Genome-wide association analysis in host characteristics of progression to high-grade cervical intraepithelial neoplasia for women with human papilloma virus infection and normal cytology.

5109 Background: Although it is well accepted that persistent human papillomavirus (HPV) is necessary for carcinogenesis of cervical neoplasms, the molecular mechanism for progression is unclear. HPV testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) in baseline HPV-positive/normal cytology women is 30-50 fold as compared with HPV-negative/normal cytoloy women. HPV positivity would cause substantial anxiety. It is important to identify a prognostic profile for predicting progression. Methods: We collected blood samples from women aged ≥ 30 years in a population-based nested cohort study enrolling women with HPV infection (n = 871) or HPV-negative (n = 902) with normal cytology in 2004-2009 for prospective follow-up. To identify the host genetic characteristics associated with cervical carcinogenesis, a genome-wide association study (analyzing 530,194 SNPs) was conducted in 23 cases who developed CIN2+ and 62 viral type- and age-matched controls who were HPV-positive at baseline without developing CIN throughout the follow-up period. Results: One SNP with significant P values (rs16969682; P=4.58 x 10-5, OR=5.9, 95% CI=2.52-13.96) located in SEC14-like 1 (SEC14L1) gene localized to chromosome 17 was identified with association between progression to CIN2+ and controls without CIN throughout follow-up. SEC14L1 belongs to the widely-expressed SEC14-superfamily. This superfamily consists of > 500 members that are involved in biological functions including membrane trafficking and phospolipid metabolism. Furthermore, using T-cell based cDNA screening, SEC14L-1a is identified as a regulator of HIV-1 replication. Conclusions: The potential role of SEC14L1 in host-viral interaction will be further elucidated. Additional statistically significant SNPs including rs16969682 will be validated on cases with CIN2+ (n = 250) and normal controls (normal cytology/HPV-negative at baseline without acquisition of HPV or abnormal cytology/histology during follow-up, n = 500).

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Genome-wide association analysis in host genetic characteristics of progression to high-grade cervical intraepithelial neoplasia or higher for women with human papillomavirus infection and normal cytology.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6033 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6033-6033

Author(s):

Chyong-Huey Lai ◽

Su-Wei Chang ◽

Lan-Yan Yang ◽

Shuen-Iu Hung ◽

Chiao-Yun Lin ◽

...

Keyword(s):

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Roc Curve ◽

Intraepithelial Neoplasia ◽

Genome Wide Association ◽

Normal Cytology ◽

Genetic Characteristics ◽

Risk Alleles ◽

Genome Wide

6033 Background: Human papillomavirus (HPV) testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in HPV-positive/ normal cytology women is 20–34 fold as compared to those with HPV-negative/normal cytology. HPV-positivity would cause substantial anxiety. Apart from viral factors such as high-risk (hr) types, it is important to identify host characteristics for predicting outcome. Methods: An initial genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) by Affymetrix Axiom™ Genome-Wide Human Arrays was conducted on 505 cases with histological diagnosis of CIN2+ (group D1) versus 920 female controls. An additional set of 2315 female controls from the Taiwan Biobank genotype array were added in the discovery stage. The identified 29 CIN2+ -associated SNPs from GWAS (p < 5 x 10−6) were verified in an independent cohort (group D2 [n = 306] versus group N [n = 600]). Group N were HPV-negative/normal cytology women from a population-based cervical cytology and HPV co-test study. A cohort with HPV-positive/normal cytology (group P, n = 755) underwent follow-up and was served as the prediction set. The predictive validity was analyzed by logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Thirty-three individuals of the group P progressed to CIN2+ (median follow-up: 23.7 months, range 4.0–122.1). A risk-predictive panel of 8 SNPs rs3097662, rs35979982, rs7763822, rs4282438, rs3128927, rs7759943, rs213194, rs17835649 which were significant in the replication (p < 0.05) was used to train models for disease risk prediction using the combination of GWAS and verification sets. Two prediction models were finalized and determined using 7 SNPs for hr- and low-risk (lr) HPV groups respectively (sensitivity 0.72 and 0.75, specificity 0.651 and 0.884, area under the ROC curve 0.703 and 0.701). Among group P with hr-HPV, those carried < 6 risk-alleles had significantly decreased hazard (log-rank p < 0·001) of progression to CIN2+ than those with ≧6 risk-alleles, while among group P with lr-HPV, those with predictive probability of ≥ 0·095 had a cumulative risk of progression of 10% at 3 years. Conclusions: Two risk-predictive SNP panels including 7 SNPs with hr- or lr-HPV groups can assist risk stratification among HPV-positive/ normal cytology women. These panels could be further tested in other ethnic populations.

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P15 Cervical intraepithelial neoplasia and cervical cancer: a genome wide association study (GWAS) of the UK biobank cohort

10.1136/ijgc-2019-esgo.78 ◽

2019 ◽

Author(s):

S Bowden ◽

I Kalliala ◽

M Wielscher ◽

B Bodinier ◽

J Flanagan ◽

...

Keyword(s):

Cervical Cancer ◽

Association Study ◽

Cervical Intraepithelial Neoplasia ◽

Genome Wide Association Study ◽

Intraepithelial Neoplasia ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

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A GENOME-WIDE ASSOCIATION STUDY IN PROGRESSIVE SUPRANUCLEAR PALSY

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2015-312379.16 ◽

2015 ◽

Vol 86 (11) ◽

pp. e4.68-e4

Author(s):

Zhongbo Chen ◽

Aleksey Shatunov ◽

Gilbert Bensimon ◽

Christine Payan ◽

Albert Ludolph ◽

...

Keyword(s):

Progressive Supranuclear Palsy ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Chromosome 17 ◽

Gene Variants ◽

Genome Wide ◽

Mapt Gene ◽

Common Genetic Variants ◽

A Genome

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as p<5×10^–8.ResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.

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