Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

BACKGROUND: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. PURPOSE: To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). MATERIAL AND METHODS: The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. RESULTS: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). CONCLUSIONS: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody.

Accurate quantification of the metabolic enzyme uridine diphospho-glucuronosyltransferase (UGT) UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers revealed strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification (r = 0.93), and three major expression patterns (absent, low, or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, located in the binding site for the transcription factor forkhead box A1 (FOXA1) of the UGT2B17 promoter. The highest level of expression was observed for individuals carrying at least one rs59678213 A allele. Multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213, reaching 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize the UGT2B17 level in various disease states and establish more precisely the contribution of the UGT2B17 enzyme to drug and hormone metabolism.

The fundamentals of cross-sector collaboration for social change to promote population health.

Cross-sector collaboration is increasingly relied upon to tackle society's pressing and intractable problems. Chief among societal problems are unfavorable structural and social determinants of health. The ability to positively change these health determinants rests on the collaborative processes and structures of governance across diverse sectors in society. The purpose of this article is to present a conceptual framework that sheds light on the basic requirements of cross-sector collaboration for social change to promote the health of populations. A search for theoretical articles on cross-sector collaboration in the fields of public administration and public health was conducted within the journal databases ABI/INFORM Complete and MEDLINE. This search strategy was supplemented by an internet search of the grey literature for high-profile models of cross-sector collaboration. The conceptual framework builds on previous scholarly work by placing emphasis on five essential conditions for collective impact, and on the pivotal role of collective learning. Collective learning, at the basis of planning and taking action, is at the core of effective cross-sector initiatives, specifically because of its critical role in constantly adapting strategies to changing circumstances and unanticipated situations within complex socio-ecological systems.

Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics.

The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) significantly influences the bioavailability and biological responses of endogenous molecule substrates and xenobiotics including drugs. UGTs participate in the regulation of cellular homeostasis by limiting stress induced by toxic molecules, and by controlling hormonal signaling networks. Glucuronidation is highly regulated at genomic, transcriptional, post-transcriptional and post-translational levels. However, the UGT protein interaction network, which is likely to influence glucuronidation, has received little attention. We investigated the endogenous protein interactome of human UGT1A enzymes in main drug metabolizing non-malignant tissues where UGT expression is most prevalent, using an unbiased proteomics approach. Mass spectrometry analysis of affinity-purified UGT1A enzymes and associated protein complexes in liver, kidney and intestine tissues revealed an intricate interactome linking UGT1A enzymes to multiple metabolic pathways. Several proteins of pharmacological importance such as transferases (including UGT2 enzymes), transporters and dehydrogenases were identified, upholding a potential coordinated cellular response to small lipophilic molecules and drugs. Furthermore, a significant cluster of functionally related enzymes involved in fatty acid ß-oxidation, as well as in the glycolysis and glycogenolysis pathways were enriched in UGT1A enzymes complexes. Several partnerships were confirmed by co-immunoprecipitations and co-localization by confocal microscopy. An enhanced accumulation of lipid droplets in a kidney cell model overexpressing the UGT1A9 enzyme supported the presence of a functional interplay. Our work provides unprecedented evidence for a functional interaction between glucuronidation and bioenergetic metabolism.

A Rare UGT2B7 Variant Creates a Novel N-Glycosylation Site at Codon 121 with Impaired Enzyme Activity.

The UDP glucuronosyltransferase (UGT) superfamily comprises glycoproteins that reside in the endoplasmic reticulum membranes and that undergo post-translational modifications (PTMs). UGT2B7 is of particular interest because of its action on a wide variety of drugs. Most studies currently survey common variants and examine only a small fraction of the genetic diversity; however, rare variants (frequency <1%) might have a significant effect because they are predicted to greatly outnumber common variants in the human genome. We discovered a rare single nucleotide UGT2B7 variant of potential pharmacogenetic relevance that encodes a nonconservative amino acid substitution at codon 121. This low-frequency variation, found in two individuals of a population of 305 healthy volunteers, leads to the translation of an asparagine instead of an aspartic acid (UGT2B7 p.D121N). This amino acid change was predicted to create a putative N-glycosylation motif NX(S/T) subsequently validated upon endoglycosidase H treatment of microsomal fractions and inhibition of N-glycosylation of endogenously produced UGT2B7 with tunicamycin in human embryonic kidney (HEK293) cells. The presence of an additional N-linked glycan on the UGT2B7 enzyme, likely affecting proper protein folding, resulted in a significant decrease of 49% and 40% in the formation of zidovudine and mycophenolic acid glucuronides, respectively. A systematic survey of the Short Genetic Variations database uncovered 32 rare, naturally occurring missense variations predicted to create or disrupt N-glycosylation sequence motifs in the other UGT2B enzymes. Collectively, these variants have the potential to increase the proportion of variance explained in the UGT pathway resulting from changes in PTMs, such as N-linked glycosylation with consequences on drug metabolism.

ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

Unitary Transformations in the Quantum Model for Conceptual Conjunctions and Its Application to Data Representation.

Quantum models of concept combinations have been successful in representing various experimental situations that cannot be accommodated by traditional models based on classical probability or fuzzy set theory. In many cases, the focus has been on producing a representation that fits experimental results to validate quantum models. However, these representations are not always consistent with the cognitive modeling principles. Moreover, some important issues related to the representation of concepts such as the dimensionality of the realization space, the uniqueness of solutions, and the compatibility of measurements, have been overlooked. In this paper, we provide a dimensional analysis of the realization space for the two-sector Fock space model for conjunction of concepts focusing on the first and second sectors separately. We then introduce various representation of concepts that arise from the use of unitary operators in the realization space. In these concrete representations, a pair of concepts and their combination are modeled by a single conceptual state, and by a collection of exemplar-dependent operators. Therefore, they are consistent with cognitive modeling principles. This framework not only provides a uniform approach to model an entire data set, but, because all measurement operators are expressed in the same basis, allows us to address the question of compatibility of measurements. In particular, we present evidence that it may be possible to predict non-commutative effects from partial measurements of conceptual combinations.

Nurses' evaluations of the CPOT use at 12-month post-implementation in the intensive care unit.

BACKGROUND: Performing routine pain assessments with all intensive care unit (ICU) patients is strongly recommended in clinical practice guidelines. As many ICU patients are unable to self-report, the Critical-Care Pain Observation Tool (CPOT) is one of the two behavioural pain scales suggested for clinical use. Still, no study has described the evaluations of its use in ICU daily practice. OBJECTIVE: To describe the nurses' evaluation of the feasibility, clinical relevance and satisfaction with the CPOT use 12 months after its implementation in the ICU. METHOD: A descriptive design was used. It was conducted in the medical-surgical ICU of a university affiliated setting at Greenfield Park (Québec, Canada). A self-administered evaluation questionnaire including four sections (i.e. feasibility, clinical relevance, satisfaction and socio-demographic information) was completed by ICU nurses who were all trained to use the CPOT. The questionnaires were completed anonymously. RESULTS: A total of 38 ICU nurses returned their completed questionnaire (63% participation rate). Regarding its feasibility, the majority rated the CPOT as quick to use, simple to understand and easy to complete (92-100%). According to clinical relevance, close to 70% of ICU nurses acknowledged that the CPOT had influenced their practice, but lower results (<50%) were found for effective communication of pain assessment findings with the physicians and other health professionals. More than 80% of ICU nurses were satisfied with its daily use. CONCLUSION: The CPOT use was deemed feasible and relevant in daily practice as per the nurses' evaluations but did not allow an effective communication with other ICU care team members. RELEVANCE TO CLINICAL PRACTICE: Training should be offered to all members of the ICU care team, and other implementation strategies should be explored as well to ensure optimal uptake of a pain assessment approach which impacts on their decision-making process for pain management.

Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia.

BACKGROUND: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort. METHODS: We performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing. RESULTS: Five patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A, immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes. CONCLUSIONS: Based on our genetic results, TTC7A is the likely causal gene for MIA.

Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population.

The majority of genes associated with breast cancer susceptibility, including BRCA1 and BRCA2 genes, are involved in DNA repair mechanisms. Moreover, among the genes recently associated with an increased susceptibility to breast cancer, four are Fanconi Anemia (FA) genes: FANCD1/BRCA2, FANCJ/BACH1/BRIP1, FANCN/PALB2 and FANCO/RAD51C. FANCA is implicated in DNA repair and has been shown to interact directly with BRCA1. It has been proposed that the formation of FANCA/G (dependent upon the phosphorylation of FANCA) and FANCB/L sub-complexes altogether with FANCM, represent the initial step for DNA repair activation and subsequent formation of other sub-complexes leading to ubiquitination of FANCD2 and FANCI. As only approximately 25% of inherited breast cancers are attributable to BRCA1/2 mutations, FANCA therefore becomes an attractive candidate for breast cancer susceptibility. We thus analyzed FANCA gene in 97 high-risk French Canadian non-BRCA1/2 breast cancer individuals by direct sequencing as well as in 95 healthy control individuals from the same population. Among a total of 85 sequence variants found in either or both series, 28 are coding variants and 19 of them are missense variations leading to amino acid change. Three of the amino acid changes, namely Thr561Met, Cys625Ser and particularly Ser1088Phe, which has been previously reported to be associated with FA, are predicted to be damaging by the SIFT and PolyPhen softwares. cDNA amplification revealed significant expression of 4 alternative splicing events (insertion of an intronic portion of intron 10, and the skipping of exons 11, 30 and 31). In silico analyzes of relevant genomic variants have been performed in order to identify potential variations involved in the expression of these spliced transcripts. Sequence variants in FANCA could therefore be potential spoilers of the Fanconi-BRCA pathway and as a result, they could in turn have an impact in non-BRCA1/2 breast cancer families.

Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families.

ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%. However, based on their frequency observed in breast cancer and unrelated healthy individuals, these are not statistically associated with breast cancer risk. Luciferase promoter assays in two breast cancer cell lines identified two haplotypes (H11 and H12) stimulating significantly the expression of ZNF350 transcript compared with the common haplotype H8. The high expression of the H11 allele was associated with the variant c.-874A. Using MatInspector and Transcription Element Search softwares, in silico analyses predicted that the variant c.-874A created a binding site for the factors c-Myc and myogenin. This study represents the first characterization step of the ZNF350 promoter. Additional studies in larger cohorts and other populations will be needed to further evaluate whether common and/or rare ZNF350 promoter variants and haplotypes could be associated with a modest risk of breast cancer.

Implementation of the critical-care pain observation tool on pain assessment/management nursing practices in an intensive care unit with nonverbal critically ill adults: a before and after study.

BACKGROUND: The Critical-Care Pain Observation Tool (CPOT) is one of the few behavioural pain scales which have been developed and validated for the purpose of detecting pain in nonverbal critically ill adults. OBJECTIVES: This study aimed to complete a pre and post evaluation of the implementation of the CPOT on pain assessment/management nursing practices in the Intensive Care Unit (ICU) with nonverbal critically ill adults. DESIGN: A before-and-after study design was used. SETTING/PARTICIPANTS: The Intensive Care Unit (ICU) of a university affiliated health care centre in Montérégie (Canada) was selected for the implementation of the CPOT. All ICU nurses were trained to use the CPOT. Medical files were selected if the patient was 18 years or older, had been mechanically ventilated for a period ≥ 24hours, was unable to communicate, and had intact motor function. METHODS: This implementation study included three steps: 1) pre-implementation phase, 2) implementation phase, and 3) post-implementation phase. The pre-implementation phase included the review of 30 medical files to describe the current nursing practice in pain assessment and management prior to the introduction of the CPOT. During the implementation phase, 60 ICU nurses attended standardized training sessions on the use of the CPOT and practiced the scoring with the CPOT using patients' videotapes. In the post-implementation phase, the interrater reliability of ICU nurses when using the CPOT was tested using three patients' videotapes. Also, pain assessment and management nursing practices were evaluated by reviewing 30 medical files at 3 months, and 30 others at 12 months post-implementation. RESULTS: Nurses' percentage of agreement when scoring patients with the CPOT by viewing the videotapes was high post-implementation of the tool (>87%). Reports of pain assessments were more frequently charted in the medical files in the post-implementation phase (10.5 to 12 assessments in a 24-hour period) compared with the pre-implementation phase (3 assessments in a 24-hour period). Interestingly, fewer analgesic and sedative agents were administered during the post-implementation phase. CONCLUSIONS: The CPOT was successfully implemented and seemed to have positive effects on pain assessment and management nursing practices in the ICU. Further research is warranted to look at its impact on patient outcomes.

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer.

BACKGROUND: The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer. METHODS: In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the NBN gene in our cohort of 97 high-risk non-BRCA1 and -BRCA2 breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. In silico programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines. RESULTS: Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone gamma-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines. CONCLUSION: Our analysis of NBN sequence variations indicated that potential NBN alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in NBN promoter region.

Analysis of GADD45A sequence variations in French Canadian families with high risk of breast cancer.

GADD45A is an evolutionary conserved gene whose expression is regulated by two major tumor suppressor proteins involved in breast cancer etiology, namely, p53 and BRCA1, and which acts primarily in the control of the G2/M cell-cycle transition, apoptosis, and DNA repair. Following genotoxic stress, the p53 protein activates GADD45A transcription, whereas in absence of DNA damage, BRCA1 represses GADD45A expression through interaction with the zinc finger protein ZNF350. Moreover, BRCA1 can activate GADD45A gene expression through interactions with transcription factors binding to the gene promoter. On the basis of the intricate network of interactions between GADD45A, p53, and BRCA1, and the fact that both BRCA1 or TP53 mutations are involved in breast cancer tumorigenesis, we undertook the characterization of the entire coding sequence, intron/exon boundaries, and p53- and ZNF350-binding sequences of this potential breast cancer susceptibility candidate gene in a sample set of 96 women affected with breast cancer from non-BRCA1 and BRCA2 French Canadian families with a high risk of breast cancer and 95 healthy controls from the same population. Although none of the 12 identified sequence variations show a significant difference in frequency between both sample sets, haplotype phasing and frequency estimations identified a common haplotype displaying a higher frequency among the control group. As the variants present on this particular haplotype are noncoding variants in either intron 2 or 3, this finding will have to be further investigated in larger cohorts and other populations. In this regard, our study also identified tagging single nucleotide polymorphisms (tSNPs), providing useful data for other large-scale association studies.

Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.

Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45. Direct sequencing of ZBRK1 entire coding region in affected breast cancer individuals from 97 high-risk French Canadian breast/ovarian cancer families and 94 healthy controls led to the identification of 18 genomic variants. Haplotype analyses, using PHASE, COCAPHASE and HaploStats programs, put in evidence 3 specific haplotypes which could potentially modulate breast cancer risk, and among which 2 that are associated with a potential protective effect (p = 0.01135 and p = 0.00268), while another haplotype is over-represented in the case group (p = 0.00143). Further analyses of these haplotypes indicated that a strong component of the observed difference between both groups emerge from the first 5 variants (out of 12 used for haplotype determination). The present study also permitted to determine a set of tagging SNPs that could be useful for subsequent analyses in large scale association studies. Additional studies in large cohorts and other populations will however be needed to further evaluate if common and/or rare ZBRK1 sequence variants and haplotypes could be associated with a modest/intermediate breast cancer risk.

The burden of adult obesity in Canada.

Obesity is a major public health problem associated with a wide range of health problems. This study estimates the prevalence of obesity, calculates the proportion (or population-attributable fraction [PAF]) of major chronic diseases which is attributable to obesity, estimates the deaths attributable to it and projects its future prevalence trends. In Canada, the overall age-standardized prevalence proportion of obesity has increased from 10 percent in 1970 to 23% in 2004 (8 percent to 23 percent in men and 13 percent to 22 percent in women). The increasing prevalence of obesity was observed for all five age groups examined: 20-34, 35-44, 45-54, 55-64 and 65+. On average, the PAF of prevalence of selected major chronic diseases which is attributable to obesity from 1970 to 2004 has increased by 138 percent for men and by 60 percent for women. Overall, in 2004, 45 percent of hypertension, 39 percent of type II diabetes, 35 percent of gallbladder disease, 23 percent of coronary artery diseases (CAD), 19 percent of osteoarthritis, 11 percent of stroke, 22 percent of endometrial cancer, 12 percent of postmenopausal breast cancer, and 10 percent of colon cancer could be attributed to obesity. In 2004, 8,414 (95 percent CI: 6,881-9,927) deaths were attributable to obesity. If current obesity prevalence trends remain unchanged, the prevalence proportion of obesity in Canada is projected to reach 27 percent in men and 24 percent in women by the year 2010. These increases will have a profound impact on the treatment needs and prevalence of a wide variety of chronic diseases, and also on the health care system in terms of capacity issues and resource allocation.