**3. Conclusions**

(PIC) and plays a role in the activation of eukaryotic genes transcribed by RNA polymerase II

Programmed cell death 2 (PDCD2) gene encodes a nuclear protein highly expressed in placenta, heart, pancreas, lung, and liver, and lowly expressed in spleen, lymph nodes, and thymus. Expression of this gene is known to be repressed by B-cell CLL/lymphoma 6 (BCL6);

In addition, despite not reaching the genome wide significance, our study observed evidence for association at three additional loci containing the candidate genes LOC100128081, TNFRSF11B and FOSL2 (Bradfield et al., 2011). Of these, it is notable that the tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) is a strongly associated locus with bone mineral density, also discovered in GWAS, and the locus harboring LOC100128081 has also been reported in the context of a GWAS of SLE. FOS-like antigen 2 (FOSL2) gene encodes a leucine zipper protein that dimerizes with the JUN family proteins and forms the transcription factor complex activator protein 1 (AP-1). The FOS proteins have been implicated as regulators

**CUX2 (12q24):**Huang et al., 2012 re-analyzed the original 2007 WTCCC study by using the 1000 Genomes imputation and reported refined variant rs1265564 in Cut-like homeobox 2 (CUX2) region for association with T1D. CUX2 is expressed exclusively in neural tissues. The protein belongs to the CUT homeobox family and contains three CUT domains and a home‐ odomain; both domains are DNA-binding motifs (Gingras et al., 2005). CUX2 gene has been shown to directly regulate the expression of NeuroD (Iulianella et al., 2008). NeuroD/BETA2, a transcription factor of the insulin gene, is reported to be associated with T1D in Asian descent (Iwata et al., 1999; Kavvoura & Ioannidis, 2005). Thus CUX2 is a plausible candidate for

**HTR1A (5p13-q13):**Asad et al., 2012 confirmed the previously suggested association between the chromosome 5p13-q13 regions and T1D in Scandinavian families (Nerup et al., 2001). None of the previous GWAS have reported any association of 5p13-q13 with T1D. This recent study identified the 5-hydroxytryptamine receptor 1A (HTR1A) and the ring finger protein 180 (RFN180) genes to be associated with T1D in multiplex (Swedish and Danish) families. However, the conditional analysis indicated HTR1A has as a primary association with T1D. Both quantitative PCR and immunohistochemical analysis confirmed the presence of the HTR1A in human pancreas (Asad et al., 2012). The study suggests that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both. The HTR1A gene is known to encode for a G-protein coupled receptor specific for serotonin, which mediates cellular signaling via the amine serotonin (Barnes & Sharp, 1999). The HTR1A receptor is mainly known to mediate signal transduction in neurons in the central nervous system (Lesurtel et al., 2008). However, serotonin is also produced in pancreatic islets of several different species (Sundler et al., 1980). Studies in rodent islets show inhibition of insulin secretion by serotonin (Zawalich et al., 2004). Sumatriptan (serotonin agonist) has an inhibitory effect on insulin secretion in humans (Coulie et al., 1998). Mohanan et al., 2006 reported a decrease in expression of HTR1A with increased insulin release during pancreatic regeneration. HTR1A also plays a role in the immune system. High level of protein expression

of cell proliferation, differentiation, and transformation (Cohen et al., 1989).

(Keutgens et al., 2010).

102 Type 1 Diabetes

a transcriptional repressor (Agata et al., 1996).

exploration in T1D pathogenesis.

This chapter provides a summary of recent advances in the identification of multiple variants associated with T1D. Genome wide association studies have revolutionized the field of autoimmune mediated disorders. In T1D only six genetic factors were well established before GWAS. GWAS has contributed greatly by expanding the number of established genetic variants to 57 genes. Most of these genes are novel and were not in any investigator's favorite list. For the first time there is real consensus on the role of specific genetic factors underpinning T1D pathogenesis.

The discoveries of genetic factors involved in the pathogenesis of T1D through GWAS present the first step in a much longer process leading to cure. Genes uncovered using this approach are indeed fundamental to disease biology and will define the key molecular pathways leading to cure of T1D. However, such genome wide scans can lack coverage in certain regions where it is difficult to genotype so it is possible that other loci with reasonable effect sizes remain to be uncovered.

To date most of T1D-associated variants have been discovered utilizing cohorts of European ancestry because the SNP arrays were designed to optimally capture the haplotype diversity in this ethnicity. Novel SNP arrays are needed with the same degree of capture in diverse populations to elucidate the full role of each locus in a worldwide context.

The next challenge is to resolve the specific causal variants and determine how they affect the expression and function of these gene products. The Next-Generation Sequencing (NGS) technology has opened new avenues to elucidate the role of coding and noncoding RNAs in health and disease and would speed up the identification of causative gene variants in T1D.

No doubt, the *in vitro* and *in vivo* biology of these genes will be fascinating areas of exploration for many scientists. Only after fully uncovering the functional context of T1D associated genes; these findings will show promise of use for preventive strategies.
