Association of interleukin-17A polymorphisms with the risk of colorectal cancer: A case-control study

International audienceBackground: Interleukin (IL)-17A is proinflammatory cytokine produced by Th17 cells, which play key, but sometimes inconsistent role in autoimmunity and cancer. Polymorphic variants in IL-17A gene were differentially associated with susceptibility to cancer, including colorectal cancer (CRC). Aim: We investigated the association between six IL-17A gene variants (rs3819024, rs2275913, rs3819025, rs10484879, rs7747909, and rs3748067) with CRC susceptibility in Tunisians. Subjects and Methods: Retrospective case-control study. Study subjects comprised 293 patients with CRC, and 268 age-, gender-, and BMI-matched healthy controls. IL-17A genotyping was done by real-time PCR, with defined clusters. Results: Of the seven tested IL-17A tag-SNPs, minor allele frequency (MAF) of rs10484879 was significantly higher in CRC patients than control subjects. Heterozygous rs10484879 [OR (95% CI) = 2.63 (1.64-4.21)] was associated with higher risk, while carriage of heterozygous rs3748067 genotype was associated with reduced risk of CRC [OR (95% CI) = 0.56 (0.37-0.84)], respectively. Carriage of rs10484879 minor allele correlated with positive family history of CRC and other cancers (P = 0.002), CRC staging (P = 0.044), CRC treatment (P = 0.038), and with chemo body reaction (P = 0.001). Of the 7 IL-17A variants, 4 were in linkage dis-equilibrium, hence allowing for construction of 4-locus haplotypes. Varied linkage disequilibrium (LD) was noted between the even tested IL-17A variants, and further analysis was limited to only 4-locus (rs3819024-rs2275913-rs10484879-rs7747909). Haploview analysis identified the 4-locus IL-17A haplotypes AGTG (P < 0.011), and GATG (P = 0.036) to be positively associated with CRC, after controlling key covariates. Conclusion: IL-17A rs10484879 SNP, and IL-17A haplotypes AGGTG and GAGTG constitute independent factors of CRC susceptibility. We propose that IL-17A may be a target for future CRC immunotherapy

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

Aging is often associated with a loss of function. We believe aging to be more an adaptation to the various, and often continuous, stressors encountered during life in order to maintain overall functionality of the systems. The maladaptation of a system during aging may increase the susceptibility to diseases. There are basic cellular functions that may influence and/or are influenced by aging. Mitochondrial function is amongst these. Their presence in almost all cell types makes of these valuable targets for interventions to slow down or even reserve signs of aging. In this review, the role of mitochondria and essential physiological regulators of mitochondria and cellular functions, ion channels, will be discussed in the context of human aging. The origins of inflamm-aging, associated with poor clinical outcomes, will be linked to mitochondria and ion channel biology

Relationships between ion channels, mitochondrial functions and inflammation in human aging

Aging is often associated with a loss of function. We believe aging to be more an adaptation to the various, and often continuous, stressors encountered during life in order to maintain overall functionality of the systems. The maladaptation of a system during aging may increase the susceptibility to diseases. There are basic cellular functions that may influence and/or are influenced by aging. Mitochondrial function is amongst these. Their presence in almost all cell types makes of these valuable targets for interventions to slow down or even reserve signs of aging. In this review, the role of mitochondria and essential physiological regulators of mitochondria and cellular functions, ion channels, will be discussed in the context of human aging. The origins of inflamm-aging, associated with poor clinical outcomes, will be linked to mitochondria and ion channel biology

Common variants in IL-1RN, IL-1β and TNF-α and the risk of ovarian cancer: a case control study

Aim of the study: Several studies implicated altered inflammatory response in the susceptibility to ovarian cancer, and polymorphisms in inflammatory cytokines were shown to play an important role in the development of malignancies, including ovarian cancer (OC). Here we investigated the relationship between polymorphisms in IL-1 (-511C>T), IL-1RN VNTR, TNF- (-308G>A), and TNF RII (-322 VNTR) and OC risk in Tunisian women. Methods and results: Study subjects comprised 62 OC patients and 126 healthy women. Genotyping was done from genomic DNA obtained from blood simple by PCR. Positive association between IL-1RN (-VNTR) A1 allele (p = 0.0069; OR = 2.04; 95% CI:1.17-3.58) and OC risk, while negative association was seen with the A3 allele (P = 0.0034; OR = 0.09; 95% CI: 0.00-0.64), suggesting a protective role by the A3 allele. For IL-1 (-511C>T), homozygous C/C genotype was associated with significantly increased risk of OC (p = 0.0002; OR = 4.14; 95% CI: 1.77-9.76), while heterozygote C/T genotype was linked with reduced risk of OC (p = 0.0033; OR = 0.40; 95% CI: 0.20-0.78). Furthermore, TNF- -308A allele was significantly associated with heightened risk of OC (p = 0.016; OR = 1.70; 95% CI: 1.08-2.69), and homozygote G/G genotype was associated with decreased risk of OC (p = 0.0018; OR = 0.25; 95% CI: 0.09-0.66). In contrast, TNFRII (-322 VNTR) polymorphism was not associated with altered OC risk in the studied group. Conclusions: The significant association between IL-1RN VNTR, IL1- (-511), TNF- (-308) and OC susceptibility in Tunisian women confirms a role for altered inflammatory response in ovarian cancer pathogenesis

Distribution of Y chromosome lineages in Jerba island population

We have analysed Y chromosome polymorphism on six STR markers (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393) and eight classical UEP markers (SRY10831a, YAP, SRY4064, M2, 92R7, M9, SRY2627 and 12f2) in three distinct ethnical, linguistic and cultural groups of Jerba island (Berbers, Arabs and a Jerban group of Sub-Saharan origin). Fst genetic distance and principal co-ordinate analysis based on STR haplotype frequencies, showed a genetic differentiation between the three Jerban groups and a genetic relationship between Jerban Berbers and Mozabites (a well defined Berber group in Algeria). Compound use of UEP and STR markers have increased discriminatory capacity. The detection of the most common haplotype (H9) in both Berbers and Mozabites may be useful in forensic special cases

Transforming growth factor beta 1 polymorphisms and haplotypes associated with breast cancer susceptibility: A case-control study in Tunisian women

Variable association of transforming growth factor beta 1 (TGFβ1) in breast cancer (BC) pathogenesis was documented, and the contribution of specific TGFB1 polymorphisms to the progression of BC and associated features remains poorly understood. We investigated the contribution of TGFB1 rs1800469, rs1800470, rs1800471, and rs1800472 variants and 4-locus TGFB1 haplotypes on BC susceptibility, and pathological presentation of BC subtypes. Study subjects comprised 430 female BC cases, and 498 cancer-free control women. BC-associated pathological parameters were also evaluated for correlation with TGFB1 variants. Results obtained showed that the minor allele frequency (MAF) of rs1800471 (+74G>C) was higher seen in BC cases than in control subjects, and was associated with increased risk of BC. Significant differences in rs1800471 and rs1800469 (−509C>T) genotype distribution were noted between BC cases and controls, which persisted after controlling for key covariates. TGFB1 rs1800472 was positively, while rs1800470 was negatively associated with triple negativity, while rs1800470 positively correlated with menarche, but negatively with tumor size and molecular type, and rs1800469 correlated positively with menstrual irregularity, distant metastasis, nodal status, and hormonotherapy. Heterogeneity in LD pattern was noted between the tested TGFB1 variants. Four-locus (rs1800472-rs1800471-rs1800470-rs1800469) Haploview analysis identified haplotype TGCT to be negatively associated, and haplotypes CGTT and CCCC to be positively associated with BC. This association of CGTT and CCCC, but not TGCT, with BC remained significant after controlling for key covariates. In conclusion, TGFB1 alleles and specific genotypes, and 4-locus TGFB1 haplotypes influence BC susceptibility, suggesting dual association imparted by specific SNP, consistent with dual role for TGFB1 in BC pathogenesis

Common matrix metalloproteinase-2 gene variants and altered susceptibility to breast cancer and associated features in Tunisian women

A role for matrix metalloproteinase polymorphisms in breast cancer development and progression was proposed, but with inconclusive results. We assessed the relation of matrix metalloproteinase-2 variants with breast cancer and related phenotypes in Tunisians. This case-control retrospective study involved 430 women with breast cancer and 498 healthy controls. Genotyping of matrix metalloproteinase-2 rs243866, rs243865, rs243864, and rs2285053 was analyzed by allelic exclusion. The minor allele frequency of rs2285053 was significantly lower in women with breast cancer cases as compared to control women; minor allele frequencies of the remaining single-nucleotide polymorphisms were similar between cases and control women. The distribution of rs243865 and rs2285053 genotypes was significantly different between breast cancer patients and control subjects. This persisted when key covariates were controlled for. None of the matrix metalloproteinase-2 variants were associated with estrogen receptor positivity, progesterone receptor positivity, or with double estrogen receptor–progesterone receptor positivity in breast cancer patients. Matrix metalloproteinase-2 rs243866, rs243865, and rs243864 were positively associated with menstrual irregularity and histological type, while rs243866 and rs2285053 were negatively associated with menarche and nodal status. In addition, rs2285053 was negatively associated with triple negativity, tumor size, distance metastasis, molecular type, and chemotherapy. Haploview analysis revealed high linkage disequilibrium between matrix metalloproteinase-2 variants. Four-locus Haploview analysis identified haplotypes GCTT and GTTC to be negatively associated with breast cancer, which remained statistically after controlling for key covariates. Matrix metalloproteinase-2 alleles and genotypes, along with four-locus haplotypes, are related to reduced susceptibility to breast cancer in Tunisian women, suggesting a protective effect

KCNB1 GENE POLYMORPHISMS AND RELATED INDEL AS PREDICTOR BIOMARKERS OF TREATMENT RESPONSE FOR COLORECTAL CANCER – TOWARD A PERSONALIZED MEDICINE

The KCNB1 gene variants were differentially associated with cancers. However, their association with colorectal cancer has not yet been explored. We investigated the contribution of the KCNB1 gene variants rs3331, rs1051295, and indel (insertion/deletion) rs11468831 Polymorphism as predictors of the treatment response in colorectal cancer patients. A retrospective study, which involved 291 Tunisian colorectal cancer patients (aged 60.0 6 13.1 years), who were stratified into responder and non-responder groups, according to TNM stages and their responsiveness to chemotherapy based on fluorouracil. KCNB1 genotyping was performed with amplification-refractory mutation system–polymerase chain reaction, and was confirmed by Sanger sequencing. Sex-specific response was found and colorectal cancer females are less likely to achieve a positive response during the chemotherapy strategy, compared to males. Weight and body mass index, tumor size, and tumor localization are considered as predictive factors to treatment responsiveness. Carriage of rs11468831 Ins allele was significantly associated with successful therapy achievement (p adjusted\ 0.001). Stratification of colorectal cancer patients’ response according to tumor localization and TNM stages reveals negative association of rs3331 Major allele to treatment response among the patients with advanced cancer stages (subgroup G2). The presence of rs3331 (homozygous minor) C/C genotype was positively associated with decline in carcinoembryonic antigen (p = 0.043) and CA19-9 (p = 0.014) serum levels. On the other hand, the presence of rs1051295 (homozygous minor) A/A genotype was correlated with marked decline in CA19-9 serum levels. KCNB1 haplotype did not reveal any association between haplotypes and treatment response. The results obtained suggest that gender-specific strategies for screening treatment and prevention protocols as well as KCNB1 variants may constitute an effective model for ongoing personalization medicine