ABSTRACT
Genetic polymorphism in pathogen recognition receptors tends to influence infection, disease susceptibility, and progression. We analyzed the association of TLR4 and TLR9 gene polymorphisms with multiple hrHPV infections and HPV16 copy number in cervicitis and cervical cancer. A total of 440 cervical cancer, cervicitis, and healthy individuals were studied using PCR-based assays. Student t-test, chi-square test, Welch's t-test, and Fisher's Exact test were utilized to evaluate the association of HPV infection with polymorphisms. Haploview and FAMHAP were used to analyze haplotype association with HPV infection and viral load. Study results revealed HPV45 infection as the most common one in cervical cancer after HPV16, and one-fourth HPV positive cervical cancer patients possessed multiple HPV infections. Mean HPV16 copy number of 264.4 ± 58.7 and 2.1 ± 3.3 copies/cell was detected in cervical cancer and cervicitis, respectively. TLR4 rs10759931 was protective against multiple hrHPV infections. TLR4 haplotype ACAC was associated with an increased risk of multiple hrHPV infections. TLR9 SNPs rs187084, rs352140, and rs352139 were associated with decreased risk of high HPV16 copy number. Augmentation of efforts for the multivalent HPV vaccination in India is suggested. The analyzed polymorphisms were shown to modulate hrHPV co-infections and HPV16 viral load that warrants further analysis.
Subject(s)
Uterine Cervical Neoplasms , Uterine Cervicitis , DNA Copy Number Variations , Female , Haplotypes , Human papillomavirus 16/genetics , Humans , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/geneticsABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
BACKGROUND: Cervicitis is one of the major health problems amongst women caused by infection of various pathogens including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) as well as human papillomavirus (HPV), and persistent cervical inflammation is one of the etiologic agents of cervical cancer. Toll-like receptors (TLRs) play an important role in the recognition and subsequent elimination of these pathogens. Variations in the Toll-like receptor genes influence susceptibility to pathogens as well as disease progression independently. METHODS: Ten single nucleotide polymorphisms, five each of TLR4 and TLR9 genes were analyzed among 130 cervicitis patients and 150 controls either using polymerase chain reaction-restriction fragment length polymorphism or allele specific-PCR. RESULTS: T. vaginalis infection was found at the highest frequency (30.7%) as compared to C. trachomatis (1.5%), N. gonorrhoeae (2.3%) and HPV (4.6%) infections in cervicitis patients. TLR4 rs11536889 CC (age-adjusted OR, 2.469 [95% CI, 1.499 to 4.065]; p < 0.001) and TLR9 rs187084 TC (age-adjusted OR, 2.165 [95% CI, 1.267-3.699]; p = 0.005) genotypes showed the higher distribution in cervicitis patients compared to controls. In addition, TLR4 rs11536889 C allele was shown to increase the risk of cervicitis (age-adjusted OR, 1.632 [95% CI, 1.132 to 2.352]; p = 0.009) compared to controls. The TLR4 haplotype GCA (OR, 0.6 [95% CI, 0.38-0.95]; p = 0.0272) and TLR9 haplotype GTA (OR, 1.99 [95% CI, 1.14-3.48]; p = 0.014) were found to be associated with decreased and increased risk of cervicitis respectively. CONCLUSIONS: TLR4 and TLR9 polymorphisms, as well as haplotypes were shown to modulate the cervicitis risk.
Subject(s)
Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics , Uterine Cervicitis/diagnosis , Alleles , Case-Control Studies , Chlamydia trachomatis/genetics , Chlamydia trachomatis/isolation & purification , Female , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Linkage Disequilibrium , Neisseria gonorrhoeae/genetics , Neisseria gonorrhoeae/isolation & purification , Odds Ratio , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Polymorphism, Single Nucleotide , Risk Factors , Trichomonas vaginalis/genetics , Trichomonas vaginalis/isolation & purification , Uterine Cervicitis/genetics , Uterine Cervicitis/microbiology , Uterine Cervicitis/virologyABSTRACT
Single nucleotide polymorphisms (SNPs) in TLR genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer. The present study was therefore designed to ascertain the role of TLR4 and TLR9 SNPs and haplotypes to hrHPV infection and cervical cancer susceptibility. The study included 110 cervical cancer biopsies and 141 cervical smears from age-matched healthy controls of Gujarati ethnicity of Western India. hrHPV 16 and 18 were detected using Real-time PCR. Eight SNPs, four each in TLR4 and TLR9 were analyzed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism and Allele-Specific PCR. HPV 16 and 18 were detected in 68% cervical cancer cases. TLR4 rs4986790, rs1927911 and TLR9 rs187084 showed association with HPV 16/18 infection. CC and CT genotypes of TLR4 rs11536889 and rs1927911 respectively, and TC, CC genotypes of TLR9 rs187084, as well as minor alleles of TLR4 rs4986790 and TLR9 rs187084, were associated with the increased risk of cervical cancer. Stage-wise analysis revealed TLR9 rs187084 and rs352140 to be associated with early-stage cancer. TLR4 haplotype GTAC and TLR9 haplotype GATC were associated with the increased risk of cervical cancer while TLR4 haplotype GCAG was associated with the decreased risk. TLR4 haplotype GCAG and TLR9 haplotype GATC showed association with increased susceptibility to hrHPV infection. In conclusion, the present study revealed association of TLR4 and TLR9 polymorphisms and haplotypes with hrHPV infection and cervical cancer risk. Further evaluation of a larger sample size covering diverse ethnic populations globally is warranted.
Subject(s)
Human papillomavirus 16/genetics , Human papillomavirus 18/genetics , Papillomavirus Infections/genetics , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics , Uterine Cervical Neoplasms/virology , Adult , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Middle Aged , Polymorphism, Restriction Fragment Length , Polymorphism, Single Nucleotide , Uterine Cervical Neoplasms/geneticsABSTRACT
Background: This study aims to compare the value of the Bishop score and cervical length measurement by transvaginal ultrasonography in predicting active labor within 6 h, induction-to-delivery interval, and the duration of active labor and to estimate the most useful cutoff points for the two methods. Methods: This is a prospective comparative study of Bishop score and cervical length measured by transvaginal sonography on 62 nulliparous subjects who underwent induction of labor. Results: The Bishop score of the subjects ranged from two to seven (2-7). The mean Bishop in this study population was 4.37 + 1.23. The mean cervical length in this study was 25.59 + 6.07. Bishop score was highly significant (P value < 0.0001) in predicting active phase of labor as compared to cervical length (P = 0.004). The best cutoff value for Bishop score to predict induction of labor within 6 h was more than 4 with sensitivity of 69% and specificity of 79%. Similarly, best cutoff value for cervical length to predict induction of labor within 6 h was less than or equal to 25 mm with sensitivity of 51% and specificity of 70%. Bishop score was more significant (P = 0.001) in predicting induction-to-delivery interval within 12 h as compared to cervical length (P = 0.01). Conclusion: The Bishop score was superior in predicting the response to induction as compared to the cervical length measured by transvaginal ultrasonography.
