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Common sequence variants in chemokine-related genes and risk of breast cancer in post-menopausal women.

ABSTRACT: UNLABELLED:Chemokines are small molecules that when secreted by tissues under pathological conditions such as inflammation are believed to be involved in carcinogenesis. Recent reports have found that the genetic variation in chemokine encoding genes are associated with risk of breast cancer. METHODS:Using data from a population-based case-control study of 845 invasive breast cases and 807 controls, we genotyped 34 single nucleotide polymorphisms (SNPs) in 8 chemokine candidate genes (CCL3, CCL4, CCL5, CCL20, CCR5, CCR6, CXCL12 and CXCR4). Associations with breast cancer were computed for individual SNPs, groups of SNPs within genes, and in a gene-set analysis. We also performed a meta-analysis of CXCL12 rs1801157 and a haplotype analysis for two SNPs: CXCR4 rs2228014 and CXCL12 rs1801157. RESULTS:We found no significant associations between the risk of breast cancer and any individual SNPs, single genes, or combined gene sets. Some individual variants were marginally associated with some histologic subtypes, but these associations were not significant after adjustment for multiple comparisons. In the meta-analysis of five studies of European ancestry, CXCL12 rs1801157 was marginally associated with breast cancer risk (OR=1.14, 95% CI: 1.00, 1.30). CONCLUSIONS:Our findings suggest that genetic variants in the 8 candidate genes coding for chemotactic cytokines have little influence in the risk of breast cancer in postmenopausal women. Additional examination of the relationship between CXCL12 rs1801157 and breast cancer risk is warranted.

SUBMITTER: Bodelon C

PROVIDER: S-EPMC3852641 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Common sequence variants in chemokine-related genes and risk of breast cancer in post-menopausal women.

Bodelon Clara C Malone Katheleen E KE Johnson Lisa G LG Malkki Mari M Petersdorf Effie W EW McKnight Barbara B Madeleine Margaret M MM

International journal of molecular epidemiology and genetics 20131128 4

<h4>Unlabelled</h4>Chemokines are small molecules that when secreted by tissues under pathological conditions such as inflammation are believed to be involved in carcinogenesis. Recent reports have found that the genetic variation in chemokine encoding genes are associated with risk of breast cancer.<h4>Methods</h4>Using data from a population-based case-control study of 845 invasive breast cases and 807 controls, we genotyped 34 single nucleotide polymorphisms (SNPs) in 8 chemokine candidate ge ...[more]

PMID: 24319537

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Project description:Background Adiposity is a well-accepted risk factor for post-menopausal breast cancer (PMBC). SNPs of the FTO gene, located on chromosome 16q12.2, have been associated with adiposity by lowering the activity of the enzyme lipase. This gene also encodes for a protein involved in DNA damage repair pathway. The current epidemiologic paradigm associates the risk of PMBC with increased aromatization of androstenedione to estradial in peripheral adipose tissue and increased serum levels of insulin-like growth-factors. The increased systemic inflammation because of adiposity motivates the inquiries for other plausible biochemical mechanism. We are conducting a pilot nested case-controls study to investigate the association between 3 SNPs of FTO gene with the risk of PMBC, adjusted for the major risk factors. Presently data are available from 50 cases and 202 controls from the cohort of MyCode Biobanking Project at Geisinger Health System. Methods We genotyped the 3 SNPs (rs1861868, rs1477196 and rs9939609) of the gene. Generalized linear model was used to evaluate the association between these 3 SNPs. We also conducted analyses of hyplotypes for 2-SNPs and 3-SNPs association, respectively; odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between haplotypes and PMBC, and between the genotypes of each SNPs (as an ordinal variable) and PMBC applying unconditional logistic regression modeling approach, while controlling for BMI, age, parity status (=3 or <3) and family history for breast cancer. Results Our analyses suggest that 2 of the SNPs (rs1861868 and rs1477196) most likely form a haplotype (P= 0.002) that is exclusive of the third SNP (rs9939609, P>0.3). None of these SNPs or hyplotypes was associated with BMI (p>0.4), diabetes and metabolic syndrome (P>0.15). Results from the multivariate logistic model suggested a trend toward a potential association (OR=1.68, CI=0.67–4.18, P=0.09) between the (rs1861868) SNP and PMBC. Conclusion Our pilot study attempts to evaluate the association between SNPs of the of FTO gene with PMBC, independent of BMI or other risk factors for PMBC. One SNP was found to be likely associated with PMBC, but the present small sample size eclipses the power of identifying a definite association.

Project description:Background Muscle ageing contributes to both loss of functional autonomy and increased morbidity. Muscle atrophy accelerates after 50 years of age, but the mechanisms involved are complex and likely result from the alteration of a variety of interrelated functions. In order to better understand the molecular mechanisms underlying muscle chronological ageing in human, we have undertaken a top-down differential proteomic approach to identify novel biomarkers after the fifth decade of age. Results Muscle samples were compared between adult (56 years) and old (78 years) post-menopausal women. In addition to total muscle extracts, low-ionic strength extracts were investigated to remove high abundance myofibrillar proteins and improve the detection of low abundance proteins. Two-dimensional gel electrophoreses with overlapping IPGs were used to improve the separation of muscle proteins. Overall, 1919 protein spots were matched between all individuals, 95 were differentially expressed and identified by mass spectrometry, and they corresponded to 67 different proteins. Our results suggested important modifications in cytosolic, mitochondrial and lipid energy metabolism, which may relate to dysfunctions in old muscle force generation. A fraction of the differentially expressed proteins were linked to the sarcomere and cytoskeleton (myosin light-chains, troponin T, ankyrin repeat domain-containing protein-2, vinculin, four and a half LIM domain protein-3), which may account for alterations in contractile properties. In line with muscle contraction, we also identified proteins related to calcium signal transduction (calsequestrin-1, sarcalumenin, myozenin-1, annexins). Muscle ageing was further characterized by the differential regulation of several proteins implicated in cytoprotection (catalase, peroxiredoxins), ion homeostasis (carbonic anhydrases, selenium-binding protein 1) and detoxification (aldo-keto reductases, aldehyde dehydrogenases). Notably, many of the differentially expressed proteins were central for proteostasis, including heat shock proteins and proteins involved in proteolysis (valosin-containing protein, proteasome subunit beta type-4, mitochondrial elongation factor-Tu). Conclusions This study describes the most extensive proteomic analysis of muscle ageing in humans, and identified 34 new potential biomarkers. None of them were previously recognized as differentially expressed in old muscles, and each may represent a novel starting point to elucidate the mechanisms of muscle chronological ageing in humans.

Project description:Muscle ageing contributes to both loss of functional autonomy and increased morbidity. Muscle atrophy accelerates after 50 years of age, but the mechanisms involved are complex and likely result from the alteration of a variety of interrelated functions. In order to better understand the molecular mechanisms underlying muscle chronological ageing in human, we have undertaken a top-down differential proteomic approach to identify novel biomarkers after the fifth decade of age.Muscle samples were compared between adult (56 years) and old (78 years) post-menopausal women. In addition to total muscle extracts, low-ionic strength extracts were investigated to remove high abundance myofibrillar proteins and improve the detection of low abundance proteins. Two-dimensional gel electrophoreses with overlapping IPGs were used to improve the separation of muscle proteins. Overall, 1919 protein spots were matched between all individuals, 95 were differentially expressed and identified by mass spectrometry, and they corresponded to 67 different proteins. Our results suggested important modifications in cytosolic, mitochondrial and lipid energy metabolism, which may relate to dysfunctions in old muscle force generation. A fraction of the differentially expressed proteins were linked to the sarcomere and cytoskeleton (myosin light-chains, troponin T, ankyrin repeat domain-containing protein-2, vinculin, four and a half LIM domain protein-3), which may account for alterations in contractile properties. In line with muscle contraction, we also identified proteins related to calcium signal transduction (calsequestrin-1, sarcalumenin, myozenin-1, annexins). Muscle ageing was further characterized by the differential regulation of several proteins implicated in cytoprotection (catalase, peroxiredoxins), ion homeostasis (carbonic anhydrases, selenium-binding protein 1) and detoxification (aldo-keto reductases, aldehyde dehydrogenases). Notably, many of the differentially expressed proteins were central for proteostasis, including heat shock proteins and proteins involved in proteolysis (valosin-containing protein, proteasome subunit beta type-4, mitochondrial elongation factor-Tu).This study describes the most extensive proteomic analysis of muscle ageing in humans, and identified 34 new potential biomarkers. None of them were previously recognized as differentially expressed in old muscles, and each may represent a novel starting point to elucidate the mechanisms of muscle chronological ageing in humans.

Project description:BackgroundSeveral observational studies have suggested a protective effect of oral bisphosphonates (BP) on the risk of breast cancer, but no such association has been seen in randomized control trials. The role of oral BP in breast cancer prevention remains unclear.AimTo investigate the association between different levels of BP exposure and breast cancer incidence in a cohort of osteoporotic post-menopausal women.Subjects and methodsThis historical prospective study was conducted using the computerized databases of Maccabi Healthcare Services (MHS) in Israel. Included in the study were osteopenic and osteoporotic women aged 55-75 years who started BP therapy between 1998 and 2012. The subjects were enrolled in MHS for at least 3 years before therapy initiation, and had a minimum follow-up of 5 years in MHS. Women with a previous cancer, and women treated with selective estrogen receptor modulators (SERMs) were excluded. BP exposure was expressed in quintiles of proportion of days covered (PDC) with BP during follow-up period and cancer incidence was ascertained by the Israel National Tumor Registry. Person-years of follow-up began on January 1st, 1998 and ended at the date of cancer diagnosis, death, or December 31st, 2012, whichever occurred first.ResultsA total of 11,717 patients (mean age = 66.87 ± 4.38) were eligible for the analysis. During a total of 130,252 person-years of follow-up, (mean 7.2 years) 173 incident cases of breast cancer were diagnosed. Compared to women with a PDC with BP of 20% or lower, the adjusted hazard ratio for breast cancer were HR = 0.81 (95%CI: 0.48-1.39), HR = 0.82 (95%CI: 0.50-1.33), HR = 0.72 (95%CI:0.45-1.15) and HR = 1.14 (95%CI:0.76-1.70) among women with 20-40%, 40-60%, 60%-80%, and 80% or higher, PDC, respectively.ConclusionIn this study, we did not find a significant association between oral BP therapy for osteoporosis and the risk of breast cancer in postmenopausal women. The discrepancy between our results and the reports of such an association in observational studies might originate from an indication bias.

Dataset Information

Common sequence variants in chemokine-related genes and risk of breast cancer in post-menopausal women.

Publications

Common sequence variants in chemokine-related genes and risk of breast cancer in post-menopausal women.

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