Keywords
Haplotype, PCOS, polymorphism, rs4889, rs5780218
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Pratama G, R Febri R, Maidarti M et al. rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:889 (https://doi.org/10.12688/f1000research.168971.1)
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Research Article
rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women
[version 1; peer review: 1 approved with reservations]
PUBLISHED 09 Sep 2025
OPEN PEER REVIEW
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This article is included in the Cell & Molecular Biology gateway.
Abstract
Corresponding author:
Gita Pratama
Competing interests:
No competing interests were disclosed.
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The author(s) declared that no grants were involved in supporting this work.
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© 2025 Pratama G et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Pratama G, R Febri R, Maidarti M et al. rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:889 (https://doi.org/10.12688/f1000research.168971.1)
First published: 09 Sep 2025, 14:889 (https://doi.org/10.12688/f1000research.168971.1)
Latest published: 09 Sep 2025, 14:889 (https://doi.org/10.12688/f1000research.168971.1)
Introduction
Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder characterized by clinical or biochemical hyperandrogenism, oligo-anovulation, and polycystic ovaries; it affects 6% to 10% of women of reproductive age.1 The etiology of PCOS is not entirely understood. The complex pathogenesis involves hypothalamic-pituitary-gonadal (HPG) axis disturbances in gonadotropin secretion and increased LH levels.2,3 Several previous studies have focused on investigating the genetic factors of the HPG axis related to PCOS and reported a disruption in the function of the HPG axis, causing increased frequency and amplitude of gonadotropin-releasing hormone (GnRH) pulsatility in the hypothalamus.4 The KISS1 gene is considered to have an essential role in regulating gonadotropin secretion in the HPG axis and may be involved in the etiology of PCOS.
KISS1 is located at 1q32 and encodes a premature 145-amino-acid protein. The major product of the KISS1 gene, kisspeptin, is a 54-amino acid peptide that was first identified as a melanoma metastasis-suppressor gene.5 The binding of kisspeptin with its receptor (GPR54) in GnRH neurons of the hypothalamus activates the HPG axis, causing stimulation of gonadotropin release into the portal circulation. Gonadotropin binds the GnRH receptors in the anterior pituitary gland, consequently releasing and stimulating the activity of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).5,6 Ovulatory dysfunction of PCOS is reflected biochemically through excessive production of LH and a low or normal level of FSH from the anterior pituitary gland.7 A study showed potential pathophysiology involving KNDy neurons, which increased the NKB levels, decreased dynorphin levels, and elevated kisspeptin secretion, which resulted in increased LH levels and decreased FSH levels.8 Kisspeptin may interfere with LH production in PCOS and disrupt ovarian function, prompting androgen hypersecretion in the theca interna cells of the ovarian follicles.7 Although the prior studies have revealed the correlation between kisspeptin and the HPG axis, whether the serum kisspeptin concentration is higher in PCOS women compared to the general population remains inconclusive.
Single nucleotide polymorphisms (SNPs) in the KISS1 gene could lead to the disruption of GnRH secretion by dysregulating HPG axis function and increasing the development of various diseases. Several studies have indicated that some SNPs in KISS1 may play a vital role in the etiopathogenesis of PCOS.4,5,9 The current study determined the impact of KISS1 gene polymorphisms and haplotypes on the development of PCOS.
Methods
Subjects
The study recruited 80 women with PCOS and 76 control women who attended a clinic in Jakarta, Indonesia. However, only sixty subjects for each group met the inclusion criteria. Written informed consent was obtained from each subject. All subjects were self-reported as having Indonesian ethnic origin. Sixty women with PCOS cases were diagnosed according to the Revised 2003 consensus on diagnostic criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004), i.e., any two of the following three criteria: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovary morphology determined by ultrasonography.10 Oligo- or anovulation was determined by self-reported irregular menstrual cycles (menstruation occurring with a frequency more than 35 days in the year before enrollment). Hyperandrogenism was defined with hirsutism using a Ferriman-Gallwey score of more than eight, and/or the serum level of total testosterone greater than 60 ng/dl. Patients with any other cause of oligomenorrhea or hyperandrogenism, such as congenital adrenal hyperplasia, Cushing’s syndrome, hypothyroidism, or significant elevations in serum prolactin, were excluded. The transvaginal ultrasonography was used to assess the ovarian morphology for further stratified evidence of women with PCOS.
Sixty healthy women with regular menstrual cycles and without hyperandrogenism were recruited as controls. In addition to meeting these recruiting criteria, no subjects had taken medications known to alter the normal function of the HPG axis in the last 3 months. For all subjects, on the 3rd to 5th day of the menstrual cycle after overnight fasting, 5 ml whole-blood samples were obtained for both SNP analysis and reproductive hormone measurement. In subjects with PCOS, fasting blood insulin and fasting blood glucose were measured to determine insulin resistance.
Analysis of the rs4889 and rs5780218 KISS1 genes
Genomic DNA was isolated from the whole blood of women with PCOS and the control individuals using the Geneaid™ DNA Isolation Kit (Geneaid Biotech Ltd., New Taipei City, Taiwan) according to the manufacturer’s protocol. The rs4889 and rs5780218 variants of the KISS1 gene were amplified with polymerase chain reaction (PCR). The sequences of the rs4889 primers were 5’-CTA AGG TGA TCG TGG TT-3’ (forward primer) and 5’-CAG TTG TAG TTC GGC AGG T-3’ (reverse primer) with the product size 388 bp. The sequences of the rs5780218 primers were 5’-AAG GTG CCA TGC TCT TCA G-3’ (forward primer) and 5’-GGA TGC ATC TGT CCG TCT TAG-3’ (reverse primer) with the product size 332 bp. PCR amplification was carried out in a final volume of 20 μl containing 10 μl 2x SensiFAST SYBR® No-ROX mix (Meridian Bioscience, Tennessee, USA), 10 μM of each primer, and 50 ng of genomic DNA. PCR was performed in a SEDI Thermal Cycler (Wealtec Bioscience Co., Ltd., New Taipei City, Taiwan) with the following conditions: 95°C for 2 min, followed by 35 cycles of 15 sec at 95°C, 15 sec at 56°C, and 10 sec at 72°C. The single-band PCR products were visualized on a 1.6% agarose gel with GelRed® Nucleic Acid gel staining (Biotium Inc., Fremont, CA, USA). For those subjects with a single band, the PCR products were directly sequenced using an ABI PRISM 3100 Genetic Analyzer (ABI, Applied Biosystems, Foster City, CA, USA), and each set of reactions was run with positive and negative controls.
Hormone measurements
Levels of total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin, prolactin and sex-hormone binding globulin were measured using TOSOH (Tosoh India Pvt. Ltd., Mumbai, India) according to the manufacturer’s protocols. The level of kisspeptin was measured using a Human KISS1 (Kisspeptin 1) ELISA kit (Elabscience, Texas, USA).
Statistical analysis
The data are presented as the mean ± SE (standard error) for demographic (age, body mass index (BMI), waist circumference, hip circumference, and waist-hip ratio) and endocrine (kisspeptin, prolactin, testosterone, SHBG, free androgen index (FAI), LH, FSH, LH-FSH ratio, insulin, fasting blood glucose, and homeostatic model assessment for insulin resistance (HOMA-IR)) characteristics. The independent t test was used to determine the differences in the variables between two groups. The chi-square test was carried out for the statistical analysis of the genotype and allele distribution of the polymorphisms, as well as to verify the Hardy-Weinberg Equilibrium (HWE). A value of p < 0.05 was considered to indicate significance. The statistical analysis was performed using Prism 5 software (GraphPad Software).
The sanger sequencing data was analyzed using the Tracy’s web application (available at https://www.gear-genomics.com). The logistic regression model was calculated using the SNPStats program (available at https://bioinfo.iconcologia.net/index.php?module=Snpstats). It was also used to evaluate the association between polymorphisms and the development of PCOS. The effect of polymorphisms was evaluated by the following models: (1) codominant (wild-type homozygote x heterozygote x polymorphic homozygote); (2) dominant (wild-type homozygote x heterozygote + polymorphic homozygote); (3) recessive (polymorphic homozygote x wild-type + heterozygote homozygote); and (4) overdominant (wild-type homozygote + polymorphic homozygote x heterozygote). The best inheritance model was assessed using the Akaike information criteria (AIC) and the Bayesian information criteria (BIC), and the model with the lowest values was considered the best fit. The haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D’) for pairwise linkage disequilibrium (LD) from KISS1 gene polymorphisms were inferred using the SNPStats program, checking the estimated population frequency of haplotypes. The LD level was defined as strong LD (D’ > 0.8), moderate LD (0.4 < D’ ≤ 0.8), and weak LD (D’ ≤ 0.4).11 The results are presented as odds ratios (ORs) and 95% confidence intervals (CIs: 95%), with the level of statistical significance defined as p < 0.05.
Results
The full results of the study must be presented in this section. The demographic and endocrine characteristics of all subjects are presented in Table 1. For this study, there were 120 women with a median age of 24 for the control group and 26 for the PCOS group. There was no significant difference in the body mass index, waist and hip circumferences, and waist-hip ratio between PCOS patients and control individuals in both groups. No significant difference was also observed in the kisspeptin level; however, the median kisspeptin of 111.26 pg/ml in the PCOS group was lower than the control group. Significant differences in testosterone, SHBG, free androgen index, LH, LH-FSH ratio, insulin, and HOMA-IR values were also observed between the four groups (p < 0.05). The testosterone and free androgen index values were elevated in the PCOS patients compared to the control individuals in both the lean and obese groups. In contrast, SHBG level was lower under the same circumstances.
Table 1. Demographic and endocrine characteristics of study subjects.
| Characteristics | Control (n = 60) | PCOS (n = 60) | p value |
|---|---|---|---|
| Age (years) | 24.00 (17.00–40.00) | 26.00 (18.00–35.00) | 0.087 |
| Body mass index (kg/m2) | 23.85 (18.50–39.40) | 24.45 (18.50–42.30) | 0.144 |
| Waist circumference (cm) | 76.00 (61.00–112.00) | 79.50 (61.00–120.00) | 0.075 |
| Hip circumference (cm) | 95.00 (77.00–135.00) | 97.75 (78.00–145.00) | 0.116 |
| Waist-hip ratio | 0.80 ± 0.01 | 0.81 ± 0.01 | 0.646 |
| Kisspeptin (pg/ml) | 259.77 (20.65–1580.36) | 111.26 (20.73–1442.05) | 0.128 |
| Testosterone total (ng/dl) | 40.03 (2.93–559.36) | 71.01 (7.80–184.08) | 0.000* |
| SHBG (nmol/l) | 66.59 (7.53–174.65) | 37.00 (14.12–429.52) | 0.000* |
| Free androgen index (FAI) | 2.41 (0.17–30.38) | 5.96 (0.54–32.02) | 0.000* |
| Prolactin (ng/ml) | 8.5 (4.10–40.80) | 8.1 (2.50–79.40) | 0.213 |
| LH (mIU/ml) | 4.55 (0.60–172.00) | 10.20 (2.30–28.60) | 0.000* |
| FSH (mIU/ml) | 5.75 (1.40–21.70) | 7.1 (1.90–10.90) | 0.051 |
| LH-FSH ratio | 0.79 (.15–7.93) | 1.45 (0.52–3.25) | 0.000* |
| Insulin (mIU/l) | 7.30 (2.60–37.80) | 10.30 (2.30–135.30) | 0.022* |
| Fasting blood glucose (mg/dl) | 92.00 (74.00–118.00) | 94.00 (74.00–125.00) | 0.270 |
| HOMA-IR | 1.70 (0.58–86.00) | 2.48 (0.52–32.74) | 0.032* |
Tracy’s web application was used for analyzing chromatogram trace file from the sanger sequencing data. The result of chromatogram for rs4889 and rs5780218 was shown in Figure 1. Table 2 describes the percentage distribution of the rs4889 and rs5780218 polymorphisms in the PCOS and control groups. There were a greater number of individuals with the homozygous mutant genotypes of the rs4889 and rs5780218 variants (GG and CT/CT, respectively) in PCOS women than their counterparts. Only the genotypic distribution of rs4889 was significantly different between the two groups (p = 0.012).
Figure 1. Chromatograms of PCR amplicon sequencing showing the DNA change in women with PCOS compared to control.
(A) The comparison between wild type and mutant genotypes of rs4889. (B) The comparison between wild type and deletion genotypes of rs5780218.
Table 2. Genotype frequencies of rs4889 and rs5780218 of the KISS1 gene.
| SNPs | Genotypes | Frequency | p value | ||
|---|---|---|---|---|---|
| Control n (%) | PCOS n (%) | Total n (%) | |||
| rs4889 | CC | 28 (46.7) | 19 (31.7) | 47 (39.2) | 0.006* |
| CG | 31 (51.6) | 30 (50.0) | 61 (50.8) | ||
| GG | 1 (1.7) | 11 (18.3) | 12 (10.0) | ||
| Total | 60 (100.0) | 60 (100.0) | 120 (100.0) | ||
| rs5780218 | CTT/CTT | 23 (38.4) | 12 (20.0) | 35 (29.2) | 0.065 |
| CTT/CT | 31 (51.6) | 37 (61.7) | 68 (56.7) | ||
| CT/CT | 6 (10.0) | 11 (18.3) | 17 (14.1) | ||
| Total | 60 (100.0) | 60 (100.0) | 120 (100.0) | ||
The allele distribution of the rs4889 KISS1 SNP was significantly different between both groups (p = 0.0005) ( Table 3). The allele frequencies indicated that the ‘G’ allele might confer risk to PCOS and that the ‘C’ allele offers protection against the disease. A significant difference in the allele distribution of rs5780218 was also observed between all groups (p = 0.027). The frequency of the “CT” allele was higher in PCOS patients than in control individuals.
Table 3. Allele frequencies of rs4889 and rs5780218 of the KISS1 gene.
| SNPs | Allele | Frequency | Total n (%) | Odds ratio (95% CI) | p value | |
|---|---|---|---|---|---|---|
| Control n (%) | PCOS n (%) | |||||
| rs4889 | C | 87 (72.5) | 66 (55.0) | 153 (63.7) | 2.157 (1.259–3.696) | 0.0005* |
| G | 33 (27.5) | 54 (45.0) | 87 (36.3) | |||
| Total | 120 (100.0) | 120 (100.0) | 240 (100.0) | |||
| rs5780218 | CTT | 77 (64.2) | 60 (50.0) | 137 (57.1) | 1.791 (1.068–3.003) | 0.027* |
| CT | 43 (35.8) | 60 (50.0) | 103 (42.9) | |||
| Total | 120 (100.0) | 120 (100.0) | 240 (100.0) | |||
The association analysis of the rs4889 and rs5780218 polymorphisms was also evaluated in this study ( Table 4). The genotypes of 120 women, 60 women with PCOS and 60 healthy control women, were assessed. The rs4889 polymorphism was significantly different between the PCOS and control groups for the codominant and recessive models (p = 0.0017 and p = 0.000, respectively). Moreover, the rs5780218 polymorphism was significantly different between the PCOS and control groups for the codominant and dominant models (p = 0.036 and p = 0.016, respectively). The model with the lowest AIC and BIC values for a given polymorphism was considered the best-fit model. The AIC and BIC values indicated that the recessive model of rs4889 and the dominant model of rs5780218 might serve as the best-fit models of the KISS1 gene polymorphisms ( Table 4).
Table 4. Associations of the rs4889 and rs5780218 polymorphisms of the KISS1 gene with PCOS.
| Model | Genotype | Control n (%) | PCOS n (%) | OR (95% CI) | p value | AIC | BIC |
|---|---|---|---|---|---|---|---|
| rs4889 | |||||||
| Codominant | C/C | 28 (46.7) | 19 (31.7) | 1.00 | 0.0017* | 159.6 | 167.9 |
| C/G | 31 (51.7) | 29 (48.3) | 1.38 (0.64-2.98) | ||||
| G/G | 1 (21.7) | 12 (20) | 17.68 (2.12–147.56) | ||||
| Dominant | C/C | 28 (46.7) | 19 (31.7) | 1.00 | 0.092 | 167.5 | 173.1 |
| C/G-G/G | 32 (53.3) | 41 (68.3) | 1.89 (0.90–3.97) | ||||
| Recessive | C/C-C/G | 59 (98.3) | 48 (80) | 1.00 | 0.000** | 158.3 | 163.8 |
| G/G | 1 (1.7) | 12 (20) | 14.75 (1.85–117.51) | ||||
| Overdominant | C/C-G/G | 29 (48.3) | 31 (51.7) | 1.00 | 0.72 | 170.2 | 175.8 |
| C/G | 31 (51.7) | 29 (48.3) | 0.88 (0.43–1.79) | ||||
| rs5780218 | |||||||
| Codominant | CTT/CTT | 24 (40.0) | 12 (20.0) | 1.00 | 0.036* | 165.7 | 174.1 |
| CTT/CT | 30 (50.0) | 36 (60.0) | 2.40 (1.03–5.59) | ||||
| CT/CT | 6 (10.0) | 12 (20.0) | 4.00 (1.20–13.28) | ||||
| Dominant | CTT/CTT | 24 (40.0) | 12 (20.0) | 1.00 | 0.016* | 164.6 | 170.1 |
| CTT/CT-CT/CT | 36 (60.0) | 48 (80.0) | 2.67 (1.18–6.03) | ||||
| Recessive | CTT/CTT-CTT/CT | 54 (90.0) | 48 (80.0) | 1.00 | 0.12 | 168.0 | 173.5 |
| CT/CT | 6 (10.0) | 12 (20.0) | 2.25 (0.78–6.46) | ||||
| Overdominant | CTT/CTT-CT/CT | 30 (50.0) | 24 (40.0) | 1.00 | 0.27 | 169.1 | 174.7 |
| CTT/CT | 30 (50.0) | 36 (60.0) | 1.50 (0.73–3.09) | ||||
After the analysis of genotypic and allele frequencies of SNPs and their association with PCOS, the haplotype frequencies ( Table 5) for multiple loci and the standardized disequilibrium coefficient (D’) for pairwise LD were also performed using the rs4889 and rs5780218 variants for all subjects to analyze the combined effect of KISS1 SNPs on PCOS development. Haplotype analysis demonstrated a strong LD (D’ = 0.864) among SNPs rs4889-rs5780218. From this analysis, the G-CT haplotype was found to be significantly different, with an OR value of 2.57 (1.33–4.96, p = 0.0057). Moreover, the remaining haplotypes were not associated with an increased risk of PCOS.
Table 5. Construction of the haplotypes of the two SNPs in the KISS1 gene.
| No | rs4889 | rs5780218 | Control Freq. | Case Freq. | Total Freq. | OR (95% CI) | p value |
|---|---|---|---|---|---|---|---|
| 1 | C | CTT | 0.606 | 0.429 | 0.542 | 1.00 | - |
| 2 | G | CT | 0.298 | 0.403 | 0.3254 | 2.57 (1.33–4.96) | 0.0057* |
| 3 | C | CT | 0.069 | 0.138 | 0.0996 | 1.38 (0.56–3.37) | 0.49 |
| 4 | G | CTT | 0.027 | 0.030 | 0.033 | 1.81 (0.36–9.18) | 0.48 |
Discussion
Impaired negative feedback from ovarian steroid hormones to the GnRH neuronal network is a crucial pathological feature of PCOS.12 This alteration likely drives abnormalities in the neuroendocrine axis, which regulates fertility and primarily mediates downstream ovarian dysfunction. Women with PCOS demonstrate persistently rapid GnRH pulse frequency. This leads to LH pulsatility elevation and FSH deficiency and contributes to increases in LH concentrations and LH:FSH ratios, which are typical of PCOS.13 Since GnRH neurons do not have specific receptors for steroid hormones, it is essential to understand the pathways involved in dysfunctional GnRH release. Kisspeptin is a potential candidate for stimulating the activity of GnRH and thus increasing LH levels.
We found that the serum level of kisspeptin was lower in women with PCOS than in healthy control individuals. In contrast with our results, several studies showed a higher expression level of kisspeptin in PCOS.7,14–16 The low level of kisspeptin is possibly caused by the different pathways determining the relationship between kisspeptin and reproduction control that involve the complex mechanisms that regulate HPG function and reproductive physiology.17 In the hypothalamus, kisspeptin cells are located in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei.18 In the ARC, the expression of KISS1 mRNA is inhibited by testosterone. Moreover, the free androgen index (FAI) is correlated with the kisspeptin level. In this study, the expression levels of testosterone and FAI were higher in PCOS patients than in control individuals. Then, we suspected that a low kisspeptin level was associated with increased testosterone levels and FAI values in this study.
Excess levels of androgen and FAI in PCOS are fundamental hormonal problems that might be caused by several upstream factors in neuroendocrine regulation, including the alteration of LH pulsatility.19 Our results demonstrated higher levels of LH, a lower FSH level, and a higher LH to FSH ratio in PCOS women than in control individuals. An elevated LH pulse frequency, increased serum LH concentration, and high LH-to-FSH ratio are common clinical characteristics of PCOS. These phenomena consequently affect the downstream pathway in the ovary; this includes the over synthesis of androgen in theca cells, leading to excess androgen production.20 Low levels of FSH contribute to follicular arrest, preventing ovulation in PCOS women.21
Multiple factors are more likely to cause PCOS since several mechanisms are involved in developing the disease.3 However, due to the heterogeneity and uncertain etiology of PCOS, genes involved in PCOS are challenging to identify. Several genes have been identified as susceptible loci in previous genome-wide association studies (GWAS), including genes associated with steroid biosynthesis and gonadotropic secretion.22 KISS1 may also be subjected to mutations and polymorphisms.6 The neuropeptide kisspeptin induces the activity of GnRH neurons, consequently releasing GnRH. Since KISS1 acts in the upstream pathway of GnRH, disruption in KISS1 might affect GnRH signaling, especially in PCOS.
The involvement of the alterations in the hypothalamic-pituitary-gonadal (HPG) axis, especially the polymorphisms of KISS1 gene loci, was evaluated. Using Sanger sequencing, we detected two sites of polymorphisms, rs4889 and rs5780218. The results revealed a significantly higher frequency of the homozygous mutant genotype GG of rs4889 in PCOS patients than in control individuals, but no significant differences in the genotype distribution of rs5780218 were observed. The rs4889 polymorphism changes a CCC codon to CGC, resulting in the substitution of the amino acid proline by arginine, consequently disrupting the ability of kisspeptin to find its receptor. A previous study on the Saudi population also demonstrated similar results to our finding in the genotype distribution of rs4889.9 In contrast with our results, a study in the Sri Lankan population by Branavan et al. demonstrated no association of rs4889 and rs5780218 with PCOS.23
The frequencies of the G allele in rs4889 and CT in rs5780218 were also significantly higher in women with PCOS than in healthy control individuals, suggesting a strong association between KISS1 polymorphisms and an increased risk of PCOS. In addition, our findings also revealed that rs4889 C > G was linked in the codominant and recessive models. Moreover, rs5782018 CTT > CT was connected with the codominant and dominant model. Genetic variation is best described by groups of associated polymorphisms, called haplotypes.24 Haplotype analysis was performed to find the most susceptible haplotype associated with PCOS. Our present data found that the presence of G-CT haplotypes was associated with an increased risk of PCOS. In summary, our results suggest that the KISS1 rs4889 and rs5780218 gene variants could be genetic predisposing factors for PCOS. Furthermore, we found that the risk haplotype G-CT in the KISS1 gene correlated with PCOS.
Conclusions
In conclusion, our results suggest that the KISS1 rs4889 and rs5780218 gene variants could be genetic predisposing factors for PCOS. Furthermore, we found that the risk haplotype G-CT in the KISS1 gene correlated with PCOS.
Ethics approval
This study was conducted in accordance with the principles of the Declaration of Helsinki ( https://www.wma.net/policies-post/wma-declaration-of-helsinki/ ). Ethical approval was obtained from the Ethics Committee of the Faculty of Medicine, University of Indonesia – Cipto Mangunkusumo Hospital (Approval No. 23-12-2107) prior to commencement of the study.
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how to cite this article
Pratama G, R Febri R, Maidarti M et al. rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:889 (https://doi.org/10.12688/f1000research.168971.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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How to cite this report:
Hamdan M. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:889 (https://doi.org/10.5256/f1000research.186221.r413858)
The direct URL for this report is:
https://f1000research.com/articles/14-889/v1#referee-response-413858
https://f1000research.com/articles/14-889/v1#referee-response-413858
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 16 Sep 2025
Approved with Reservations
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Congratulations on a great research report. It focuses on an upstream neuroendocrine gene (KISS1) with mechanistic plausibility, also including haplotype analysis, Day 3–5 sampling attempt, and exclusion of recent HPG-altering medications with open data availability.
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HOW TO CITE THIS REPORT
Hamdan M. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:889 (https://doi.org/10.5256/f1000research.186221.r413858)
The direct URL for this report is:
https://f1000research.com/articles/14-889/v1#referee-response-413858
https://f1000research.com/articles/14-889/v1#referee-response-413858
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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