Hormone profiling of adults with the KISS1 p.P81R and its implications on fertility

Abstract

Kisspeptin is an excitatory neuropeptide. Its gene, KISS1, is found at 1q32, encoding for a 145 amino acid protein. KISS1 was initially recognized as a suppressor of metastasis in melanoma cell lines. However, in 2003 it was shown that kisspeptin also has a crucial role in the neuropeptide regulation of reproductive physiology through the binding of the KISS1 receptor, known as the KISS1R, thus stimulating the release of gonadotropin-releasing hormone (GnRH), a crucial hormone that governs the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. Dysregulation in this kisspeptin-GnRH pathway can result in a heritable disorder that affects both sexes, known as Idiopathic Hypogonadotropic Hypogonadism (IHH). One variant in KISS1 is the missense mutation p.P81R, whose functional role is still undetermined. This variant warrants further investigation to elucidate its potential implications on fertility and reproductive health. The effect of the KISS1 p.P81R variant on hormone levels and its possible contribution to the IHH phenotype, median hormone levels of sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEASO4), Testosterone, Estradiol, LH, and FSH for each genotype was investigated by analysis using existing whole genome sequencing (WGS) data and hormone data from the MAMI study. Genotypes were confirmed in selected individuals using PCR and post-PCR methods. Statistical analysis accounted for sex, age, and MI case-control-relative status. This study found that KISS1 p.P81R was associated with lower LH levels in post-menopausal individuals homozygous for alternative alleles. Additionally, elevated DHEASO4 levels were observed in pre-menopausal women carrying the homozygous alternative genotype.