HLA class II alleles associated with infection by HPV16 in cervical cancer in situ.
ABSTRACT HLA class II alleles have been associated with an increased risk of developing cervical cancer through infection with oncogenic forms of human papilloma virus (HPV). We have examined the association of variation at the DRB1 and DQB1 loci with HPV16 infection and risk of development of cervical cancer by analysis of 440 cases diagnosed with cervical cancer in situ and 476 age-matched controls in a retrospective case-control study. The infection history of a woman was studied by analysis of cervical smears taken at multiple times during a period of up to 27 years (1969-95). The frequency of a number of alleles are either increased (DRB1*0801, DRB1*1501, DQB1*0402 and DQB1*0602) or decreased (DRB1*0101, DRB1*1301, DQB1*0501 and DQB1*0603) in the cancer patients compared to the controls. After correction for multiple testing, only the DQB1*0602 and the DRB1*1501 alleles remain associated with cancer and only in HPV16-infected patients (DQB1*0602: 102/264 (39%) vs. 130/476 (28%), p = 0.028 and DRB1*1501: 104/259 (40%) vs. 132/469 (28%), p = 0.027). These alleles are associated primarily with infection by HPV and only indirectly affect the risk of developing cervical cancer in situ. To study the impact of these alleles on persistence of infection, women with short-term infections were compared to those with long-term infections. Carriers of DQB1*0602 and DRB1*1501 were more frequent in the group with long-term HPV infections, indicating that these class II alleles contribute to the inability to clear an HPV infection.
Article: Association of HLA-DRB1, interleukin-6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population--a candidate gene approach.[show abstract] [hide abstract]
ABSTRACT: High-risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case-control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population-based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL-6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79-0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78-0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02-1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04-1.45 and OR = 1.29, 95% CI: 1.11-1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47-0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle.International Journal of Cancer 05/2009; 125(8):1851-8. · 5.44 Impact Factor
Article: Patterns of persistent genital human papillomavirus infection among women worldwide: A literature review and meta-analysis.[show abstract] [hide abstract]
ABSTRACT: Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV-positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was 10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6 to 12 months. Repeat HPV testing at 12-month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.International Journal of Cancer 09/2012; · 5.44 Impact Factor
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ABSTRACT: High-risk α mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas β cutaneous HPV types (e.g. HPV8) have been implicated in non-melanoma skin cancer. Although antibodies against the capsid protein L1 of HPV are considered as markers of cumulative exposure, not all infected persons seroconvert. To identify common genetic variants that influence HPV seroconversion, we performed a two-stage genome-wide association study. Genome-wide genotyping of 316 015 single nucleotide polymorphisms was carried out using the Illumina HumanHap300 BeadChip in 4811 subjects from a central European case-control study of lung, head and neck and kidney cancer that had serology data available on 13 HPV types. Only one association met genome-wide significance criteria, namely that between HPV8 seropositivity and rs9357152 [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.24-1.50 for the minor allele G; P=1.2 × 10(-10)], a common genetic variant (minor allele frequency=0.33) located within the major histocompatibility complex (MHC) II region at 6p21.32. This association was subsequently replicated in an independent set of 2344 subjects from a Latin American case-control study of head and neck cancer (OR=1.35, 95% CI=1.18-1.56, P=2.2 × 10(-5)), yielding P=1.3 × 10(-14) in the combined analysis (P-heterogeneity=0.87). No heterogeneity was noted by cancer status (controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a proof of principle that genetic variation plays a role in antibody reactivity to HPV infection.Human Molecular Genetics 09/2011; 20(23):4714-23. · 7.64 Impact Factor