Exome Sequencing of a Type 1 Diabetes Mellitus Family Exposes Both Common and Individualized Rare Variants...

Type 1 diabetes mellitus (T1D) is a disease of complex inheritance where genetic, immunological, and environmental factors interact in rendering the ultimate phenotype. To gain insights into the molecular etiology of the disease in a subset of a population that is sparsely investigated in genetic terms, like in Africa, exome sequence data from a T1D multicase family and a T1D cohort were investigated. The exome analysis identified several candidate genes related to T1D, like human leukocyte antigen (HLA), insulin (INS) gene, Cytotoxic T-lymphocyte-Associated Protein 4 (CTLA4), Protein Tyrosine Phosphatase Nonreceptor Type 22 (PTPN22), and Interferon-Induced Helicase C Domain 1 (IFIH1). A total of eight pathways were significantly overrepresented (p value ≤ 0.05) in target lists analyzed, including WNT, MARS2, TARS, STK36, TYR, TP73, ATIC, and HNF4. Based on Condel functionality scores and centrality positions in genetic interaction networks, two prominent candidates in diabetes mellitus and maturity-onset diabetes of the young (MODY)-HNF1A rs2464195 and HNF4A rs147638455-were identified. The two candidate variants were subsequently genotyped for further replication in a total of 47 T1D cases and 20 unrelated controls. No significant differences were observed (p = 0.73 and p = 1), as the variants turned out to be relatively common among Sudanese and absent or rare in a global sample. Expression analysis of these loci was carried out alongside two miRNAs, miR-105 and miR-518, which were selected based on in silico prediction (p = 0.057 and 0.038, respectively). The results revealed profound miRNA differential expression between T1D cases and controls, suggesting a role for miRNA in the regulation of susceptibility networks, but also the existence of within-family differences in the fold change. Such differences, especially if taken in connection with the clinical differences encountered in this family and the population variation, highlight the potential of both population-based and individualized approaches in fathoming underlying causes of pathogenesis leading to a T1D phenotype.