Genetic variations in the 3'-untranslated region of SLC18A2 are associated with serum FSH concentration in polycystic ovary syndrome patients and regulate gene expression in vitro

Abstract

Study question: Are genetic variations at the human solute carrier family 18 member A2 (SLC18A2) locus associated with the etiology of polycystic ovary syndrome (PCOS) and/or with follicle stimulating hormone (FSH) levels and insulin secretion in PCOS?

Summary answer: We found two common genetic variants in the 3'-untranslated region of SLC18A2 (rs363282 and rs363238) that are associated with serum FSH concentration in the PCOS group.

What is known already: SLC18A2 is a vesicular monoamine transporter that is essential in dopamine regulation. Dopamine can negatively regulate FSH and insulin secretion through the D2 receptor.

Study design, size, duration: This study was a cross-sectional examination in women with PCOS (n = 319) and controls (n = 220) from China.

Participants/materials, setting, methods: The PCOS patients were diagnosed based on the criteria of the Androgen Excess Society, including clinical and/or biochemical signs of hyperandrogenemia plus oligoamenorrhea or polycystic ovaries. Controls had regular menstrual cycles and no hyperandrogenism or other endocrine disorders related to PCOS. Tag single nucleotide polymorphisms (SNPs) were selected based on resequencing data in 48 PCOS patients and linkage disequilibrium analysis. Allele frequencies for variants (rs363282 and rs363238) were examined in PCOS cases and controls along with their relationship to quantitative traits. The samples were further divided into two subgroups for association analysis: AA + AG group and GG group (rs363282), CC + AC group and AA group (rs363238). The functional effects of SLC18A2 variants were measured by luciferase assay. The gene expression of SLC18A2 was compared with the NCBI's Gene Expression Omnibus datasets.

Main results and the role of chance: Two common genetic variants in the 3'-untranslated region (rs363282 and rs363238) are associated with serum FSH in the PCOS group (P= 0.005 and P= 0.001, respectively), while no associations were found in controls. Functional studies showed that minor alleles of the two variants (rs363282-G and rs363238-A) had significantly lower luciferase activities than rs363282-A (P= 0.009) and rs363238-C (P = 0.009).

Limitations, reasons for caution: Results were not validated in another independent cohort, though we provided functional evidence of the two SNPs. Because of limited condition, more specific parameters, including ovarian follicle count and anti-Müllerian hormone were not included and relationship between SLC18A2 and these parameters cannot be evaluated.

Wider implications of the findings: We found a novel association between two genetic variants in SLC18A2 and FSH levels in PCOS patients. These findings might indicate a novel regulatory mechanism in follicular development and maturation in PCOS.

Study funding/competing interests: This work was supported by the National Natural Science Foundation of China (grant numbers 81571501 and 81270747), National Basic Research Program of China (grant number 2015CB943300). No competing interests declared.

Keywords: FSH; PCOS; SLC18A2; SNP; insulin; luciferase assay.