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Development of Novel Allele Specific PCR Based Assays to Investigate the Contribution of Cortisol to Metabolic Syndrome
Author(s) -
Godlewski Brianna R.,
Salm Justin R.,
Cohen Brian D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.944.4
Subject(s) - endocrinology , medicine , glucocorticoid receptor , cortisone , population , metabolic syndrome , 11β hydroxysteroid dehydrogenase type 1 , allele , glucocorticoid , hydrocortisone , single nucleotide polymorphism , biology , hypercortisolemia , obesity , genetics , genotype , enzyme , dehydrogenase , gene , biochemistry , environmental health
A diagnosis of Metabolic Syndrome (MSX) requires patients to present with three or more of the following symptoms: elevated fasting blood glucose levels, elevated serum triglyceride levels, low serum HDL levels, elevated blood pressure, and truncal obesity. This pathology shares many similarities with Cushing's Syndrome (CS) but a diagnosis of CS requires hypercortisolemia. This similarity has led our lab and others to hypothesize that MSX may be a Cushingoid‐like state caused by hypersensitivity of the glucocorticoid receptor (GR), a nuclear hormone receptor that is activated when cortisol binds. Using an allele specific polymerase chain reaction (PCR) protocol, previous research in our lab has found significant correlations between the BclI and N363S polymorphisms of the glucocorticoid receptor and altered patient metabolic profiles in a population of patients seeking bariatric surgery, suggesting their possible contribution to diseases such as obesity and Metabolic Syndrome. Recent work in our lab has expanded our study to include the cortisol resistance polymorphism TthIIIi (rs10052957) to test the hypothesis that there would be a decreased prevalence of this polymorphism in our subject population. The TthIIIi allele is present at a lower frequency in our research population compared to reported frequencies, consistent with our hypothesis. In addition to investigating the glucocorticoid receptor, we have also developed an allele specific PCR assay for previously identified single nucleotide polymorphisms (rs12086634 and rs846910) in the cortisol reductase enzyme, also known as 11beta‐hydroxysteroid dehydrogenase (11β‐HSD) type 1. The 11β‐HSD1 enzyme is responsible for the conversion of inactive cortisone to cortisol, and works primarily in the adipose tissue. The two polymorphisms listed above are both associated with overactivity of the enzyme and are another possible cause for the Cushingoid‐state observed in MSX patients. In our patient population, the frequency of heterozygosity for the rs12086634 SNP was nearly 50% higher than the reported frequency in the general population, suggesting that this polymorphism may contribute to increased obesity and the MSX metabolic profile by increasing the localized cortisol in adipose tissue. Greater understanding of the interplay between these single nucleotide polymorphisms can help physicians and patients make more informed decisions about treatment options for obesity and metabolic syndrome.