**Genes Involved in Type 1 Diabetes**

Marina Bakay, Rahul Pandey and Hakon Hakonarson

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52435

**1. Introduction**

The prevalence of diabetes is increasing worldwide and to date it impacts the lives of approx‐ imately 200 million people (Steyn et al., 2009). It is estimated that by 2030, there will be 439 million adults affected by diabetes (International Diabetes Federation/diabetes prevalence: www.idf.org). Type 1 diabetes (T1D) represents approximately 10% of these patients and is most prevalent in populations of European ancestry, where there is ample evidence of increased annual incidence during the past five decades (Onkamo et al., 1999; EURODIAB ACE Study Group, 2000).

T1D is a complex trait that results from the interplay between environmental and genetic factors. Much evidence supports a strong genetic component associated with T1D. The epidemiological data showing differences in geographic prevalence is one clear indicator, with populations of European ancestry having the highest presentation rate. T1D has high con‐ cordance among monozygotic twins (33 to 42%) (Redondo et al., 2001) and runs strongly in families with sibling risk being approximately 10 times greater than in the general population (Clayton, 2009); this is in clear contrast to the "less genetic" type 2 diabetes, where the sibling risk ratio is relatively modest at 3.5 (Rich, 1990).

T1D develops at all ages and occurs through the autoimmune destruction of pancreatic β-cells with resulting lack of insulin production. The immune system participates in β-cell destruction through several of its components including natural killer (NK) cells, B lymphocytes, macro‐ phages, dendritic cells (DC), and antigen-presenting cells (APCs). Studies in human and animal models have shown that both innate and adaptive immune responses participate in disease pathogenesis, possibly reflecting the multifactorial nature of this autoimmune disorder.

© 2013 Bakay et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In this review, we provide an update on genome-wide association studies (GWAS) discoveries to date and discuss the latest associated regions added to the growing repertoire of gene networks predisposing to T1D.

The design involved 561 cases, 1,143 controls and 467 triads in the discovery stage, followed by a replication effort in 939 nuclear families. In addition to finding the "usual" suspects, including an impressive 392 SNPs capturing the very strong association across the major histocompatibility complex (MHC), we identified significant association with variation at the KIAA0350 gene, which we replicated in an additional cohort. The WTCCC study investigated seven common complex diseases including T1D by genotyping 2,000 cases and 3,000 controls with ~500,000 SNPs using the Affymetrix GeneChip, and reported a number of novel T1D loci, including the KIAA0350 genomic region (WTCCC, 2007). Todd et al., 2007 confirmed these findings, using 4,000 cases, 5,000 controls and 3,000 T1D families as well as association reported in the WTCCC study to the 12q13 region. In a separate effort we fast-tracked 24 SNPs at 23 distinct loci from our original study and established association to the 12q13 region with a combined *P*-value of 9.13x10-10 (Hakonarson et al., 2008); this was the same locus as reported by the WTCCC and Todd et al., 2007. The 12q13 region harbors several genes, including ERBB3, RAB5B, SUOX, RPS26 and CDK2. However, the causative variants at this locus remain unknown. Concannon et al., 2008 reported an association between SNP at the UBASH3A locus on 21q22.3 and T1D by using SNP genotyping data from a linkage study of affected sib pairs in nearly 2,500 multiplex families, a finding also corroborated by our efforts as well as

Genes Involved in Type 1 Diabetes http://dx.doi.org/10.5772/52435 93

In order to get the most from GWAS and to increase the statistical power, several independent research groups carried out meta-analyses using datasets from different investigative groups. Cooper et al., 2008 performed the first meta-analysis by using T1D datasets from the WTCCC, 2007 and the Genetics of Kidneys in Diabetes (GoKind) study (Mueller et al, 2006; Manolio et al., 2007), and confirmed associations for PTPN22, CTLA4, MHC, IL2RA, 12q13, 12q24, CLEC16A and PTPN2. The SNPs with lowest nominal *P*-values were taken forward for further genotyping in an additional British cohort of 6,000 cases, 7,000 controls and 2,800 families. As a result, the IL2-IL21 association strengthened further and they found strong evidence for four additional loci: BACH2; a 10p15 region harboring the protein kinase C, theta gene (PRKCQ); a 15q24 region harboring nine genes including cathepsin H (CTSH) and a 22q13 region harboring tumor necrosis factor related protein 6 (C1QTNF6). Additional studies are required

Barrett et al., 2009 meta-analysis uncovered in excess of 40 loci, including 18 novel regions, plus they confirmed a number of previously reported (Smyth et al., 2008; Fung et al., 2009; Cooper et al., 2009). The study included samples from WTCCC, 20070, the GoKind study (Mueller et al., 2006) and controls and family sets from Type 1 Diabetes Genetics Consortium (T1DGC). The meta-analysis observed association to 1q32.1 (which harbors the immunoregu‐ latory interleukin genes IL10, IL19 and IL20), 9p24.2 contains only Glis family zinc finger protein 3 (GLIS3; first suggested by us in Grant et al., 2009), 12p13.31 which harbors a number of immunoregulatory genes including CD69 and 16p11.2 harboring IL27. These findings were

to elucidate the culprit genes and their mechanism at the 15q24 and 22q13 loci.

further supported by our *in silico* replication efforts (Qu et al., 2010).

association to the BACH2 gene (Grant et al., 2009).

**2.3. Meta-analyses of T1D GWAS datasets**
