Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry.
ABSTRACT: Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status.
Project description:African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women's Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.
Project description:American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. We hypothesized that racial differences in 25OHD levels, as well as in inherited genetic variations, may contribute, in part, to the differences in tumor characteristics.In a case (n = 928)-control (n = 843) study of breast cancer in AA and EA women, we measured serum 25OHD levels in controls and tested associations between risk and tag single nucleotide polymorphisms (SNPs) in VDR, CYP24A1 and CYP27B1, particularly by ER status.More AAs had severe vitamin D deficiency (< 10 ng/ml) than EAs (34.3% vs 5.9%), with lowest levels among those with the highest African ancestry. Associations for SNPs differed by race. Among AAs, VDR SNP rs2239186, associated with higher serum levels of 25OHD, decreased risk after correction for multiple testing (OR = 0.53, 95% CI = 0.31-0.79, p by permutation = 0.03), but had no effect in EAs. The majority of associations were for ER-negative breast cancer, with seven differential associations between AA and EA women for CYP24A1 (p for interaction < 0.10). SNP rs27622941 was associated with a > twofold increased risk of ER-negative breast cancer among AAs (OR = 2.62, 95% CI = 1.38-4.98), but had no effect in EAs. rs2209314 decreased risk among EAs (OR = 0.38, 95% CI = 0.20-0.73), with no associations in AAs. The increased risk of ER-negative breast cancer in AAs compared to EAs was reduced and became non-significant (OR = 1.20, 95% CI = 0.80-1.79) after adjusting for these two CYP24A1 SNPs.These data suggest that genetic variants in the vitamin D pathway may be related to the higher prevalence of ER-negative breast cancer in AA women.
Project description:It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene-environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women's Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in the ESR1 gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20-1.80, P=0.0002; rs2046210, OR=1.24, 95% CI=1.04-1.47, P=0.02; and rs3020314, OR=1.43, 95% CI=1.19-1.70, P=0.00009), but not in AA women. The only other gene associated with breast cancer risk was CYP1A2 in AA women (rs2470893, OR=1.42, 95% CI=1.00-2.02, P=0.05), but not in EA women. When stratified by ER status, ESR1 rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with the ESR1 SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer.
Project description:Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER-) or triple negative breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER-/triple negative breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e., DEmiRs defined as >2-fold change in expression and false discovery rate <0.05, were identified as up- or downregulated by tumor ER status or by ancestry. We found that among 102 ER-subtype-related DEmiRs identified in breast tumors, the majority of these DEmiRs were race specific, with only 23 DEmiRs shared in tumors from both AAs and EAs; this finding indicates that there are unique subsets of miRNAs differentially expressed between ER- and ER positive tumors within AAs versus EAs. Our overall results support the notion that miRNA expression patterns may differ not only by tumor subtype but by ancestry, indicating differences in tumor biology and heterogeneity of breast cancer between AAs and EAs. These results will provide the basis for further functional analysis to elucidate biological differences between AAs and EAs and to help develop targeted treatment strategies to reduce disparities in breast cancer.
Project description:The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations, but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women's Health Study, which included 1191 cases and 1941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women's Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer [odds ratio (OR) = 1.14; 95% confidence interval (CI) = 1.02-1.28], and the rs2046211-G allele was associated with reduced risk (OR = 0.80; 95% CI = 0.67-0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplotypes. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African-American women, and we report the presence of a novel signal that is tagged by rs2046211.
Project description:The pro-inflammatory cytokine interleukin-15 (IL15) and its receptor ? (IL15RA) participate in the regulation of musculoskeletal function and metabolism. Deletion of the Il15ra gene in mice increases spontaneous activity, improves fatigue resistance in the glycolytic extensor digitorum longus (EDL) and protects from diet-induced obesity. In humans, IL15RA single-nucleotide polymorphisms (SNPs) have been linked to muscle strength, metabolism and performance in elite endurance athletes. Taken together, these features suggest a possible role for IL15RA in muscle mitochondrial structure and function. Here, we have investigated the consequences of loss of IL15RA on skeletal muscle fiber-type properties and mitochondrial ultrastructure. Immunostaining of the EDL for myosin heavy chain (MyHC) isoforms revealed no significant changes in fiber type. Electron microscopy (EM) analysis of the EDL indicated an overall higher mitochondria content, and increased cristae density in subsarcolemmal and A-band mitochondrial subpopulations. The higher cristae density in Il15ra -/- mitochondria was associated with higher OPA1 and cardiolipin levels. Overall, these data extend our understanding of the role of IL15RA signaling in muscle oxidative metabolism and adaptation to exercise.
Project description:Interleukin-15 receptor alpha (IL15RA) is an important component of interleukin-15 (IL15) pro-inflammatory signaling. In addition, IL15 and IL15RA are present in the circulation and are detected in a variety of tissues where they influence physiological functions such as muscle contractility and overall metabolism. In the skeletal system, IL15RA was previously shown to be important for osteoclastogenesis. Little is known, however, about its role in osteoblast function and bone mineralization. In this study, we evaluated bone structural and mechanical properties of an Il15ra whole-body knockout mouse (Il15ra-/-) and used in vitro and bioinformatic analyses to understand the role IL15/IL15RA signaling on osteoblast function. We show that lack of IL15RA decreased bone mineralization in vivo and in isolated primary osteogenic cultures, suggesting a cell-autonomous effect. Il15ra-/- osteogenic cultures also had reduced Rankl/Opg mRNA ratio, indicating defective osteoblast/osteoclast coupling. We analyzed the transcriptome of primary pre-osteoblasts from normal and Il15ra-/- mice and identified 1150 genes that were differentially expressed at a FDR of 5%. Of these, 844 transcripts were upregulated and 306 were downregulated in Il15ra-/- cells. The largest functional clusters, highlighted using DAVID analysis, were related to metabolism, immune response, bone mineralization and morphogenesis. The transcriptome analysis was validated by qPCR of some of the most significant hits. Using bioinformatic approaches, we identified candidate genes, including Cd200 and Enpp1, that could contribute to the reduced mineralization. Silencing Il15ra using shRNA in the calvarial osteoblast MC3T3-E1 cell line decreased ENPP1 activity. Taken together, these data support that IL15RA plays a cell-autonomous role in osteoblast function and bone mineralization.
Project description:Interleukin-15 (IL-15) is a cytokine which inhibits lipid deposition in cultured adipocytes and decreases adipose tissue deposition in laboratory rodents. In human subjects, negative correlations between circulating IL-15 levels and both total and abdominal fat have been demonstrated. Deletions of IL15 in humans and mice are associated with obesity, while gain-of-function IL-15 overexpressing mice are resistant to diet-induced obesity. IL-15 is highly (but not exclusively) expressed at the mRNA level in skeletal muscle tissue, and the regulation of IL-15 translation and secretion is complex. Conflicting evidence exists concerning whether circulating IL-15 is released from skeletal muscle tissue in response to exercise or other physiological stimuli. The IL-15 receptor-alpha (IL-15R?) subunit has a complex biochemistry, encoding both membrane-bound and soluble forms which can modulate IL-15 secretion and bioactivity. The gene encoding this receptor, IL15RA, resides on human chromosome 10p, a location linked to obesity and type-2 diabetes. Several single-nucleotide polymorphisms (SNPs) in human IL15RA and IL15 correlate with adiposity and markers of the metabolic syndrome. Genetic variation in IL15RA may modulate IL-15 bioavailability, which in turn regulates adiposity. Thus, IL-15 and the IL-15R? may be novel targets for pharmacologic control of obesity in the human population.
Project description:MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in six miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women's Circle of Health Study. Allele frequencies of most SNPs (87 %) differed significantly by race. We found a number of SNPs in miRNAs and processing genes in association with breast cancer overall or stratified by estrogen receptor (ER) status. Several associations were significantly different by race, with none of the associations being significant in both races. Using a polygenic risk score to combine the effects of multiple SNPs, we found significant associations with the score in each subgroup analysis. For ER-positive cancer, each unit increment of the risk score was associated with a 51 % increased risk in AAs (OR = 1.51, 95 % CI = 1.30-1.74, p = 3.3 × 10(-8)) and a 73 % increased risk in EAs (OR = 1.73, 95 % CI = 1.45-2.06, p = 1.4 × 10(-9)). These data show, for the first time, that miRNA-related genetic variations may underlie the etiology of breast cancer in both populations of African and European ancestries. Future studies are needed to validate our findings and to explore the underlying mechanisms.
Project description:Folate-mediated one-carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate-metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one-carbon metabolism and risk of breast cancer in 1,275 European-American (EA) and 1,299 African-American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single-SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p?<?0.0005) in EAs or AAs. In summary, our data suggest that one-carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women.