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PubMed2005

Granular self-organizing map (grSOM) for structure identification.

This work presents a useful extension of Kohonen's Self-Organizing Map (KSOM) for structure identification in linguistic (fuzzy) system modeling applications. More specifically the granular SOM neural model is presented for inducing a distribution of nonparametric fuzzy interval numbers (FINs) from the data. A FIN can represent a local probability distribution function and/or a conventional fuzzy set; moreover, a FIN is interpreted as an information granule. Learning is based on a novel metric distance d(K)(.,.) between FINs. The metric d(K)(.,.) can be tuned nonlinearly by a mass function m(x), the latter attaches a weight of significance to a real number 'x' in a data dimension. Rigorous analysis is based on mathematical lattice theory. A grSOM can cope with ambiguity by processing linguistic (fuzzy) input data and/or intervals. This work presents a simple grSOM variant, namely greedy grSOM, for classification. A genetic algorithm (GA) introduces tunable nonlinearities during training. Extensive comparisons are shown with related work from the literature. The practical effectiveness of the greedy grSOM is demonstrated comparatively in three benchmark classification problems. Statistical evidence strongly suggests that the proposed techniques improve classification performance. In addition, the greedy grSOM induces descriptive decision-making knowledge (fuzzy rules) from the training data.

Fuzzy Logic↗
PubMed1999

Variations in the recognition of echovirus type 11 strains by a group-specific anti-VP1 monoclonal antibody.

BACKGROUND: Mab 5-D8/1 is a monoclonal antibody (Mab) that was shown to be directed towards a conserved epitope of the capsid protein VP1 among the genus enterovirus. The use of this Mab for the routine detection of enteroviruses in clinical specimens led to the observation that several strains of echovirus type 11 (EV-11) could not be detected on spontaneously detached cells from 26-h cultures using a two-step immunofluorescence (IF) assay. Conversely, these strains were detected positive with the same Mab when tested on adherent or trypsinizated cells. OBJECTIVES: The aim of this study was to understand the misrecognition of some strains of EV-11 by this Mab. STUDY DESIGN AND RESULTS: IF tests at different times of the viral cycle brought evidence that the detection of a variant strain of EV-11 decreased rapidly with time, becoming undetectable 26 h post-infection, since the reference strain remained positive up to 46 h post-infection. The infective titres of the variant strains were shown to be high in comparison with those of well-recognised strains. Sequencing the Mab binding epitope confirmed that the variant strains exhibited no antigenic shift. CONCLUSION: These results suggest that the poor recognition of some strains of EV-11 by Mab 5-D8/1 is due to a rapid decrease of the expression of the binding epitope in the cell, maybe in relation with the high lytic power of these strains. From a practical point of view, our data indicate that a negative result when Mab 5-D8/1 is used for enterovirus typing must be interpreted cautiously with highly replicative strains and that detached cells should not be used for enterovirus identification under these circumstances.

Antibodies, Monoclonal↗
PubMedDate not supplied

Differential dimethyl labeling of N-termini of peptides after guanidination for proteome analysis.

We describe an enabling technique for proteome analysis based on isotope-differential dimethyl labeling of N-termini of tryptic peptides followed by microbore liquid chromatography (LC) matrix-assisted laser desorption and ionization (MALDI) mass spectrometry (MS). In this method, lysine side chains are blocked by guanidination to prevent the incorporation of multiple labels, followed by N-terminal labeling via reductive amination using d(0),(12)C-formaldehyde or d(2),(13)C-formaldehyde. Relative quantification of peptide mixtures is achieved by examining the MALDI mass spectra of the peptide pairs labeled with different isotope tags. A nominal mass difference of 6 Da between the peptide pair allows negligible interference between the two isotopic clusters for quantification of peptides of up to 3000 Da. Since only the N-termini of tryptic peptides are differentially labeled and the a(1) ions are also enhanced in the MALDI MS/MS spectra, interpretation of the fragment ion spectra to obtain sequence information is greatly simplified. It is demonstrated that this technique of N-terminal dimethylation (2ME) after lysine guanidination (GA) or 2MEGA offers several desirable features, including simple experimental procedure, stable products, using inexpensive and commercially available reagents, and negligible isotope effect on reversed-phase separation. LC-MALDI MS combined with this 2MEGA labeling technique was successfully used to identify proteins that included polymorphic variants and low abundance proteins in bovine milk. In addition, by analyzing a mixture of two equal amounts of milk whey fraction as a control, it is shown that the measured average ratio for 56 peptide pairs from 14 different proteins is 1.02, which is very close to the theoretical ratio of 1.00. The calculated percentage error is 2.0% and relative standard deviation is 4.6%.

Animals↗
PubMed1999

Diffusion and scaling in escapes from two-degrees-of-freedom Hamiltonian systems.

This paper summarizes an investigation of the statistical properties of orbits escaping from three different two-degrees-of-freedom Hamiltonian systems which exhibit global stochasticity. Each time-independent H=H(0)+ varepsilon H('), with H(0) an integrable Hamiltonian and varepsilon H(') a nonintegrable correction, not necessarily small. Despite possessing very different symmetries, ensembles of orbits in all three potentials exhibit similar behavior. For varepsilon below a critical varepsilon (0), escapes are impossible energetically. For somewhat higher values, escape is allowed energetically but still many orbits never escape. The escape probability P computed for an arbitrary orbit ensemble decays toward zero exponentially. At or near a critical value varepsilon (1)> varepsilon (0) there is a rather abrupt qualitative change in behavior. Above varepsilon (1), P typically exhibits (1) an initial rapid evolution toward a nonzero P(0)( varepsilon ), the value of which is independent of the detailed choice of initial conditions, followed by (2) a much slower subsequent decay toward zero which, in at least one case, is well fit by a power law P(t) proportional, variant t(-&mgr;), with &mgr; approximately 0.35-0.40. In all three cases, P(0) and the time T required to converge toward P(0) scale as powers of varepsilon - varepsilon (1), i.e., P(0) proportional, variant ( varepsilon - varepsilon (1))(alpha) and T proportional, variant ( varepsilon - varepsilon (1))(beta), and T also scales in the linear size r of the region sampled for initial conditions, i.e., T proportional, variant r(-delta). To within statistical uncertainties, the best fit values of the critical exponents alpha, beta, and delta appear to be the same for all three potentials, namely alpha approximately 0.5, beta approximately 0.4, and delta approximately 0.1, and satisfy alpha-beta-delta approximately 0. The transitional behavior observed near varepsilon (1) is attributed to the breakdown of some especially significant KAM tori or cantori. The power law behavior at late times is interpreted as reflecting intrinsic diffusion of chaotic orbits through cantori surrounding islands of regular orbits. (c) 1999 American Institute of Physics.

Journal Article↗
PubMed2001

Assessing non-metric skeleton characters as a morphological tool.

The appearance of non-metric skeletal characters in vertebrates results mainly from basic genetic control, as proved and documented for house mice and humans. Although the heritability of non-metric traits, mainly the presence of foramina and similar structures for blood vessels and nerves or dental occlusal variants, have been evaluated as rather low, the simultaneous consideration of several traits allows estimation of epigenetic variation in time and space as a result of genetic relationship. Thus, the main use of non-metric characters has been aimed at assessing epigenetic variability and divergence among populations. Applications extend from the problem of genetic isolation of populations, the lack of reproductive contact, detection of genetic drift, systematic studies to clarify species taxonomy, to phylogenetic interpretation. Additionally, non-directional deviations from bilateral symmetry in non-metric characters, e.g. fluctuating asymmetry, could be caused by current environmental conditions in general. Fluctuating asymmetry is regarded as a measure of developmental instability to indicate the presence of genomic changes or the influence of contamination and/or habitat deterioration, and is also used as a further population parameter with integrated information. However, standpoints on the use of fluctuating asymmetry are quite inconsistent, fluctuating themselves between considering it a powerful biomonitoring tool to being merely a curious scientific toy.

Journal Article↗
PubMed1995

Mammary Paget's disease confined to the areola and associated with multifocal Toker cell hyperplasia.

A hitherto unreported variant of mammary Paget's disease (MPD) limited to the areola, leaving the nipple unaffected, has been analyzed by serial sectioning of the whole areola and nipple. This otherwise characteristic MPD proved to be confined to the epidermis. There was no underlying carcinoma. This MPD was associated with a multifocal presence of monomorphic but otherwise similar cells in small collections surrounding the ostia of areolar mammary glands in the clinically unaffected area. This condition was interpreted as hyperplasia of mammary gland-related cells also found in normal nipples (so-called Toker cells). The observations hint at a possible derivation of some cases of mammary and extramammary Paget's disease from such Toker cells.

Antigens, Neoplasm↗
PubMed2005

Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis.

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)-binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of poleta and poliota to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of poleta is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

Amino Acid Motifs↗
PubMed1996

The presence of arterial anatomical variations can affect the results of duplex sonographic evaluation of penile vessels in impotent patients.

PURPOSE: Since penile arterial communications are present in a significant percentage of impotent patients, we evaluated whether peak systolic cavernous blood velocity after intracavernous prostaglandin E1 injection might be different in patients with and without arterial variants. MATERIALS AND METHODS: Cavernous blood flow was assessed with echo color Doppler ultrasound before and after intracavernous injection of prostaglandin E1 in 63 impotent patients. The penile shaft was accurately evaluated to detect arterial anatomical variants. Clinical erectile response was assessed by visual inspection and palpation. RESULTS: Of 23 patients who obtained a full erection with full rigidity after prostaglandin E1 injection the cavernous peak blood velocities in 11 with penile arterial communications were significantly less than those in 12 without arterial communications. CONCLUSIONS: The generally accepted limit of normal for cavernous peak blood flow obtained after prostaglandin E1 injection (greater than 25 to 30 cm. per second) must be interpreted carefully because lower peak blood velocities may be found in subjects with a full erectile response if arterial communications are present.

Alprostadil↗
PubMed2003

The characterization of somatic APC mutations in colonic adenomas and carcinomas in Ashkenazi Jews with the APC I1307K variant using linkage disequilibrium.

Mutations of the adenomatous polyposis coli (APC) gene play a critical role in the development of colorectal neoplasms. A novel mechanism involves a germline variant, at codon 1307 of the APC gene. The mutation is thought to create an unstable segment of DNA, which facilitates the development of somatic mutations. I1307K has been shown to be ancestral in Middle Eastern populations. The aim of the present study was to confirm this observation for a Western population and to utilize this information in the characterization of the somatic changes in colorectal neoplasia in carriers of I1307K. DNA from 182 US Ashkenazim was screened for the I1307K variant, which was found in 22 (12.1%), and the ancestral nature of this variant was confirmed in this population by showing that all of those with the I1307K variant carried a specific allele at the D5S346 locus, while the majority shared a D5S1385 allele. Subsequently, 79 neoplasms were analysed from 15 I1307K carriers for loss of heterozygosity (LOH) at the D5S346 locus. LOH was detected in 18 neoplasms (23%). Of these 18, four neoplasms showed loss of the I1307K-associated allele, while 14 neoplasms had retained the I1307K-associated allele and, by implication, the I1307K variant. PCR products were also cloned into a plasmid vector to isolate individual APC alleles. For those neoplasms with LOH, 13 of the 18 neoplasms (72%) had a somatic mutation, of which 12 involved the I307K-bearing chromosome. This study is consistent with two previous studies in showing that additional somatic mutations close to codon 1307 are almost always on the I1307K-bearing chromosome, but either allele may demonstrate LOH. Further evidence for the interpretation of the action of I1307K as producing DNA instability is provided by analysing multiple neoplasms from the same person and by showing that these neoplasms have differing patterns of LOH and associated somatic mutations.

Adenoma↗
PubMed1993

Covalent binding properties of the human complement protein C4 and hydrolysis rate of the internal thioester upon activation.

The complement proteins C3 and C4 have an internal thioester. Upon activation on the surface of a target cell, the thioester becomes exposed and reactive to surface-bound amino and hydroxyl groups, thus allowing covalent deposition of C3 and C4 on these targets. The two human C4 isotypes, C4A and C4B, which differ by only four amino acids, have different binding specificities. C4A binds more efficiently than C4B to amino groups, and C4B is more effective than C4A in binding to hydroxyl groups. By site-directed mutagenesis, the four residues in a cDNA clone of C4B were modified. The variants were expressed and their binding properties studied. Variants with a histidine residue at position 1106 showed C4B-like binding properties, and those with aspartic acid, alanine, or asparagine at the same position were C4A-like. These results suggest that the histidine is important in catalyzing the reaction of the thioester with water and other hydroxyl group-containing compounds. When substituted with other amino acids, this reaction is not catalyzed and the thioester becomes apparently more reactive with amino groups. This interpretation also predicts that the stability of the thioester in C4A and C4B, upon activation, will be different. We measured the time course of activation and binding of glycine to C4A and C4B. The lag in the binding curve behind the activation curve for C4A is significantly greater than that for C4B. The hydrolysis rates (k0) of the thioester in the activated proteins were estimated to be 0.068 s-1 (t1/2 of 10.3 s) for C4A and 1.08 s-1 (t1/2 of 0.64 s) for C4B. These results indicate that the difference in hydrolysis rate of the thioester accounts, at least in part, for the difference in the binding properties of C4A and C4B.

Amino Acid Sequence↗
PubMed1975

[Isolation of Drosophila melanogaster cell lines of different genotypes and study of multiplication of two variants of sigma rhabdovirus in those lines (author's transl)].

Strains of sigma virus which are called P- do not multiply in Drosophila strains called Paris, homozygous for the Pp allele of gene ref(2)P. Adsorption is normal and the virus is not destroyed. It seems that the viral function concerned is an early one. P+ variants isolated from a P- population do multiply in flies from the Paris strain. Three continuous cell lines homozygous for the Pp allele and one homozygous for the Po allele were isolated. Several attempts to infect those cell lines with P- and P+ variants of sigma virus were done. Cultures homozygous for the Pp allele reacted differently whether infection was initiated with P+ or P- viral strains, while cultures homozygous Po/Po gave the same result with both viral strains. Similarity between results obtained with two independent P- viral strains leads to the conclusion that the ref (2) P gene is active in cells from continuous cell lines; its Pp allele does not allow multiplication of P- viral types. An interpretation of the slight multiplication observed with concentrated inoculum is discussed.

Animals↗
PubMed2026

Integrated Genomic and Immune Profiling of Early Onset Lung Cancer in East Asians Reveals a Distinct Molecular Architecture.

BACKGROUND: The age cut-off for early-onset lung cancer (EOLC) varies across studies (40-50 years). Here, we define EOLC as diagnosis at &#x2264; 40 years, a threshold identifying a subgroup with distinct clinical characteristics. However, whether EOLC differs fundamentally from late-onset lung cancer (LOLC) at the molecular level and represents a distinct subtype requiring different management remains unclear. METHODS: This integrated analysis included genomic and immune profiling data from 8,021 lung cancer patients, comprising 302 EOLC and 7,719 LOLC cases. Using targeted sequencing, we assessed somatic and germline alterations, mutational signatures, and immune biomarkers including tumor mutational burden (TMB), MSI status, and PD-L1 expression. RESULTS: EOLC patients were more often female, had adenocarcinoma, and earlier-stage disease. Molecular profiling revealed significant enrichment of ERBB2 mutations in EOLC, while KRAS, TP53, and MET mutations were more common in LOLC. Mutational signature analysis indicated tobacco-related signatures predominated in LOLC, whereas endogenous processes contributed more substantially in EOLC. Germline analysis showed a higher burden of pathogenic variants in EOLC (14.57% vs. 8.93%, P < .01), with TP53 and BRCA1 being particularly prominent. Immunologically, LOLC tumors exhibited higher TMB and PD-L1 positivity. CONCLUSION: Integrated profiling establishes EOLC as a distinct molecular subtype, defined by a unique triad: an ERBB2-driven somatic profile, germline susceptibility in DNA damage response pathways, and an endogenous mutagenic process within a low-TMB microenvironment. The findings are specific to the selected threshold and should be interpreted accordingly, while elucidating EOLC pathogenesis and supporting age-specific management strategies.

Humans↗
PubMed2006

Beyond the data deluge: data integration and bio-ontologies.

Biomedical research is increasingly a data-driven science. New technologies support the generation of genome-scale data sets of sequences, sequence variants, transcripts, and proteins; genetic elements underpinning understanding of biomedicine and disease. Information systems designed to manage these data, and the functional insights (biological knowledge) that come from the analysis of these data, are critical to mining large, heterogeneous data sets for new biologically relevant patterns, to generating hypotheses for experimental validation, and ultimately, to building models of how biological systems work. Bio-ontologies have an essential role in supporting two key approaches to effective interpretation of genome-scale data sets: data integration and comparative genomics. To date, bio-ontologies such as the Gene Ontology have been used primarily in community genome databases as structured controlled terminologies and as data aggregators. In this paper we use the Gene Ontology (GO) and the Mouse Genome Informatics (MGI) database as use cases to illustrate the impact of bio-ontologies on data integration and for comparative genomics. Despite the profound impact ontologies are having on the digital categorization of biological knowledge, new biomedical research and the expanding and changing nature of biological information have limited the development of bio-ontologies to support dynamic reasoning for knowledge discovery.

Animals↗
PubMed2005

On derivatives of surface charge curves of minerals.

Surface titrations of minerals in aqueous electrolyte solutions are used as building blocks for surface complexation modelling. However, these potentiometric data may contain less model relevant information than previously and presently assumed. In the literature, derivative analyses have been applied to experimental surface charge versus pH curves and four or more pK values were extracted for goethite or aluminium oxide. Derivative analysis of specific surface charge versus pH curves calculated for various published model variants for goethite shows that not more than the net-zero proton surface charge condition can be extracted from computer generated data. Generated data can be produced in density and precision superior to experimental data, but yield only relatively little output from such derivative analysis compared to what has previously been extracted from derivatives of experimental data. For the generated goethite data and for all model variants only the point of zero could be extracted. For the various goethite model variants tested a nearly symmetrical peak appeared at the point of zero charge in the derivative curve. A different pattern could be obtained for generic models, for which two sites with unequal sites densities and different pK values were assumed. Variation of these parameters could result in derivatives of the charging curves with two maxima or one maximum and a broad tailing. In the literature, curves with features nearly identical to these generated curves have been interpreted by up to four pK values (i.e., four different sites within a 1-pK model). It is concluded that the interpretation of the generated data is in all cases hampered by the overwhelming electrostatic contributions to the free energy of proton ad/desorption. In no case except for the one-site 1-pK model was it possible to extract the input pK value(s) from the derivatives. Plausible explanations for the discrepancy between generated data and published experimental data are discussed.

Journal Article↗
PubMed1979

Relationship between antibiotic resistance, the production of "virulence factors", and virulence for experimental animals in Staphylococcus aureus.

Variants that had lost some of their antibiotic-resistance determinants were selected from a multiple-antibiotic-resistant strain of Staphylococcus aureus. When tested by subcutaneous injection into guinea-pigs, and measured as the number of cocci needed to produce a skin lesion of an arbitrarily chosen diameter, the virulence of strains fell progressively with loss of resistance determinants. When the staphylococci were injected intracutaneously into mice, however, the results were less easy to interpret, but loss of resistance appeared to be associated with a reduction of the slope of the dose-response line. There was no association between the antibiogram of the strains and their production of certain enzymes and haemolysins.

Animals↗
PubMed2000

A high frequency of XO offspring from X(Paf)Y* male mice: evidence that the Paf mutation involves an inversion spanning the X PAR boundary.

It has previously been reported that 19% of the daughters of males carrying the X-linked mutation patchy fur (Paf) are XO with a maternally derived X chromosome. We now report that hemizygous Paf males that also carry the variant Y chromosome Y*, show a much increased XO production ( approximately 40% of daughters). We hypothesize that the Paf mutation is associated with an inversion spanning the pseudoautosomal region (PAR) boundary, and that this leads to preferential crossing over between the resulting inverted region of PAR and an equivalent inverted PAR region within the compound Y* PAR. This would lead to the production of dicentric X and acentric Y products and consequent sex chromosome loss. This interpretation is supported by analysis of the sex chromosome complements at the second meiotic metaphase, which revealed a high incidence of dicentrics. Another curious feature of the Paf mutation is that mice that are homozygous Paf have more hair than mice that are hemizygous Paf. This can be explained if the Paf mutation is a hypomorphic mutation that escapes X inactivation because, unlike the wild type allele, it is now located within the PAR.

Animals↗
PubMed2004

Evolutionary relationships of Aurora kinases: implications for model organism studies and the development of anti-cancer drugs.

BACKGROUND: As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. RESULTS: Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. CONCLUSIONS: In this study, we found that invertebrate Aurora-A and Aurora-B kinases are highly divergent protein families from their chordate counterparts. Furthermore, while the Aurora-A family is ubiquitous among all vertebrates, the Aurora-B and Aurora-C families in humans arose from a gene duplication event in mammals. These findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. In addition, given the important role of Aurora kinases in cancer, evolutionary analysis and comparisons of ATP-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both Aurora-B and Aurora-C kinases.

Amino Acid Sequence↗
PubMed2026

Genetically Predicted Gene Expression and Circulating Metabolites Associated with Cervical High-Grade Squamous Intraepithelial Lesion: A Mendelian Randomization Study.

BACKGROUND: High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition of the cervix. Identifying risk factors associated with HSIL and understanding their potential mechanisms may inform prevention strategies. This study aimed to investigate the associations of genetically predicted gene expression and circulating metabolites with HSIL risk using Mendelian randomization (MR). METHODS: We performed two-sample MR analysis to evaluate the associations of genetically predicted gene expression (eQTLGen consortium, N=31,684) and circulating metabolites (genome-wide association study [GWAS], N=8,299) with HSIL risk (FinnGen R12, N=293,218; 8,291 cases). Mediation analysis was conducted to explore whether metabolites might mediate the associations between genes and HSIL. Sensitivity analyses, including Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out, and colocalization, were performed to assess the robustness of the findings. All GWAS data used in this study were derived from European-ancestry populations. RESULTS: Eleven genes showed significant associations with HSIL after false discovery rate (FDR) correction (q<0.05), including VWA7, PAX8, GUSBP1, IKZF3, PAX8-AS1, NFKBIL1 (interpret with caution due to an influential single nucleotide polymorphism [SNP]), ERBB2, COL11A2, SKIV2L, TCF19, and PGAP3. Eleven circulating metabolites were also significantly associated with HSIL. Mediation analysis suggested that two phospholipid metabolites (GCST90200685 and GCST90200692) might mediate a small proportion of the total protective association of COL11A2 with HSIL (1.46% and 1.45%, respectively), indicating that the protective association of COL11A2 is largely independent of these circulating metabolites. Colocalization analysis showed strong evidence of shared causal variants for eight genes (PP.H4>0.98), while COL11A2 showed weak evidence of colocalization (PP.H4=1.58&#xd7;10-15). Functional enrichment analysis indicated that COL11A2-related genes were enriched in extracellular matrix (ECM)-receptor interaction and PI3K-Akt signaling pathways. CONCLUSION: This MR study identified 11 genes and 11 circulating metabolites associated with HSIL risk. Among these, COL11A2 showed a protective association that appeared to be largely independent of circulating phospholipid metabolites, suggesting potential local mechanisms. These findings provide genetic and metabolic clues for future studies on HSIL etiology.

COL11A2↗