Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women

Abstract

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.

In depth analysis of the association of FTO SNP (rs9939609) with the expression of classical phenotype of PCOS: a Sri Lankan study

“…Statistical analysis was carried out with previously reported SNPs of the obesity gene (FTO), selected candidate genes of HPG axis (Kiss1, GPR54, GnRH, FSHB, FSHR, LHB, LHCGR) and insulin receptor gene (INSR) [28,29] and serum kisspeptin and testosterone concentration [27].…”

“…Diagnosis of PCOS was based on the Rotterdam criteria [25]. Details of sample size calculation [26], inclusion and exclusion criteria of study subjects and control group are described in previous reports [27][28][29] are given below:…”

“…Women with all 3 following diagnostic criteria were recruited as cases: oligomenorrhoea/oligo-ovulation, clinical or biochemical hyperandrogenism and polycystic ovaries on ultrasound. Details of diagnostic criteria were described briefly in our previous studies [27][28][29].…”

“…Socio demographic, reproductive information (menstruation, fertility), age and degree of severity of clinical feature of PCOS, drug history, family history of diabetes, anthropometry (BMI and central obesity), resting blood pressure, hyperandrogensim assessed by a single clinical observer that includes hirsutism (modified FG score), temporal hair loss, acne, acanthosis nigricans, ovarian ultrasound, serum kisspeptin and testosterone concentrations of all subjects were utilized from our previously reported studies [27][28][29].…”

The Correlation between Hormonal Disturbance in PCOS Women and Serum Level of Kisspeptin

“…It is worth mentioning that all types of kisspeptin act collectively via the G protein-coupled receptor GPR54 [3]. e kiss1 gene located in chromosome 1q32 consists of three exons, in which only part of the second and third exons is finally translated into the precursor 145 amino acid peptide, which is cleaved into three mentioned forms of kisspeptin [4].…”