Thyroid hormones play major roles in the regulation of protein synthesis, basal metabolism, and lipolysis and lipogenesis. These wide ranging actions suggest that thyroid hormone variation may be intimately connected with variation in health related characteristics such as fat distribution, bone metabolism, and lipoprotein metabolism. Because these variables are risk factors in many common diseases such as atherosclerosis, diabetes, and osteoporosis, information on the genetic component of variation in thyroid hormone levels is a crucial factor in understanding the genetic basis of common disease susceptibility. A multidisciplinary investigation coupling molecular genetic methods and statistical genetic approaches will be conducted to examine the genetic components of variation in thyroid hormone phenotypes in a set of Mexican American families that is currently under investigation with regard to genetic factors in susceptibility to atherosclerosis, diabetes, osteoporosis, and obesity. The overall objectives are to detect genetic effects on normal thyroid hormone variation and to localize and identify them by statistical genetic analyses of pedigree data.
The specific aims are to: 1) measure serum concentrations of nine thyroid hormone phenotypes; 2) evaluate each individual's genotype at 24 polymorphic candidate loci; 3) detect evidence of linkage between quantitative trait loci (QTLs) for thyroid hormone phenotypes and approximately 325 polymorphic short tandem repeat (STR) markers via initial genome-wide screening using two-point variance component analysis; and 4) refine preliminary evidence of linkage of candidate genes and selected STR loci (determined via Aim 3) with thyroid hormone QTLs by performing more powerful multipoint variance component and penetrance-based quantitative trait linkage analyses. DNA samples from 1,000 individuals from 24 families will be analyzed by polymerase chain reaction (PCR) based approaches and blot hybridization methods to determine genotypes at the 24 candidate loci. Genotypes at the 325 STR loci will be obtained from another research project currently underway. Concentrations of nine serum thyroid hormones from the same 1,000 individuals will be assessed by radioimmunometric methods. QTL linkage analyses will be performed to test for linkage between genes that influence thyroid hormone variation and the two sets of genetic markers, i.e., candidate genes and STR markers.
