Long Non-Coding RNA Gene Variants Linked to Polycystic Ovary Syndrome Risk in Exploratory Case-Control Study

Two common genetic variants within long non-coding RNA genes may be associated with an increased likelihood of developing polycystic ovary syndrome (PCOS), according to a case-control study conducted at a fertility clinic in Rostov-on-Don, Russia. The research, published in the Egyptian Journal of Medical Human Genetics, examined polymorphisms in the MALAT1 and NEAT1 genes, two regulatory RNA genes located side by side on chromosome 11q13.1, and found preliminary evidence that variation in at least one of them tracks with PCOS susceptibility in a cohort of Russian women undergoing in vitro fertilization.

The study enrolled 168 women aged between 22 and 40 years, all receiving assisted reproductive treatment at the Center for Human Reproduction and IVF. Of these, 76 had been diagnosed with PCOS according to the Rotterdam criteria, which require at least two of three features: clinical or biochemical signs of hyperandrogenism, oligo- or anovulation, and polycystic ovarian morphology on ultrasound. The remaining 92 women served as controls and were undergoing IVF or intracytoplasmic sperm injection because of male factor or tubal infertility. Individuals with other endocrine disorders, including ovarian neoplasms, Cushing’s syndrome, hyperprolactinemia, and congenital adrenal hyperplasia, were excluded from both groups, and all participants gave informed consent under a protocol approved by the Local Ethics Committee of Southern Federal University.

The researchers selected two candidate variants from the dbSNP database, screening for single nucleotide polymorphisms with a minor allele frequency above five percent in the two long non-coding RNA genes and for prior links to PCOS, reproductive disorders, or metabolic disease. This process identified rs3200401, a C-to-T substitution in MALAT1, and rs674485, a G-to-A substitution within the single exon of NEAT1. Genotyping was performed on peripheral blood DNA using TaqMan allele-specific real-time PCR on an Applied Biosystems QuantStudio 5 instrument, with primers, probes, and reagents supplied by a Russian manufacturer.

Before analyzing the genetic data, the team confirmed that the PCOS group displayed the expected hormonal and metabolic profile. Compared with controls, women with PCOS had significantly higher serum levels of total and free testosterone, dehydroepiandrosterone, luteinizing hormone, the LH-to-FSH ratio, anti-Müllerian hormone, insulin, body mass index, the HOMA-IR index of insulin resistance, and 17-hydroxyprogesterone, while follicle-stimulating hormone and sex hormone-binding globulin were significantly lower. Dehydroepiandrosterone sulfate, estradiol, progesterone, prolactin, and glucose did not differ significantly between the groups, a pattern consistent with the typical endocrine signature of the syndrome.

The central genetic finding concerned MALAT1 rs3200401. The T allele appeared significantly more often among women with PCOS, at a frequency of 28.3 percent, than among controls, where it occurred at 18.4 percent, a difference that reached statistical significance with a p-value of 0.0373. Although the combined CT and TT genotypes were also more common in the PCOS group, at 33 percent versus 27 percent in controls, this genotype-level difference fell just short of significance at p = 0.0581. A post-hoc power analysis indicated that the study had approximately 82 percent power to detect the observed allelic difference for this variant, lending some confidence to the result, although the authors emphasized that the association remains preliminary.

For NEAT1 rs674485, the picture was more tentative. The heterozygous GA genotype was significantly more frequent in PCOS patients, at 35.5 percent, than in controls, at 18.4 percent, with a p-value of 0.0223. However, the effect size was small and the post-hoc power analysis indicated that the sample provided only about 10 to 12 percent power for this comparison, meaning the result could easily be a false positive. The authors explicitly cautioned that the NEAT1 findings should be interpreted with care and that larger, adequately powered studies are required before any association between this variant and PCOS susceptibility can be considered established.

Within the PCOS group itself, the variants also showed relationships with metabolic measurements. Patients carrying at least one copy of the MALAT1 rs3200401 variant had a significantly higher body mass index, with a p-value of 0.0412, and women with the NEAT1 GA genotype showed elevated HOMA-IR and fasting insulin levels, at p = 0.0288 and p = 0.0350 respectively. These within-group observations hint that the two variants may relate to the metabolic dimension of PCOS, which fits with earlier reports that NEAT1 expression in serum correlates positively with body mass index, total testosterone, total cholesterol, triglycerides, and low-density lipoprotein levels, and that NEAT1 promotes adipogenesis in adipocyte-derived stem cells in laboratory studies.

To explore possible functional mechanisms, the researchers turned to computational predictions rather than laboratory experiments. Using the RNAfold web server, they estimated that the C-to-T change at rs3200401 slightly alters the predicted minimum free energy of the MALAT1 transcript, from minus 46.40 to minus 45.90 kilocalories per mole, suggesting a modest change in secondary structure. The lncRNASNP2 database further predicted that the variant allele is associated with the loss of binding sites for two microRNAs, hsa-miR-1324 and hsa-miR-3661, which could in principle modify how MALAT1 interacts with its regulatory partners. These predictions align with previously published work showing that the same substitution can disrupt a binding site for hsa-miR-1324 and weaken the stability of a MALAT1 hairpin domain that binds miR-217-5p.

Similar in silico analysis of NEAT1 rs674485 predicted a change in minimum free energy from minus 64.80 to minus 64.30 kilocalories per mole, along with the emergence of potential binding sites for hsa-miR-487b-5p and hsa-miR-487a-5p and the loss of predicted sites for several other microRNAs, including hsa-miR-4504, hsa-miR-1273g-5p, hsa-miR-323b-5p, and hsa-miR-410-5p. The authors stressed that all of these structural and microRNA-binding findings are computational predictions only and require experimental validation before any functional role for either variant can be claimed. Long non-coding RNAs are transcripts longer than 200 nucleotides that lack protein-coding potential, and MALAT1 and NEAT1 are among the most abundant and best studied members of this class, with documented roles in transcriptional regulation, alternative splicing, epigenetic modification, and microRNA sponging.

The study carries several important limitations that temper its conclusions. The genotype distributions of both variants in the control group deviated from Hardy-Weinberg equilibrium, which the authors attribute to the relatively limited sample size, possible population stratification, or recruitment from a specific clinical population, and which alone warrants caution in interpreting the associations. No correction for multiple testing was applied, and the authors note that the candidate-gene, hypothesis-driven design makes the findings exploratory in nature, with the possibility of false-positive results that cannot be excluded. The use of IVF patients as controls may also introduce bias, since fertility treatment seekers are not representative of the general population. The authors call for validation in larger and ethnically diverse cohorts, and they frame MALAT1 and NEAT1 variants as potential biomarkers and therapeutic targets for PCOS only in the tentative sense that future, better-powered research will need to confirm whether these associations hold and whether the predicted functional effects are real.

Subject of Research: Association of MALAT1 and NEAT1 long non-coding RNA gene polymorphisms with polycystic ovary syndrome risk

Article Title: The involvement of polymorphisms in the MALAT1 and NEAT1 lncRNA genes in PCOS etiology

Article References: Lomteva, S. V., Sagamonova, K. Y., Ali, R. M., Ammar, M. N. A., Yachneva, S. V., & Aleksandrova, A. A. (2026). The involvement of polymorphisms in the MALAT1 and NEAT1 lncRNA genes in PCOS etiology. Egyptian Journal of Medical Human Genetics, 27(1), Article 84. https://doi.org/10.1186/s43042-026-00913-w

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00913-w

Keywords: polycystic ovary syndrome, MALAT1, NEAT1, long non-coding RNA, single nucleotide polymorphism, case-control study, insulin resistance, genetic association study, microRNA binding sites, in silico analysis, reproductive endocrinology, Hardy-Weinberg equilibrium