Biased Paternal Transmission of TRH Variant to Female down Syndrome Probands: Possible Correlation with Low Breast Cancer Frequency

Abstract

Thyroid malfunction is more common in individuals with Down syndrome (DS) than in the general population. It has been hypothesized that thyroid may influence cancer risk. Individuals with DS are at greater risk of developing leukemia than the general population, while solid tumors especially breast cancer (BC) are rare. BC patients have higher levels of circulating thyroid-stimulating hormone (TSH) and prolactin (PRL), both regulated by the thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide. This study was aimed at investigating the status of TRH functional polymorphisms in subjects with DS and BC. Unrelated families with DS probands (n=180), individuals with BC (n=99) and ethnically matched controls (n=216) were recruited. Genomic DNA isolated from peripheral blood was subjected to PCR amplification followed by DNA sequence analysis. Data obtained were analyzed by population- and family-based statistical analysis. Among 30 studied sites, only 2 (rs7645772 and rs13097335) were polymorphic. Case-control analysis showed a lack of any significant association with DS, while the rs13097335 GG and GT genotype frequency was significantly different in the BC samples. A paternal-biased transmission of the G allele was observed in female DS probands. It may be concluded that rs13097335 may have a protective role toward the development of BC.

Explorative Investigation on Thyroid Peroxidase and Sodium Iodide Symporter Gene Variants in Down Syndrome

“…Since some physiological abnormalities like, cognitive impairment, growth retardation, muscle hyporonia, lethargy, dullness, as well as large tongue with underdeveloped nasal bridge and short neck are observed in subjects with DS as well as those with irregular thyroid functions, we speculated that abnormal function of the thyroid gland, due to defects in genes encoding for proteins involved in thyroid hormone (TH) synthesis, secretion, or recycling, may have a role in DS related thyroid abnormalities. Our preliminary investigation revealed that the thyrotropin releasing hormone (TRH) gene variant, rs13097335 "G" allele, in addition to having lower occurrence in the BC population than female control, was preferentially transmitted from parents to female DS probands and based on the observation we hypothesized that higher occurrence of rs13097335 "G" allele in female DS probands may confer protection to BC [18]. In the present study, we investigated two other TH biosynthesis pathway genes, Solute carrier family 5 member 5 (SLC5A5) or NIS [19] and thyroid peroxidase (TPO) [20,21], in nuclear families with DS probands to find out their role.…”