 2016),
(American Diabetes Association, 2009). In the United States, T1D occurs at a rate of 15-30
cases per 100,000 children aged 0-14 years annually (International Diabetes Foundation,
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2017; Maahs et al., 2010), with similar prevalence in Canada, Europe, Australia, and New
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Zealand (Figure 1) (Derraik et al., 2012; International Diabetes Foundation, 2017; Maahs et
al., 2010). By contrast, the estimated incidence rate of T1D among Asians, South Americans,
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and Africans is below 15 cases per 100,000 children (Figure 1) (International Diabetes
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Foundation, 2017; Maahs et al., 2010). The global incidence of T1D has been rising by 3-5 %
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per annum over the past two decades, with a notable increase in children below 10 years of
The marked increase of T1D incidence cannot be solely attributed to genetic risk (Snouffer,
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environmental factors contribute to the aetiology of T1D (Redondo et al., 2008). These
methylation (Cepek et al., 2016; Paul et al., 2016; Stefan et al., 2014), which has been
reported to play a key role in the transcriptional regulation of gene expression, and in some
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part, contributes to the aetiology of T1D (Stefan et al., 2014). Other environmental exposures
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attributable to the rising prevalence of T1D include diet (Hansen et al., 2006), gestational
infections (Rešić Lindehammer et al., 2012), and viral infections (Lönnrot et al., 2000). As
such, it is highly likely that these non-genetic triggers interact with susceptibility genes in
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Figure 1. Global prevalence rates of T1D in children. Numbers are an estimate of new cases
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of T1D in children and adolescents (0-14 years) by geographical region per year (2017). Data
obtained with permission from the IDF (International Diabetes Foundation) Diabetes Atlas
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(8TH Edition) (International Diabetes Foundation, 2017).
The early signs of T1D onset begin with the detection of islet autoantibodies, which
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progresses to loss of pancreatic beta cells, and subsequent insulin deficiency and
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hyperglycaemia (Figure 2) (Insel et al., 2015). The complex aetiology of T1D remains to be
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destruction of the insulin-producing pancreatic beta cells over a period of several years
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culminating to clinical diabetes (Figure 2). During clinical onset of T1D, the extent of beta
cell loss is dependent on age (i.e. at 20 years of age, a loss of 40% beta cell mass is sufficient
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to cause clinical symptoms) (Klinke, 2008), with a detectable decrease in plasma C-peptide
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peptide loss indicates late-onset disease (Kühtreiber et al., 2017; Laugesen et al., 2015).
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Figure 2. The pathogenesis of Type 1 diabetes. (A) The pancreas contains both endocrine
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(the islet) and exocrine tissues. The islet is comprised of glucagon producing alpha (α) cells
which make up approximately 20% of total islet cells; insulin-producing beta (β) cells (70%);
and somatostatin-producing delta (ߜ) cells (<10 %). Other minor pancreatic endocrine cells
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(not shown) include gamma (γ) and epsilon (ε) cells. The beta cell regulates blood glucose by
releasing insulin as a result of rising glucose levels. (B) T cells (CD4+ and CD8+) have a role
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Wenzlau and Hutton, 2013; Willcox et al., 2009) and are widely understood to be markers of
beta cell destruction in the clinical onset of the disease (Wenzlau and Hutton, 2013).
(ZnT8), glutamic acid decarboxylase (GAD65), insulin, and islet antigen 2 (IA-2) have been
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defined (Han et al., 2013; Verge et al., 1996). Presentation of these autoantigens to cytotoxic
T cells (CD8+) is performed by the major histocompatibility complexes class I and II (MHC I
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and II), which consequently destroys the antigen-presenting beta cells (Knip and Siljander,
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2008).
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Overexpression of the human leukocyte antigen (HLA) class I has been observed with the
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presence of beta cell antigen-specific CD8+ T cells in pancreatic lesions of patients with
either long-term and recent-onset T1D (Coppieters et al., 2012; Itoh et al., 1993). Despite the
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apparent role for autoantibodies in T1D, a study of recent-onset T1D patients demonstrated
that insulin secretion could be restored in islets cultured ex vivo from pancreatic biopsies
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(Krogvold et al., 2015). Moreover, a majority of adults with T1D, referred to as latent
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LADA, which accounts for less than 10% of diabetes cases, presents as an intermediate
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feature between T1D and type 2 diabetes (T2D), with the autoantibodies considered to be
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non-pathological (Tuomi et al., 1993). Arguably, LADA should be defined as a distinct form
of T1D, thereby making it easier to distinguish between young- and adult-onset autoimmune
diabetes. Notably, there is a growing focus on reclassifying the different forms of diabetes
which could potentially improve the clinical management of diabetes. (Ahlqvist et al., 2018).
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2. The genetics of Type 1 Diabetes
There is a strong genetic risk to T1D. This is exemplified by (Redondo et al., 2001) who
monozygotic twin pairs. That is, when one sibling is afflicted, there is a high probability that
the other twin will develop T1D by the age of 60 years. Additionally, autoantibody positivity
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and islet destruction was observed after a prospective long-term follow-up of monozygotic
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twins of patients with T1D, despite initial disease-discordance among the twins (Redondo et
al., 2008).
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Genome-wide association studies (GWAS) have made a significant contribution to our
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current knowledge of the role(s) of genetic variation in population-level susceptibility to T1D
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(Mychaleckyj et al., 2010). More than 60 susceptibility loci have been identified (Table 1).
The greatest genetic risk (~50%) for T1D is conferred by alterations to immune genes,
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especially those encoding the classical HLAs (Ounissi-Benkalha and Polychronakos, 2008).
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Other genetic loci (Table 1) are believed to influence population-level risk for T1D, although
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it is poorly understood how these non-HLA loci contribute to disease susceptibility (Ram et
al., 2016a).
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Table 1. Polymorphisms in the human genome associated with type 1 diabetes (Adapted from (Ram et al.,
2016b))
Gene/locus SNP Chromosome Locus P values Reference
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IKZF1 rs10272724 7 7p12.2 4.8E-9 Swafford et al. (Swafford et al., 2011)
GLIS3 rs7020673 9 9p24.2 5.4E-12 Barrett et al. (Barrett et al., 2010)
GLIS3 rs10758593 9 9p24.2 3.0E-6 Bradfield et al. (Bradfield et al., 2011)
RNLS rs10509540 10 10q23.31 1.0E-28 Barrett et al. (Barrett et al., 2010)
PRKCQ rs947474 10 10p15.1 1.2E-7 Barrett et al. (Barrett et al., 2010)
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IL2RA rs12251307 10 10p15.1 1.0E-13 Barrett et al. (Barrett et al., 2010)
Noble et al. (Noble and Erlich, 2012)
INS rs689 11 11p15.5 8.9E-195 Smyth et al. (Smyth et al., 2008)
Barrett et al. (Barrett et al., 2010)
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SH2B3 rs17696736 12 12q24.12 2.8E-27 Barrett et al. (Barrett et al., 2010)
ERBB3 rs2292239; 12 12q13.2 2.0E-20 Barrett et al. (Barrett et al., 2010)
rs1701704 9.0E-10
CUX2 rs1265564 12 12q24.12 1.0E-16 Huang et al. (Huang et al., 2012)
CD69 rs4763879 12 12p13.31 1.9E-11 Barrett et al. (Barrett et al., 2010)
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LMO7 rs539514 13 13q22.2 6.0E-11 Bradfield et al. (Bradfield et al., 2011)
DLK1-MEG3 rs941576 14 14q32.2 1.0E-10 Bradfield et al. (Bradfield et al., 2011)
Intergenic rs4900384 14 14q32.2 4.0E-9 Barrett et al. (Barrett et al., 2010)
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ZFP36L1 rs1465788 14 14q24.1 1.8E-12 Barrett et al. (Barrett et al., 2010)
RASGRP1 rs17574546 15 15q14 1.3E-6 Bradfield et al. (Bradfield et al., 2011)
CTSH rs3825932 15 15q25.1 3.0E-15 Barrett et al. (Barrett et al., 2010)
IL27 rs4788084 16 16p11.2 5.2E-08 Barrett et al. (Barrett et al., 2010)
PRM3; ORF;TNP2 rs416603 16 16p13.13 3.0E-6 Barrett et al. (Barrett et al., 2010)
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The association between T1D and the HLA complex was first demonstrated in 1973
compared to controls (Singal and Blajchman, 1973). The gene encoding HL-W15 antigen is
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located within the HLA class I genetic locus (Singal and Blajchman, 1973). The hypothesized
link between T1D and the HLA complex gained further support when a correlation between
the HL-A8 and W15 alleles (now known as HLA-B62 (B*1501) and B8 (B*0801)), and a 2-3
fold risk of juvenile T1D onset was identified (Nerup et al., 1974). Interestingly, HLA-
encoding genes were also found to be strongly associated with the pathogenesis of several
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additional autoimmune conditions that include multiple sclerosis (MS) (Naito et al., 1972),
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rheumatoid arthritis (RA) (Stastny, 1976), and celiac disease (CD) (Falchuk et al., 1972).
As such, the HLA-encoding region is the most strongly associated T1D locus (Mychaleckyj
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et al., 2010). However, the molecular understanding of how HLA contributes to T1D remains
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unclear due the large number of distinctive HLA alleles and unusual frequencies that make
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the overall mechanism difficult to interpret (Sanchez-Mazas and Meyer, 2014). This has
raised new questions, particularly with respect to the approximation of genetic distances, and
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other significant statistics in population genetics studies (Buhler and Sanchez-Mazas, 2011;
Sanchez-Mazas and Meyer, 2014). As such, improving our understanding of the basic
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biology of the HLA locus is an essential facet of research into the mechanisms and causes of
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T1D.
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The HLA locus spans 4 mega base pairs (Mb) of chromosome 6p21, and encodes the major
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histocompatibility complex (MHC) molecules (Figure 3). The HLA encoded glycoproteins
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interact with peptide antigen for recognition by T cell receptors (TCR). Their classically
accepted function is to help the immune system differentiate between self and non-self
(Bjorkman and Parham, 1990). The MHC proteins are classified into HLA class I and class II
molecules, with class I chains containing A, B, and C antigen, and class II chains having DR,
DQ and DP antigens. Additionally, the HLA class III genes are mapped within the HLA
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region and encode for proteins that form part of the complement system (i.e. C2, C4a, C4b,
and Bf). Notably, the HLA region spans 4 mega base pairs (Mb), with the class I genes
located at the telomere proximal end of the locus, while the class II genes are more
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Figure 3. The structure and arrangement of the HLA locus (chromosome 6p21). Green bars,
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classical HLA genes; yellow bars, other T1D-associated genes located within the HLA locus;
Double ended arrows approximate HLA class I, II and III boundaries. Modified with
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The HLA class I gene cluster comprises approximately 20 genetic features including six
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expressed genes, non-processed pseudogenes, and an array of partial gene copies (Choo,
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2007). The HLA class I genes (HLA-A, HLA-B, and HLA-C) encode polypeptide chains
which combine into a heterodimer with the non-polymorphic beta 2-microglobulin (i.e. α3 and
β2m) (Figure 4) (Bjorkman and Parham, 1990). Other class I HLA genes encode non-classical
MHC molecules like HLA-E, which is involved in the presentation of peptides to natural
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killer (NK) cells, and HLA-G, which protects the foetus from the maternal immune response
The classical HLA class II genes (HLA-DP, HLA-DQ, and HLA-DR) encode cell surface
glycoproteins that exist as heterodimers produced from two polypeptides (i.e. α2 and β2
chains) (Figure 4). These glycoproteins are usually present exclusively on antigen presenting
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cells that include Langerhans cells, B cells, dendritic cells, macrophages, and activated T
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cells (Holling et al., 2004). Notably, several nucleated cells (e.g. keratinocytes, epithelial
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glycoproteins (Holling et al., 2004). Numerous distinct alleles of the HLA gene have been
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documented (Horton et al., 2004), resulting in a myriad of MHC protein encoding variants.
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Figure 4. The major histocompatibility class I and II molecules showing the single-chain
HLA class I molecule attachment to the transmembrane segment and its interaction with the
β2-microglobulin. The position of the peptides illustrates the binding groove. The two HLA
class II chains are formed by immunoglobulin-like domains α1, α2, β1, and β2, and are
attached to the transmembrane segment.
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3. HLA genetic variation and T1D autoimmunity
There are many forms of population level genetic variation that can be identified by analyses
al., 2007). SNPs are the most prevalent variants in the human genome, with an average
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genomic SNPs (Huang et al., 2012). Most SNPs have no impact on development or health;
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however, GWAS data on human populations has revealed thousands of SNPs that associate
with minor traits including height (Yang et al., 2010) and susceptibility to complex diseases
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such as T1D (http://www.gwascentral.org/studies) (Barrett et al., 2010; Bradfield et al., 2011;
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Cooper et al., 2012). AN
The most frequently detected genetic variations in the HLA locus on chromosome 6p (Table
2) are observed predominantly in the HLA-DQ, -DR, and -DP alleles (Barrett et al., 2010;
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Erlich et al., 2008). The HLA DR/DQ region is a strongly linked T1D susceptibility locus,
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with the alleles reported to have a high likelihood of associating non-randomly (i.e. they are
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in close linkage disequilibrium (LD)) (Erlich et al., 2008). Notably, either or both the
DR4/DQ8 or DR3/DQ2 haplotypes are detected in approximately 90% of all T1D phenotypes
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(Erlich et al., 2008; Smigoc Schweiger et al., 2016). The presence of the DQ8 (DQA1*0301,
DQB1*0302) allele raises the odds ratio for T1D onset significantly to roughly 11 (Erlich et
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al., 2008), suggesting that T1D is 11 times more likely to develop in an individual with the
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allele than those without. Surprisingly, the DQB1*0602 allele of the variant DQ6 haplotype
has a low odds ratio of 0.03, predominantly protecting individuals from T1D onset (Erlich et
Although previous analyses of DP alleles and T1D have shown conflicting results, increasing
evidence supports the role of DPB1 in modulating the DQ-DR associated risk in T1D onset
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(Cucca et al., 2001; Johansson et al., 2003b; Noble et al., 2000). A study involving 269
Caucasian families in America found that DPB1*0301 was associated with T1D among
patients carrying the DQ2-DR3/DQ8-DR4 genotype (Noble et al., 2000). By contrast, a study
performed on families from the United Kingdom and Sardinian by Coca et al. suggested that
association of DPB1 alleles with T1D onset occurred in non-DQ8-DR4 haplotypes (Cucca et
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al., 2001). Finally, DPB1*0402 was observed to confer a level of protection on DQ8-DR4-
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negative haplotypes, suggesting a minimal role for DPB1 in influencing HLA-associated T1D
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The DPB1*0202 allele, found only in the susceptible DR3-B18 familial haplotype (18.2AH)
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among Caucasians, is consistently associated with high risk of T1D (Cucca et al., 2001;
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Johansson et al., 2003a). These reports also suggest a weak link between DPB1*0301 and
Johansson et al. found that the alleles were probably markers of genes for other HLA-
associated predisposing gene(s) and were indirectly associated T1D susceptibility (Johansson
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et al., 2003b). Despite this, it is worth noting that the DPB1 alleles increase genetic
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(an autoimmune disease) and chronic beryllium disease (an inflammatory lung disease
resulting from beryllium toxicity) (Begovich et al., 1989; Rosenman et al., 2011).
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Numerous studies have established T1D genetic risk associated with HLA class 1 (Noble et
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al., 2010, 2002; Valdes et al., 2005). The class I HLA gene products have critical roles in
killing (Bjorkman and Parham, 1990). As such, these gene products make a significant
contribution to shaping and maintaining the T cell repertoire (Noble, 2015a). Importantly,
producing pancreatic beta cells leads to clinical onset (Itoh et al., 1993; Knip and Siljander,
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2008). Therefore, it is possible that particular associations of peptides and class I HLA
molecules can influence destruction of beta cells. Notably, the presence of the HLA-A*24
allele is associated with low residual islet function in patients with T1D, indicating that the
A*24 allele facilitates complete beta cell destruction (Nakanishi et al., 1993).
Studies by Valdes et al. have reported that HLA class I alleles associate with age-of-onset of
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T1D (Valdes et al., 2012, 1999). Several alleles in the HLA class I region (Table 2) appear to
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confer high risk, but this effect is modified when accounting for LD with class II haplotypes
(Noble et al., 2002). The HLA-B*39:06 allele, for instance, has the strongest risk of T1D
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susceptibility with an odds ratio of 10.31, while HLA-B*57:01 appears to be highly protective
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with an OR of 0.19 even after considering the LD with DQ and DR (Noble et al., 2010).
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Notably, Mikk et al. suggested that B*39:06 can significantly improve the prognosis of T1D
haplotypes (Mikk et al., 2014). Therefore, it is important to account for LD when elucidating
A 3,913
B 4,765
C 3,510
E 25
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F 22
G 54
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DRA 7
DRB1 2,058
DRB3 137
DRB4 60
DRB5 48
DQA1 78
DQB1 1,079
DPA1 45
DPB1 828
The most polymorphic HLA genes are HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1. * Polymorphism
numbers were retrieved from the IPD-IMGT/HLA database release 3.28.0, 2017-04-13.
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3.1 HLA variations across populations
Since the early 1970s, over 13,000 HLA alleles have been reported (Robinson et al., 2015)
albeit approximately 90% of these alleles have been detected only once or twice (Mack et al.,
2013). The class II HLA alleles are consistently observed to impact on T1D across different
ethnic populations even allowing for significant variations in allele frequencies (Ikegami et
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al., 2008; Noble, 2015b). In Caucasian populations, the DR4-DQ8 (DRB1*04-DQB1*0302)
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and DR3-DQ2 (DRB1*0301-DQB1*0201) haplotypes are associated with a high risk of T1D
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risk of 1:15 in the general populations (Noble et al., 1996). Among the African population,
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the DRB1*07:01- DQA1*03:01-DQB1*02:02 haplotype is frequently detected among T1D
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patients, suggesting a role in disease predisposition (Mijovic et al., 1991; Noble et al., 2013).
Haplotypes can predispose to T1D in one population while protecting against it in a second.
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protect individuals of European descent against T1D (Erlich et al., 2008). Similarly,
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population and is observed to confer protection (Howson et al., 2013). By contrast, the
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other ethnicities, suggesting opposing effects of alleles across populations (Noble et al.,
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2013). Moreover, the DRB1*04:03 haplotype which is detected more widely among Asian
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than European populations, confers protection in the Asian population (Gragert et al., 2013).
Thus, the effects of HLA haplotype combinations are dependent on the overall genotype,
The HLA class III locus contains genes involved in immunological responses that include the
MIC-A, TNFA, and complement protein genes, and it is widely understood that these genes
have a reproducible contribution in the autoimmune pathogenesis of T1D (White, 1989). For
instance, deficiency of the C4 complement gene can increase the risk of T1D onset among
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DR3/DR4 individuals at a young age (Mason et al., 2014).
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Copy number variations within the C4A and C4B complement genes have been linked to the
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aetiology of autoimmune disorders including human systemic lupus erythematosus (SLE)
(Yang et al., 2007). Studies in mice have demonstrated an association with TNF-α and T1D
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pathogenesis, revealing an important role of cytokines in disease onset (Koulmanda et al.,
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2012; Lee et al., 2005). Interestingly, associations of TNF-α gene variants at the promoter
region, TNF-308A (rs1800629) and TNF-238A (rs361525), and T1D development have
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shown conflicting results in different ethnic populations (Bouqbis et al., 2003; Ilonen et al.,
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1992; Nishimura et al., 2003). Notably, associations between the TNF-308A allele
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(rs1800629) and T1D were not significant when effects of -HLA- alleles were considered in a
Reports on different ethnic groups implicate MIC-A alleles, which encode a stress-induced
antigen in the epithelium of the gut, in conferring either increased risk or protection to T1D
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pathogenesis (Bilbao et al., 2006; Gambelunghe et al., 2000; Gupta et al., 2003; Kumar et al.,
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2012). Reports have associated MICA5 (a polymorphism in the MIC-A gene) with childhood-
onset T1D (Gupta et al., 2003; Nikitina-Zake et al., 2004; Shtauvere-Brameus et al., 2002). In
contrast to this finding, other studies have identified the MIC-A5.1 allele as a distinctive
genetic marker for adult-onset T1D and suggests it contributes to disease protection
(Gambelunghe et al., 2007; Kumar et al., 2012). Again this is consistent with a possible
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linkage disequilibria between MICA alleles and other genes within the HLA locus that cause
There are variable number of tandem repeats within the 5’upstream region of the INS-
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susceptibility locus (11p15.5) known as INS-VNTR (Perez De Nanclares et al., 2003). The
short VNTR alleles (class I) within this region have been observed to positively increase the
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genetic risk of T1D as they influence the expression of (pro)insulin in the thymus (an allele-
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specific mechanism) (Pugliese et al., 1997). Notably, increased insulin transcription levels
and reduced T1D risk are promoted by long VNTR alleles (class III) consistent with the
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possibility that high insulin transcript may protect against T1D. (Bennett et al., 1995). In
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addition to the length of the VNTR alleles, studies also indicate that the INS-allele specific
sequence(Bennett et al., 1995; Perez de Nanclares et al., 2003; Pugliese et al., 1997).
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An association between the CTLA4 locus and the T1D phenotype was previously identified
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in different ethnic populations (Marron et al., 1997). Meta-analyses have confirmed the
associations between CTLA4 and T1D, however, the association was observed to vary across
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different ethnic groups (Wang et al., 2014). These variants contribute to T1D development
PTPN22 (e.g. at nucleotide 1858 in codon 620) have also been associated with T1D (Bottini
et al., 2004). This SNP directly hinders the formations of the LYP-Csk complex which causes
hyper-reactivity in T cells and thus a destructive autoimmune aetiology (Bottini et al., 2004).
Other PTPN22 polymorphisms (e.g. R620W due to rs2476601) are associated with
pathogenesis. Notably, T1D risk associated with the IL4/IL13 pathway was attributable to the
haplotypes at the IL-4R region and specific genotype combinations at the IL4, IL13, and
IL4R loci (Bugawan et al., 2003). Polymorphisms at the IL-4R loci (I50V IL4R SNP) have
also been observed to be high-risk genetic markers for rheumatoid arthritis (Prots et al.,
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2006). There is a growing interest in the associations between the killer-cell immunoglobulin-
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like receptor (KIR) locus (mapped on chromosome 19q13) and T1D susceptibility, largely
because HLA class I glycoproteins are KIR ligands (Campbell and Purdy, 2011; Noble,
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2015a). The variant KIR allele, KIR2DL2, binds to HLA-C alleles and has been reported to
positively influence T1D development (Mogami et al., 2007; Shastry et al., 2008). However,
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further analyses are needed to clearly annotate the reported risk of KIR-HLA association with
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T1D.
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Transcription factors have also been reported to play a role in the development of T1D. The
transcription factor, Autoimmune Regulator (AIRE) on chromosome 21, has been associated
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with T1D and the mechanism of this association may be through the differential expression of
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auto-peptides (Chentoufi and Polychronakos, 2002; Sabater et al., 2005). The AIRE protein is
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highly expressed in the thymus marrow. Therefore, the presence of AIRE mutations in T1D
patients strongly suggests that AIRE affects the expression and presentation of diabetes-
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associated autoantigens (e.g. insulin) in the thymus (Sabater et al., 2005). Similarly,
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activity of T cells which potentially causes autoimmunity (Visperas and Vignali, 2016).
Finally, deno novo activating mutations in the STAT3 transcription factor, which regulates
cytokine production, have been reported to contribute to the development of early-onset T1D
GWAS studies have contributed significantly to our current knowledge of the role(s) of
However, GWAS analyses do not automatically determine the particular gene(s) in a specific
locus that are mechanistically associated with disease pathogenesis, or elucidate the manner
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in which disease gene(s) interact (Zhong et al., 2010). The difficulty associated with ascribing
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functional impacts to SNPs is partly explained by the fact that most disease-associated SNPs
identified by GWAS are intergenic and fall outside of genes. Therefore, association studies
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only provide low-level insights into the molecular mechanisms that underlie the pathogenesis
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of diseases which makes it difficult to understand disease mechanisms.
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Several research approaches have made progress towards understanding the functional
relevance of disease-associated genetic variants (Bergholdt et al., 2012; Boyle et al., 2017).
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These advances are based on a growing awareness that the three-dimensional juxtaposition of
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DNA regions within nuclei means that genes can be regulated by regulatory elements that are
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located at some distance from the gene (Figure 5) (Javierre et al., 2016; Kadauke and Blobel,
2009). As a result of this, disease associated SNPs have been shown to fall in gene regulatory
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elements (Chen and Tian, 2016; Fadason et al., 2017; Farh et al., 2014; Lee et al., 2014;
There have been several efforts to elucidate the effect of T1D-associated SNPs on the
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differential expression of genes (i.e. expression quantitative trait loci (eQTLs)), particularly
in immune cell types (Newman et al., 2017; Ram and Morahan, 2017). Recent studies are
al., 2016). In fact, Fadason et al., demonstrated that functionally relevant type 2 diabetes-
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associated SNPs are spatially linked with specific changes in the expression levels of genes
within disease-associated tissues (Fadason et al., 2017). Similarly, a study demonstrated that
genes that modulate regulatory networks in autoimmune diseases (McGovern et al., 2016).
As such, the spatial organization of DNA within the nucleus (Figure 5) can impact gene
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regulation in a spatio-temporal manner that affects development (Won et al., 2016).
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Therefore, there is a strong possibility that functionally relevant intergenic T1D-associated
SNPs (imputed by GWAS) disrupt gene regulatory networks in the pancreas and other cell
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types that contribute to the development of T1D.
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Figure 5. DNA is organized in a non-random fashion in the nucleus. (A) Cartoon of the
three-dimensional organization of chromatin within eukaryotic nuclei. Chromatin binding
proteins (e.g. CTCF and cohesin), transcription factors, and chromatin modifiers organize
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stretches of DNA from distant genomic sites in close proximity to each other (e.g. (Gassler et
al., 2017)), providing a mechanism through which co-regulated topological domains co-
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localize in three-dimensions. The chromatin loops within topological domains contact other
domains and enable gene promoters to interact with regulatory elements from many kilobases
away, or in some cases, on different chromosomes. (B) Mutations (such as SNPs) in one
locus can affect the localisation or composition of the transcription factory which has a
significant effect on the expression of genes associated with that particular factory.
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6. Conclusions and future directions
autoimmune T1D. For instance, some patients with T1D have a prevalence of other
autoimmune disorders (Hughes et al., 2016). Interestingly, this apparent association is often
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ubiquitous amongst T1D patients, rather only a small proportion of T1D patients exhibit
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symptoms consistent with very specific diseases: celiac disease; adrenal insufficiency;
Grave’s disease; Hashimoto’s thyroiditis; and vitiligo (Hughes et al., 2016). Despite this, it is
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apparent that there is an identifiable pathological activation of the immune system in most
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T1D patients, as demonstrated by the detection of islet-targeting autoantibodies and islet
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antigen-specific T cells (Gepts, 1965; Wenzlau and Hutton, 2013). Notably, similar
pathological activations are discernible in other diseases that involve cellular death, e.g. type
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remains as to whether such immunological reactions are the fundamental drivers, or just
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The strong association of T1D with the HLA region supports an autoimmune aetiology
(Concannon et al., 2009). Nevertheless, this cannot be regarded as conclusive, since this loci
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is gene dense and encodes many non-immune associated genes which may influence beta cell
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exciting opportunity for further research into T1D, targeted at understanding disease
Determinants of Diabetes in the Young), DAISY (The Diabetes Autoimmunity Study in the
Young), BABYDIAB, and the TrialNet, continue to provide valuable information regarding
the genetic predisposition and progression of T1D (Redondo et al., 2018). Translating this
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information into knowledge through the hypothesis driven integration of genomic and
(CRISPR/Cas9), and functional eQTL analyses) is imperative to: 1) design predictive genetic
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Funding
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This work was supported by the University of Auckland (The Sir Colin Giltrap Liggins
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