ADAM metallopeptidase with thrombospondin type 1 motif 16 is a potential marker for prognosis in clear cell renal cell carcinoma.

The mortality rate of clear cell renal cell carcinoma (ccRCC) remains high. Immunohistochemical staining, Western blotting and real-time quantitative polymerase chain reaction were employed to evaluate ADAM (a disintegrin and metalloproteinase) metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) levels in ccRCC tissues and paired normal tissues, and all tissues were obtained from clinical samples of 46 cases of ccRCC patients. Moreover, we analyzed the role ADAMTS16 in the progression of ccRCC using Cell Counting Kit-8 assay and flow cytometry. ADAMTS16 levels in ccRCC tissues were markedly low, relative to normal tissues, and ADAMTS16 level closely correlated with tumor stage, lymph node metastasis as well as pathological grade. Patients with elevated ADAMTS16 expressions have a more favorable survival outcome, relative to patients with low expression of ADAMTS16. In vitro study showed ADAMTS16 expression markedly decreased in ccRCC cells and acted as a tumor suppressor compared with the normal cells. The expression of ADAMTS16 is down-regulated in ccRCC tissues, relative to normal tissues, and it may inhibit the malignancies of ccRCC. Such inhibitory effect may be ascribed to the involvement of AKT/mammalian target of rapamycin signaling. Hence, the present study of ADAMTS16 will provide new insight into the underlying biological mechanisms of ccRCC.

The C-Mannosylome of Human Induced Pluripotent Stem Cells Implies a Role for ADAMTS16 C-Mannosylation in Eye Development.

C-mannosylation is a modification of tryptophan residues with a single mannose and can affect protein folding, secretion, and/or function. To date, only a few proteins have been demonstrated to be C-mannosylated, and studies that globally assess protein C-mannosylation are scarce. To interrogate the C-mannosylome of human induced pluripotent stem cells, we compared the secretomes of CRISPR-Cas9 mutants lacking either the C-mannosyltransferase DPY19L1 or DPY19L3 to WT human induced pluripotent stem cells using MS-based quantitative proteomics. The secretion of numerous proteins was reduced in these mutants, including that of A Disintegrin And Metalloproteinase with ThromboSpondin Motifs 16 (ADAMTS16), an extracellular protease that was previously reported to be essential for optic fissure fusion in zebrafish eye development. To test the functional relevance of this observation, we targeted dpy19l1 or dpy19l3 in embryos of the Japanese rice fish medaka (Oryzias latipes) by CRISPR-Cas9. We observed that targeting of dpy19l3 partially caused defects in optic fissure fusion, called coloboma. We further showed in a cellular model that DPY19L1 and DPY19L3 mediate C-mannosylation of a recombinantly expressed thrombospondin type 1 repeat of ADAMTS16 and thereby support its secretion. Taken together, our findings imply that DPY19L3-mediated C-mannosylation is involved in eye development by assisting secretion of the extracellular protease ADAMTS16.

The Novel Protein ADAMTS16 Promotes Gastric Carcinogenesis by Targeting IFI27 through the NF-κb Signaling Pathway.

A disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16) has been reported to be involved in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) is unclear. In this study, the role of ADAMTS16 in gastric cancer was investigated. The effects of ADAMTS16 on cell migration, invasion, and proliferation were investigated by functional experiments in vivo and in vitro. Downstream signal pathways of ADAMTS16 were confirmed by using bioinformatics analysis, co-immunoprecipitation, and immunofluorescence. Meanwhile, bioinformatics analysis, qRT-PCR, western blot, and dual-luciferase reporter gene analysis assays were used to identify ADAMTS16 targets. The expression of ADAMTS16 in GC was analyzed in public datasets. The expression of ADAMTS16 and its correlations with the clinical characteristics of GC were investigated by immunohistochemistry. Ectopic ADAMTS16 expression significantly promoted tumor cell migration, invasion, and growth. Bioinformatics analysis and western blot showed that ADAMTS16 upregulated the IFI27 protein through the NF-κb pathway, which was confirmed by immunofluorescence and western blot. Dual-luciferase reporter gene analysis identified a binding site between P65 and IFI27 that may be directly involved in the transcriptional regulation of IFI27. IFI27 knockdown reversed the promoting effect of ADAMTS16 on cell invasion, migration, and proliferation indicating that ADAMTS16 acts on GC cells by targeting the NF-κb/IFI27 axis. ADAMTS16 was associated with poor prognosis in clinical characteristics. ADAMTS16 promotes cell migration, invasion, and proliferation by targeting IFI27 through the NF-κB pathway and is a potential progressive and survival biomarker of GC.

Aberrant DNA methylation of ADAMTS16 in colorectal and other epithelial cancers.

BACKGROUND: ADAMs (a disintegrin and metalloproteinase) have long been associated with tumor progression. Recent findings indicate that members of the closely related ADAMTS (ADAMs with thrombospondin motifs) family are also critically involved in carcinogenesis. Gene silencing through DNA methylation at CpG loci around e.g. transcription start or enhancer sites is a major mechanism in cancer development. Here, we aimed at identifying genes of the ADAM and ADAMTS family showing altered DNA methylation in the development or colorectal cancer (CRC) and other epithelial tumors. METHODS: We investigated potential changes of DNA methylation affecting ADAM and ADAMTS genes in 117 CRC, 40 lung cancer (LC) and 15 oral squamous-cell carcinoma (SCC) samples. Tumor tissue was analyzed in comparison to adjacent non-malignant tissue of the same patients. The methylation status of 1145 CpGs in 51 ADAM and ADAMTS genes was measured with the HumanMethylation450 BeadChip Array. ADAMTS16 protein expression was analyzed in CRC samples by immunohistochemistry. RESULTS: In CRC, we identified 72 CpGs in 18 genes which were significantly affected by hyper- or hypomethylation in the tumor tissue compared to the adjacent non-malignant tissue. While notable/frequent alterations in methylation patterns within ADAM genes were not observed, conspicuous changes were found in ADAMTS16 and ADAMTS2. To figure out whether these differences would be CRC specific, additional LC and SCC tissue samples were analyzed. Overall, 78 differentially methylated CpGs were found in LC and 29 in SCC. Strikingly, 8 CpGs located in the ADAMTS16 gene were commonly differentially methylated in all three cancer entities. Six CpGs in the promoter region were hypermethylated, whereas 2 CpGs in the gene body were hypomethylated indicative of gene silencing. In line with these findings, ADAMTS16 protein was strongly expressed in globlet cells and colonocytes in control tissue but not in CRC samples. Functional in vitro studies using the colorectal carcinoma cell line HT29 revealed that ADAMTS16 expression restrained tumor cell proliferation. CONCLUSIONS: We identified ADAMTS16 as novel gene with cancer-specific promoter hypermethylation in CRC, LC and SCC patients implicating ADAMTS16 as potential biomarker for these tumors. Moreover, our results provide evidence that ADAMTS16 may have tumor suppressor properties.

A novel role of ADAMTS16 in renal fibrosis through activating TGF-ß/Smad signaling.

Chronic Kidney Disease (CKD) has emerged as a global public health concern, with its primary pathological basis being Renal Fibrosis (RF), crucial to halt its progression to End-Stage Renal Disease (ESRD). However, effective treatment options are currently lacking. Therefore, exploring the mechanisms of RF, identifying drug targets and diagnostic biomarkers are important. In this study, we identified ADAMTS16 as a newly expressed regulatory factor highly expressed in renal fibrosis tissue. ADAMTS16 interacts with latency-associated peptide (LAP)-transforming growth factor (TGF)-ß, leading to the activation of TGF-ß. Loss of ADAMTS16 expression effectively reduces TGF-ß-dependent transcription activity. Furthermore, the use of RRFR tetrapeptide derived from ADAMTS16 can activate the TGF-ß/Smad signaling axis, promoting RF. In summary, ADAMTS16 is induced in the progression of CKD, interacting with LAP-TGF-ß and potentially activating SMAD2/3. Therefore, targeting ADAMTS16 may serve as a crucial new strategy to alleviate RF and treat CKD patients.

ADAMTS16 Suppression by MicroRNA-25 Leads to Oncogenic Properties in Renal Cell Carcinoma.

INTRODUCTION: Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in modulating tumor growth. This study is centered on investigating the contribution of miR-25 to the progression of Renal Cell Carcinoma (RCC). METHODS: The investigators examined the expression levels of miR-25 and ADAMTS16 in RCC samples and cell lines. The association between miR-25 and ADAMTS16 was validated via a luciferase reporter assay. Cell viability, apoptosis, migration, and invasion were evaluated utilizing CCK-8 and flow cytometry techniques, while the expression levels of ADAMTS16, ß-catenin, GSK-3ß, and p-GSK-3ß were assessed through western blot analysis. RESULTS: The investigation revealed elevated expression levels of miR-25 in RCC tissues. Subsequently, ADAMTS16 was identified as a target of miR-25. Increased miR-25 levels were associated with decreased expression of ADAMTS16, resulting in enhanced cell viability and diminished apoptosis. Conversely, inhibition of miR-25 led to decreased cell viability, proliferation, and migration. Additionally, the researchers observed that miR-25 triggered the phosphorylation of GSK-3ß and ß-catenin while leaving the total GSK-3ß level unaffected. CONCLUSION: This study suggests that miR-25 regulates the expression of ADAMTS16 through the Wnt/ß-catenin signaling pathway, providing new insights into the cause and potential treatment of RCC.

Genetic predictors of risk and resilience in psychiatric disorders: a cross-disorder genome-wide association study of functional impairment in major depressive disorder, bipolar disorder, and schizophrenia.

Functional impairment is one of the most enduring, intractable consequences of psychiatric disorders and is both familial and heritable. Previous studies have suggested that variation in functional impairment can be independent of symptom severity. Here we report the first genome-wide association study (GWAS) of functional impairment in the context of major mental illness. Participants of European-American descent (N = 2,246) were included from three large treatment studies of bipolar disorder (STEP-BD) (N = 765), major depressive disorder (STAR*D) (N = 1091), and schizophrenia (CATIE) (N = 390). At study entry, participants completed the SF-12, a widely used measure of health-related quality of life. We performed a GWAS and pathway analysis of the mental and physical components of health-related quality of life across diagnosis (∼1.6 million single nucleotide polymorphisms), adjusting for psychiatric symptom severity. Psychiatric symptom severity was a significant predictor of functional impairment, but it accounted for less than one-third of the variance across disorders. After controlling for diagnostic category and symptom severity, the strongest evidence of genetic association was between variants in ADAMTS16 and physical functioning (P = 5.87 × 10(-8) ). Pathway analysis did not indicate significant enrichment after correction for gene clustering and multiple testing. This study illustrates a phenotypic framework for examining genetic contributions to functional impairment across psychiatric disorders.

Quantitative proteomics identifies tumour matrisome signatures in patients with non-small cell lung cancer.

Introduction: The composition and remodelling of the extracellular matrix (ECM) are important factors in the development and progression of cancers, and the ECM is implicated in promoting tumour growth and restricting anti-tumour therapies through multiple mechanisms. The characterisation of differences in ECM composition between normal and diseased tissues may aid in identifying novel diagnostic markers, prognostic indicators and therapeutic targets for drug development. Methods: Using tissue from non-small cell lung cancer (NSCLC) patients undergoing curative intent surgery, we characterised quantitative tumour-specific ECM proteome signatures by mass spectrometry. Results: We identified 161 matrisome proteins differentially regulated between tumour tissue and nearby non-malignant lung tissue, and we defined a collagen hydroxylation functional protein network that is enriched in the lung tumour microenvironment. We validated two novel putative extracellular markers of NSCLC, the collagen cross-linking enzyme peroxidasin and a disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16), for discrimination of malignant and non-malignant lung tissue. These proteins were up-regulated in lung tumour samples, and high PXDN and ADAMTS16 gene expression was associated with shorter survival of lung adenocarcinoma and squamous cell carcinoma patients, respectively. Discussion: These data chart extensive remodelling of the lung extracellular niche and reveal tumour matrisome signatures in human NSCLC.

Interplay between collagenase and undescended testes in Adamts16 knockout rats.

BACKGROUND: The inguinoscrotal stage of testicular descent is characterized by an increase in cell density and collagen fibers as the gubernaculum undergoes cell division and increases Extracellular Matrix (ECM) activity. Rats that lack the enzyme Adamts16, a known ECM proteinase, develop cryptorchidism postnatally and are infertile. Therefore, this study aims to investigate the link between the Adamts16 enzyme and congenital undescended testes (UDT) in Adamts16 knockout (KO) rats during postnatal development. METHODS: Formalin-fixed specimens of Wild-Type, Adamts16 heterozygous and Adamts16 homozygous KO rats post birth were sectioned and used for standard H&E histology and Masson's trichrome staining. A quantitative analysis on image J was performed to determine the intensity of collagen fibers within the inguinoscrotal fat pad (IFP) (n = 3 age/genotype). RESULTS: The migration of the gubernaculum within the Adamts16 heterozygous and Adamts16 KO rat was considerably disrupted. Furthermore, the Masson's trichrome staining demonstrated a significant increase in collagen fibers around the gubernaculum of rats that lacked Adamts16 enzyme at day 8. CONCLUSION: This study reports a failure of gubernacular migration leading to UDT in Adamts16 KO rats during development, suggesting that the expression of Adamts16 gene is critical for normal gubernacular migration through the breakdown of collagen fibers within the IFP.

ADAMTS16 activates latent TGF-ß, accentuating fibrosis and dysfunction of the pressure-overloaded heart.

AIMS: Cardiac fibrosis is a major cause of heart failure (HF), and mediated by the differentiation of cardiac fibroblasts into myofibroblasts. However, limited tools are available to block cardiac fibrosis. ADAMTS16 is a member of the ADAMTS superfamily of extracellular protease enzymes involved in extracellular matrix (ECM) degradation and remodelling. In this study, we aimed to establish ADAMTS16 as a key regulator of cardiac fibrosis. METHODS AND RESULTS: Western blot and qRT-PCR analyses demonstrated that ADAMTS16 was significantly up-regulated in mice with transverse aortic constriction (TAC) associated with left ventricular hypertrophy and HF, which was correlated with increased expression of Mmp2, Mmp9, Col1a1, and Col3a1. Overexpression of ADAMTS16 accelerated the AngII-induced activation of cardiac fibroblasts into myofibroblasts. Protein structural analysis and co-immunoprecipitation revealed that ADAMTS16 interacted with the latency-associated peptide (LAP)-transforming growth factor (TGF)-ß via a RRFR motif. Overexpression of ADAMTS16 induced the activation of TGF-ß in cardiac fibroblasts; however, the effects were blocked by a mutation of the RRFR motif to IIFI, knockdown of Adamts16 expression, or a TGF-ß-neutralizing antibody (ΝAb). The RRFR tetrapeptide, but not control IIFI peptide, blocked the interaction between ADAMTS16 and LAP-TGF-ß, and accelerated the activation of TGF-ß in cardiac fibroblasts. In TAC mice, the RRFR tetrapeptide aggravated cardiac fibrosis and hypertrophy by up-regulation of ECM proteins, activation of TGF-ß, and increased SMAD2/SMAD3 signalling, however, the effects were blocked by TGF-ß-NAb. CONCLUSION: ADAMTS16 promotes cardiac fibrosis, cardiac hypertrophy, and HF by facilitating cardiac fibroblasts activation via interacting with and activating LAP-TGF-ß signalling. The RRFR motif of ADAMTS16 disrupts the interaction between ADAMTS16 and LAP-TGF-ß, activates TGF-ß, and aggravated cardiac fibrosis and hypertrophy. This study identifies a novel regulator of TGF-ß signalling and cardiac fibrosis, and provides a new target for the development of therapeutic treatment of cardiac fibrosis and HF.

Microglandular adenosis is an advanced precursor breast lesion with evidence of molecular progression to matrix-producing metaplastic carcinoma.

Microglandular adenosis (MGA) is a rare breast lesion reported to be associated with invasive carcinoma in up to 20% to 30% of cases and has been proposed as a nonobligate precursor to basal-like breast cancers. We identified a case of matrix-producing metaplastic carcinoma with morphologic and immunohistochemical evidence of progression from MGA to atypical MGA, carcinoma in situ, and invasive carcinoma. We performed whole-exome sequencing of each component (MGA, atypical MGA, carcinoma in situ, and cancer) to characterize the mutational landscape of these foci. There was a significant copy number overlap between all foci, including a segmental amplification of the CCND1 locus (partial chromosome 11 trisomy) and MYC (8q24.12-13). Using a bioinformatics approach, we were able to identify 3 putative mutational clusters and recurrent, stop-gain nonsynonymous mutations in both ZNF862 and TP53 that were shared across all foci. Finally, we identified a novel deleterious splice-acceptor site mutation of chr5:5186164 G>T (chromosome 5p15) encoding the gene, ADAMTS16, in the invasive component.

Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study.

Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10-5, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10-4, OR 2.77; combined data set P = 2.7 × 10-8, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10-6, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10-2) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10-2). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT. KEY MESSAGES: We identified and validated a HIT-associated locus on chromosome 5. Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates. In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus.

ADAMTS16 mutations sensitize ovarian cancer cells to platinum-based chemotherapy.

Ovarian cancer is one of the most lethal malignant tumors in women. The prognosis of ovarian cancer patients depends, in part, on their response to platinum-based chemotherapy. Our recent analysis of genomics and clinical data from the Cancer Genome Atlas demonstrated that somatic mutations of ADAMTS 1, 6, 8, 9, 15, 16, 18 and L1 genes were associated with higher sensitivity to platinum and longer progression-free survival, overall survival, and platinum-free survival duration in 512 patients with high-grade serous ovarian carcinoma. Among the ADAMTS mutations, ADAMTS16 is the most commonly affected gene in ovarian cancer. However, the functional role of these mutations in ovarian cancer cells is largely unknown. We performed in vitro studies to compare the functional effects of the six identified ADAMTS missense mutations on the platinum sensitivity of ovarian cancer cells. We also used a well-characterized in vivo mouse model to evaluate the response of ovarian cancer cells with ADAMTS16 mutations to platinum-based therapy. Our results showed that exogenously expressed ADAMTS16 missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth in vivo. Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed ADAMTS16 mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of ADAMTS16 actively contribute to therapeutic response in ovarian cancer.

Evaluation of ADAMTS12, ADAMTS16, ADAMTS18 and IL-33 serum levels in pre-eclampsia.

OBJECTIVE: Pre-eclampsia is the result of impaired trophoblast invasion and spiral artery remodeling managed by inflammatory response in its etiology and physiopathology. The aim of this study was to compare serum molecules including IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels between pre-eclampsia and control groups and to investigate the role of these molecules in pre-eclampsia. METHODS: Forty-one women diagnosed as pre-eclampsia between 30 and 40 weeks of gestation and 41 non-complicated pregnant women were enrolled in this cross-sectional, case-control prospective study. ELISA method was used to determine IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels within serums in two groups. RESULTS: Serum ADAMTS12 and IL-33 levels were significantly lower in pre-eclampsia group (p < 0.001 and p: 0.028, respectively), however, in sub-group analysis, no significant difference was observed (p > 0.05). The cut-off value of ADAMTS12 levels to discriminate pre-eclampsia with %73.17 sensitivity and %92.68 specificity was 8.27 ng/ml while the cut-off value for IL-33 was 0.23 pg/ml with 82.93% sensitivity and 53.66% specificity. CONCLUSION: Pre-eclampsia is associated with lower serum IL-33 and ADAMTS12 levels.

The Investigation of ADAMTS16 in Insulin-Induced Human Chondrosarcoma Cells.

OBJECTIVES: A disintegrin-like metalloproteinase with thrombospondin motifs (ADAMTS) is a group of proteins that have enzymatic activity secreted by cells to the outside extracellular matrix. Insulin induces proteoglycan biosynthesis in chondrosarcoma chondrocytes. The purpose of the present in vitro study is to assess the time course effects of insulin on ADAMTS16 expression in OUMS-27 (human chondrosarcoma) cell line to examine whether insulin regulates ADAMTS16 expression as well as proteoglycan biosynthesis with multifaceted properties or not. METHODS: Chondrosarcoma cells were cultured in Dulbecco's modified Eagle's medium having either 10 µg/mL insulin or not. While the experiment was going on, the medium containing insulin had been changed every other day. Cells were harvested at 1st, 3rd, 7th, and 11th days; subsequently, RNA and proteins were isolated in every experimental group according to their time interval. RNA expression of ADAMTS was estimated by quantitative real-time polymerase chain reaction (qRT-PCR) by using primers. Immunoreactive protein levels were encountered by the western blot protein detection technique by using proper anti-ADAMTS16 antibodies. RESULTS: ADAMTS16 mRNA expression level of chondrosarcoma cells was found to be insignificantly decreased in chondrosarcoma cells induced by insulin detected by the qRT-PCR instrument. On the other hand, there was a gradual decrease in immune-reactant ADAMTS16 protein amount by the time course in insulin-treated cell groups when compared with control cells. CONCLUSION: It has been suggested that insulin might possibly regulate ADAMTS16 levels/activities in OUMS-27 chondrosarcoma cells taking a role in extracellular matrix turnover.

Interaction between thyroglobulin and ADAMTS16 in premature ovarian failure.

OBJECTIVE: The aim of the present study was to examine whether interactions between polymorphisms in the thyroglobulin and ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) genes are associated with the development of premature ovarian failure (POF). METHODS: A total of 75 patients with POF and 196 controls were involved in this study. We used a GoldenGate assay to genotype single nucleotide polymorphisms (SNPs). Logistic regression analysis was performed to identify POF-associated polymorphisms and synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes. RESULTS: Single gene analyses using logistic regression analysis showed no significant association between polymorphisms in the two genes and POF. In the results from interaction analyses, we found seven synergistic interactions between the polymorphisms in thyroglobulin and ADAMTS16, although there was no combination showing p-values lower than the significant threshold using the Bonferroni correction. When the AG genotype was present at the rs853326 missense SNP, the A and G alleles at the tagging SNPs rs16875268 and rs13168665 showed significant interactions (odds ratios=5.318 and 16.2 respectively; 95% confidence intervals, 1.64-17.28 and 2.08-126.4; p=0.0054 and 0.0079). CONCLUSION: Synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes were associated with an increased risk of POF development in Korean women.