Quantitative trait loci associated with elevated thyroid-stimulating hormone in the Wistar-Kyoto rat

Area of Science:

• Endocrinology
• Genetics
• Animal Models

Background:

• Thyroid hormones regulate crucial developmental and physiological processes.
• Genetic factors contributing to natural variations in mammalian thyroid function are not fully understood.
• The Wistar-Kyoto (WKY) rat strain exhibits distinct thyroid function parameters, including elevated thyroid-stimulating hormone (TSH).

Purpose of the Study:

• To investigate the genetic basis of elevated TSH in WKY rats.
• To identify quantitative trait loci (QTLs) associated with altered thyroid function in an WKY x Fisher 344 (F344) rat cross.
• To explore potential candidate genes within identified QTLs.

Main Methods:

• Comparative analysis of thyroid function in WKY and F344 rat strains.
• Induction of quantitative trait locus (QTL) analysis in an F2 intercross population derived from WKY and F344 rats.
• Assessment of serum TSH, T3, and T4 levels following acute T3 challenge.

Main Results:

• WKY rats consistently exhibited elevated TSH levels compared to F344 rats.
• QTL analysis revealed a highly significant locus (TSH-1) on chromosome 6 (LOD=11.7) and a suggestive locus (TSH-2) on chromosome 5 (LOD=2.3) associated with elevated TSH.
• The TSH-1 locus interval includes the TSH receptor and type 2 deiodinase genes, while TSH-2 encompasses the type 1 deiodinase gene. Sequence alterations were noted in WKY alleles of these genes.

Conclusions:

• Genetic alterations within the TSH-1 locus on chromosome 6 significantly contribute to the altered thyroid function observed in WKY rats.
• The identified loci provide a foundation for further research into the specific genes governing thyroid axis regulation.
• These findings highlight the utility of the WKY rat model for studying the genetic control of thyroid function.