Linkage and association of rs3110045 and rs28499085 variants in the thyrotropin-releasing hormone receptor (TRHR) gene with the risk of familial type 2 diabetes

Type 2 diabetes (T2D) is a chronic and prevalent multisystemic disease that significantly increases morbidity and mortality. Dysfunction of the thyroid hormone system is common in patients with T2D, increasing their risk of both hyperthyroidism and hypothyroidism. Several components of the thyroid system are candidate risk genes for T2D. The thyrotropin-releasing hormone receptor (TRHR) gene encoding for TRHR is of particular interest since it is expressed by the dorsomedial hypothalamus neurons, which are known to regulate food intake. In humans, a variant in the TRHR gene has been previously reported in T2D patients in a population-based case-control study but not in familial T2D. We recruited 212 multigenerational families with T2D originated from the Italian peninsula with multiple cases of T2D and tested, via Pseudomarker 9 single nucleotide polymorphisms (SNPs) in the TRHR gene for linkage and linkage disequilibrium (i.e., linkage plus association) to/with T2D. We identified 2 novel risk variants (rs3110045 and rs28499085) significantly linked to and associated with the risk of T2D in the Italian families across several inheritance models. Our study is the first to confirm the previously reported association of TRHR gene with T2D and extends the risk to familial inheritance. However, functional and replication studies are still needed to confirm these results.