Genetic Determinants of Premature Menopause in A Mashhad Population Cohort

Premature menopause is characterized by amenorrhea before age of 40 years, markedly raised serum luteinizing hormone (LH) level, follicle-stimulating hormone (FSH) level and reduced serum level of estradiol. Genome-wide analysis suggested several loci associated with premature menopause. Here, we aimed to analyze association of variants at the MCM8, FNDC4, PRRC2A, TLK1, ZNF346 and TMEM150B gene loci with premature menopause.

In this cross-sectional study, a total of 117 women with premature menopause were compared to 183 healthy women. Anthropometric indices were measured in all participants: height, weight, body mass index (BMI), waist circumference (WC) and wrist circumference. Eight single-nucleotide polymorphisms (SNPs) of the indicated genes (rs16991615, rs244715, rs451417, rs1046089, rs7246479, rs4806660, rs10183486 and rs2303369) were identified from the literature. Genotyping was performed using tetra-ARMS polymerase chain reaction (PCR) and ASO-PCR methods.

T allele of the rs16991615, rs1046089, rs7246479 and rs10183486, C allele of rs244715, rs451417 and rs4806660 as well as TT genotype of rs2303369 were associated with an increased risk of premature menopause, likely causing susceptibility to primary ovarian insufficiency (POI) in comparison with C allele. We also found an association between the rs16991615 SNP with premature menopause. Frequency of the minor allele in cases was increased for all SNPs in comparison with controls. All minor alleles, except for rs2303369, showed a statistically significant increased odds ratio (OR). However, after Bonferroni correction for multiple testing, none of the P values were remained significant.

The selected polymorphisms in MCM8, FNDC4, PRRC2A, TLK1, ZNF346 and TMEM150B genes may potentially affect susceptibility to premature menopause, although replication of the results in larger cohort could clarify this.