Interleukin-1B (IL1B) and interleukin-6 (IL6) gene polymorphisms are associated with risk of chronic lymphocytic leukaemia

Common polymorphisms in genes encoding for cytokines implicated in the inflammatory response and Th1/Th2 balance might play a role in the development and prognosis of chronic lymphocytic leukaemia (CLL). To test the hypothesis, we investigated 13 single nucleotide polymorphisms (SNPs) in nine of such genes in a population-based case-control study, conducted in the Italian region of Sardinia in 1999-2003. Forty incident CLL cases and 113 population controls were available for study. The following SNPs were selected: IL1A-889C > T, IL1RN 9589A > T, IL1B-31C > T, IL1B-511C > T, IL2-384T > G, IL6-174G > C, IL6-597G > A, IL10-1082A > G, IL10-3575T > A, TNF-308G > A, LTA- 91A > C, LTA 252A > G and CARD15 nt1007. After adjusting by age and gender, individuals homozygous for the IL1B-511T allele run a lower risk of CLL (OR = 0.1, 95% CI 0.0, 0.8, p = 0.032), while risk showed a 4.5-fold increase associated with the genotype homozygous for the IL6-174C allele (OR = 4.5; 95% CI 1.1, 19.3, p = 0.041). Individuals homozygous for the IL6-174C allele and carrying the homozygous IL1B-511C allele showed an 11-fold increase in CLL risk (OR = 11.4, 95% CI 1.9, 69.4, p = 0.008). None of the other interleukin SNPs evaluated showed any association with CLL risk. Large multicentre pooled studies are warranted, achieving the statistical power required to confirm whether IL6 and IL1B gene polymorphisms might play a role in CLL development and prognosis, as well as the null associations herein reported.     

Interleukin-10 gene promoter polymorphisms in multiple myeloma

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of malignant plasma cells in the bone marrow. It is unclear whether genetic background could have an etiological impact on MM or influence the course of the disease. Interleukin-10 (IL-10) has been implicated in the growth and differentiation of normal B cells, and has also been shown to enhance the proliferation of MM cells. To address the putative involvement of IL-10 genetic variation in MM, we analyzed previously defined loci for bi-allelic polymorphism at position -1082 and two microsatellite loci (IL10.G and IL10.R) in the IL-10 promoter region. Seventy-three patients with MM, 27 with monoclonal gammopathy of undetermined significance, and 109 ethnically matched individuals as controls were included in the study. Significantly increased frequencies of the IL10.G genotype 136/136 and the IL10.R genotype 112/114, in addition to a decreased frequency of the IL10.R genotype 114/116, were found among the MM patients. Increased production of IL-10 was detected in the supernatants of lipopolysaccharide-stimulated peripheral blood mononuclear cells from MM patients who were homozygotes (136/136) and heterozygotes (136/non-136) for the IL10.G allele 136, as compared with the other IL10.G genotype carriers (non-136/non-136). These results suggest that the genetic variation in the IL-10 promoter region may play a role in the development of MM.     

Interleukin-10, interleukin-6 and interferon-gamma gene polymorphisms in melanoma patients

The immune response against melanoma can be influenced by cytokines with potentially opposite effects on tumour cell growth, such as interleukin-10 (IL10), interleukin-6 (IL6) and interferon-gamma (IFNgamma). Our objective in this study was to investigate whether polymorphisms in the regulatory regions of IL10, IL6 and IFNgamma genes are associated with the development of primary cutaneous melanoma and/or the prognosis of this tumour. We studied genotypic variations at positions -1082, -819 and -592 in the IL10 promoter, -174 in the IL6 promoter and +874 in the IFNgamma intron 1 in 42 melanoma patients and 48 healthy controls. These two populations showed very similar genotypic frequencies for IL10, IL6 and IFNgamma gene polymorphisms. There was a significant increase in the prevalence of IL10 low expression genotypes, specially the ACC/ATA genotype, among patients with a poorer prognosis. In contrast, IL6 promoter and IFNgamma intron 1 gene polymorphisms did not correlate with melanoma prognosis. These data indicate that investigation of polymorphisms in the regulatory regions of IL10, IL6 and INFgamma genes does not seem to be useful for predicting the risk of development of primary cutaneous melanoma. However, IL10 low expression genotypes may be associated with a poorer outcome in melanoma patients.     

Effect of plasma micronutrients on clearance of oncogenic human papillomavirus (HPV) infection (United States)

Objective: Data have suggested that higher levels of nutrients are protective against HPV persistence and cervical neoplasia. This study assessed the role of circulating nutrients on clearance of oncogenic HPV infections. Methods: Women were followed prospectively with visits at baseline and approximately 4- and 10-months post-baseline. At each visit, 15 oncogenic HPV types were determined. Plasma levels were assessed at the 4-month visit for retinol, carotenoids (i.e., -, trans--, cis--carotene, -, -cryptoxanthin, lutein, zeaxanthin, trans- and cis-lycopene), tocopherols (i.e., -, -, and -tocopherol), folate and vitamin B₁₂. Using multivariate Cox proportional hazards models, time to clearance analyses of oncogenic HPV infections were conducted for 84 women with at least one oncogenic infection at baseline. Hazard ratios (HR) were estimated for the association of HPV clearance to each nutrient tertile and to determine linear trends. Results: The likelihood of clearing an oncogenic HPV infection was significantly higher with increasing levels of trans-lycopene (p for trend, 0.025) and cis-lycopene (p for trend, 0.010). The adjusted hazard ratios of the highest tertiles of trans- and cis-lycopene were 2.79 (95% CI = 1.17–6.66) and 2.92 (95% CI = 1.28–6.63) compared with the lowest tertiles. Conclusions: Higher concentrations of trans- and cis-lycopene may reduce the time to clearance of an oncogenic HPV infection.     

Type-specific incidence,clearance and predictors of cervical human papillomavirus infections (HPV) among young women: a prospective study in Uganda

Background  

While infections with human papillomavirus (HPV) are highly prevalent among sexually active young women in Uganda, information on incidence, clearance and their associated risk factors is sparse. To estimate the incidence, prevalence and determinants of HPV infections, we conducted a prospective follow-up study among 1,275 women aged 12-24 years at the time of recruitment. Women answered a questionnaire and underwent a pelvic examination at each visit to collect exfoliated cervical cells. The presence of 42 HPV types was evaluated in exfoliated cervical cells by a polymerase chain based (PCR) assay (SPF10-DEIA LiPA).     

Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis

BACKGROUND: Proinflammatory cytokines are a major determinant in the inflammatory events leading to sarcoidosis. Genetic variations in the genes encoding these cytokines might contribute to sarcoidosis susceptibility, disease severity and outcome. METHODS: In the present study we genotyped two clinically well-defined cohorts of Caucasian sarcoidosis patients from different European countries (each with their own controls) for the following polymorphisms using SSP-PCR: IL6 -174(G/C), IL6 intron 4(A/G) and IL1A-889(C/T). In total, 516 individuals were studied (147 UK + 102 Dutch patients, 101 UK + 166 Dutch controls). Disease severity data at presentation included chest radiographic stage, FVC, DL(CO), and extrapulmonary manifestations. Disease progression was evaluated on follow-up chest radiographs and sequential lung function measurements (2, 4 years). RESULTS: No differences in genotype, carriage and allele frequencies of the investigated polymorphisms were found in either of the populations. Analysis of genotype data in relation to disease severity data, however, showed a slightly increased carrier frequency of the rarer-174C allele in patients with Stage IV sarcoidosis (p = 0.03, Pc = 0.09). Pulmonary function progression analysis did not reveal significant associations. CONCLUSIONS: Although the investigated polymorphisms are unlikely to contribute to sarcoidosis susceptibility, the IL6-174C allele might have a role in the genetics underlying sarcoidosis severity or the progression towards pulmonary fibrosis in a particular subgroup.     

Interleukin-10 and Gp130 cytokines in human multiple myeloma.

Interleukin (IL)-10 is a critical cytokine involved in the terminal differentiation of B cells into plasma cells. IL-10 is also involved in multiple myeloma, a malignant plasma cell disorder. IL-6 and, more generally the cytokines activating the gp130 IL-6 transducer, are major survival and proliferation factors of myeloma cells. IL-10 is also a growth factor of malignant plasma cells, produced by myeloma cells from about half the patients and is detected in the plasma of patients with plasma cell leukemia or solitary plasmacytoma. The myeloma cell growth activity of IL-10 is mediated through a gp130 cytokine, oncostatin M (OSM), that is frequently produced by myeloma cells. Myeloma cells fail to express OSM receptors but IL-10, by inducing it, confers on them the sensitivity to OSM.     

Prevalence, incidence and clearance of human papillomavirus infection among young primiparous pregnant women in Kampala, Uganda

The proportion of women who have already been exposed to human papillomavirus (HPV) infection by the time they first become pregnant, and the influence of pregnancy and delivery on the course of HPV infection are unclear. In Kampala, Uganda, 987 young primiparous pregnant women aged <25 years had gynaecological examination and liquid-based cytology. In the follow-up, women acted as their own controls, i.e., 1st/2nd versus 3rd trimesters (105 women), and during pregnancy versus after delivery (289 women). HPV was assessed using highly sensitive PCR assays. Prevalence of HPV and HIV infections at baseline were 60.0% and 7.3%, respectively. HPV16 and 18 were detected in 8.4% and 5.8%, respectively, i.e., less frequently than HPV51 (8.7%) and 52 (12.1%). At follow-up new HPV infections were detected in 42.9% of women between the 1st/2nd and 3rd trimesters, and 38.1% between pregnancy and delivery, but 50.4% and 71.8% of HPV infections, respectively, cleared, leaving HPV prevalence unchanged in the different periods. Prevalence of cytological abnormalities diminished after delivery (from 21.2% to 12.4%). Presence of genital warts and sexually transmitted infections other than HPV were the strongest risk factors for prevalent or incident HPV infection. Clearance was lower among HIV-positive women. In conclusion, HPV prevalence was high in primiparous women in Uganda, but pregnancy did not seem to be a period of special vulnerability to the infection.     

Prevalence and predictors of human papillomavirus (HPV) vaccination among young women surviving childhood cancer

Purpose

Human papillomavirus (HPV) is a sexually transmitted infection and the cause of cervical and other cancers. Vaccination is available to protect against genital HPV and is recommended for individuals aged 9–26 years. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and to identify factors associated with vaccine outcomes.

Methods

Young adult females with (n?=?114; M age?=?21.18 years, SD?=?2.48) and without (n?=?98; M age?=?20.65 years, SD?=?2.29) a childhood cancer history completed surveys querying HPV vaccination initiation/completion, as well as sociodemographic, medical, and health belief factors. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for vaccine outcomes.

Results

Among survivors, 38.6 % (44/114) and 26.3 % (30/114) initiated or completed vaccination compared to 44.9 % (44/98) and 28.6 % (28/98) among controls, respectively. In the combined survivor/control group, physician recommendation (OR?=?11.24, 95 % CI 3.15–40.14) and familial HPV communication (OR?=?7.28, 95 % CI 1.89–28.05) associated with vaccine initiation. Perceptions of vaccine benefit associated with vaccine completion (OR?=?10.55, 95 % CI 1.59–69.92), whereas perceptions of HPV-related severity associated with non-completion (OR?=?0.14, 95 % CI 0.03–0.71).

Conclusion

Despite their increased risk for HPV-related complication, a minority of childhood cancer survivors have initiated or completed HPV vaccination. Modifiable factors associated with vaccine outcomes were identified.

Implications for Cancer Survivors

HPV vaccination is a useful tool for cancer prevention in survivorship, and interventions to increase vaccine uptake are warranted.

     

Time to clearance of human papillomavirus infection by type and human immunodeficiency virus serostatus

Persistent infection with high-risk human papillomavirus (HPV) is central to cervical carcinogenesis. Certain high-risk types, such as HPV16, may be more persistent than other HPV types, and type-specific HPV persistence may differ by HIV serostatus. This study evaluated the association between HPV type and clearance of HPV infections in 522 HIV-seropositive and 279 HIV-seronegative participants in the HIV Epidemiology Research Study (HERS, United States, 1993-2000). Type-specific HPV infections were detected using MY09/MY11/HMB01-based PCR and 26 HPV type-specific probes. The estimated duration of type-specific infections was measured from the first HPV-positive visit to the first of two consecutive negative visits. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HPV clearance were calculated using Cox models adjusted for study site and risk behavior (sexual or injection drugs). A total of 1,800 HPV infections were detected in 801 women with 4.4 years median follow-up. HRs for clearance of HPV16 and related types versus low-risk HPV types were 0.79 (95% CI: 0.64-0.97) in HIV-positive women and 0.86 (95% CI: 0.59-1.27) in HIV-negative women. HRs for HPV18 versus low-risk types were 0.80 (95% CI: 0.56-1.16) and 0.57 (95% CI: 0.22-1.45) for HIV-positive and -negative women, respectively. HPV types within the high-risk category had low estimated clearance rates relative to low-risk types, but HRs were not substantially modified by HIV serostatus.     

Determinants of incidence and clearance of high-risk human papillomavirus infections in rural rakai, Uganda.

BACKGROUND: We used self-administered vaginal swabs to assess the incidence and clearance of carcinogenic human papillomavirus (HPV) infections in rural Rakai, Uganda. METHODS: Women provided self-administered vaginal swab at annual home-based visits. Type-specific carcinogenic HPV incidence and clearance and risk factors were assessed. RESULTS: Carcinogenic HPV incidence was 17.3 per 100 person-years among HIV-positive women compared with 7.0 per 100 person-years among HIV-negative women (P < 0.001). HPV-51 had the highest incidence followed by HPV-16 (1.8 per 100 and 1.5 per 100 person-years, respectively). In multivariate model, HIV-positive women were twice as likely to have incident infection compared with HIV-negative women. Younger women were at higher risk for incident infection, as were women with higher lifetime and recent sexual partners, and high perception of AIDS. Married women were less likely to have incident infection. Approximately half of all carcinogenic HPV infections cleared over the study follow-up of 3 years. HPV-31, HPV-35, and HPV-16 had the lowest clearance (16.7%, 27.9%, and 38.3%, respectively). In multivariate model, HIV-positive, women over 30 years with higher HPV viral, burden and more lifetime sex partners were less likely to clear infections. CONCLUSIONS: Self-collected vaginal swabs provide accurate HPV exposure assessment for studying HPV exposure and epidemiology and can be an important tool for research in populations unwilling to undergo pelvic exam.     

Interleukin-1β gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms and gastric cancer risk in an Omani Arab population

Background Gastric cancer (GC) is the most common malignancy in Oman. Interleukin-1β gene (IL-1B) and interleukin-1 receptor antagonist gene (IL-1RN) polymorphisms have been associated with increased GC risk. No previous studies have examined their role in an Arab population. We tested the associations between polymorphisms of IL1B at positions −31, −511, and +3954 and the IL-1RN polymorphism [variable number of tandem repeats (VNTR) and TC polymorphism at the −2018 position] and GC in Omani Arab patients. Methods Genomic DNA was extracted from peripheral blood of 245 control subjects and 118 gastric cancer patients. The DNA samples were analyzed using the TaqMan allelic discrimination test for IL-1B −31, −511, and +3954 polymorphisms and IL-1RN −2018 polymorphism. The VNTR of IL-1RN was genotyped using the polymerase chain reaction followed by agarose gel electrophoresis. Results There was an association between the presence of IL-1RN*2 allele and gastric cancer [odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.0–3.3, P = 0.04). The GC risk further increased to OR = 3.5 (95% CI = 1.0–11.9) in Helicobacter pylori-positive patients. No association was found between any of the other polymorphisms studied and GC. Conclusion IL-1RN polymorphism increased the risk of GC in an Omani Arab population, consistent with previous reports. In contrast, the IL-1B −31 polymorphism was not associated with an increased GC risk. These findings underscore the role of cytokine gene polymorphisms in the development of GC and further support the ethnic differences in the effect of IL-1B polymorphism on GC carcinogenesis.     

HPV基因型与宫颈病变的关系探讨

  目的  了解HPV基因型与宫颈病变的关系。  方法  选取2010年3月至2011年1月在广州中山大学第三医院妇科就诊并愿意接受HPV检查和问卷调查的妇女为对象。剔除标准:1）已切除子宫;2）已行宫颈锥切;3）不愿意参加本研究。入选360例,年龄为19~66岁,平均为35.6岁,户籍均为广州地区。利用核酸分子杂交技术检测21种HPVDNA。宫颈正常/炎症组为256例,CIN1组为34例,CIN2/3组为61例,宫颈癌组为9例。  结果  HPV感染率宫颈正常/炎症组为18.4%（47/256）,CIN1组为67.6%（23/34）,CIN2/3组为96.7%（59/61）,宫颈癌组为100%（9/9）。CIN1组、CIN2/3组HPV感染率均比正常/炎症组高（P < 0.001）;CIN2/ 3组的HPV感染率比CIN1组高（P < 0.001）。CIN主要感染类型依次为HPV16（44.2%）、HPV58（24.2%）、HPV52（11.6%）、HPV33（8.4%）。宫颈癌主要感染类型为HPV16（88.9%）。  结论  随着宫颈病变程度进展HPV感染率呈升高的趋势,HPV16、58、52、33相关的感染与宫颈癌前病变关系密切,应引起足够重视,其中HPV16感染易致病变进展及癌变发生。      

IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL‐23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A ?197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction‐restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A ?197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A ?197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL‐17 and IL‐23R polymorphisms may affect severity, bone lesions, and extra‐medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.     

Chapter 14. Ah receptor gene polymorphisms and human cancer susceptibility.

The Ah receptor (Ahr) gene occupies a central role in the metabolic pathways involved in the detoxification of important environmental carcinogens. The structures of the rodent and human genes have been elucidated, and the molecular details of the receptor function, including its interaction with other proteins such as Arnt and hsp90, have been thoroughly investigated. The Ahr gene is polymorphic in mice and in humans. In mice, good correlations have been found between structural polymorphisms in the gene and functional variants in various genetic strains. In humans, work on polymorphisms and their possible role in gene function as well as cancer susceptibility is just beginning.     

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.