Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.

OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10-8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity.

OBJECTIVES: Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations. METHODS: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model. RESULTS: There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10-10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10-10). CONCLUSION: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.

A common variant associated with prostate cancer in European and African populations.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Mutational landscape of candidate genes in familial prostate cancer.

BACKGROUND: Family history is a major risk factor for prostate cancer (PCa), suggesting a genetic component to the disease. However, traditional linkage and association studies have failed to fully elucidate the underlying genetic basis of familial PCa. METHODS: Here, we use a candidate gene approach to identify potential PCa susceptibility variants in whole exome sequencing data from familial PCa cases. Six hundred ninety-seven candidate genes were identified based on function, location near a known chromosome 17 linkage signal, and/or previous association with prostate or other cancers. Single nucleotide variants (SNVs) in these candidate genes were identified in whole exome sequence data from 33 PCa cases from 11 multiplex PCa families (3 cases/family). RESULTS: Overall, 4,856 candidate gene SNVs were identified, including 1,052 missense and 10 nonsense variants. Twenty missense variants were shared by all three family members in each family in which they were observed. Additionally, 15 missense variants were shared by two of three family members and predicted to be deleterious by five different algorithms. Four missense variants, BLM Gln123Arg, PARP2 Arg283Gln, LRCC46 Ala295Thr and KIF2B Pro91Leu, and one nonsense variant, CYP3A43 Arg441Ter, showed complete co-segregation with PCa status. Twelve additional variants displayed partial co-segregation with PCa. CONCLUSIONS: Forty-three nonsense and shared, missense variants were identified in our candidate genes. Further research is needed to determine the contribution of these variants to PCa susceptibility.

District health board engagement with the living wage movement: evidence from official information requests.

From a public health perspective, there is strong evidence that income is a major modifiable determinant of health. District health boards (DHBs), who were responsible for providing and/or funding regional health services across Aotearoa, are major employers. International literature suggests implementing a living wage strategy can improve health outcomes, contribute until July 2022 to the reduction of ethnic health inequities, and is ethical and socially responsible business practice. In February 2021, official information requests were sent to all DHBs to determine engagement with the living wage movement. This was augmented through a content analysis of publicly available collective employment contracts to benchmark practice. The review found no DHBs were registered living wage employers, nor is it a requirement of those whom they sub-contract. Two out of twenty DHBs are planning to become living wage employers, and several confirmed they were working collectively to improve working conditions of lower paid workers. This paper makes a scholarly argument for DHBs to commit to becoming living wage employers. As significant regional employers this is an opportunity for DHBs to positively contribute to the alleviation of entrenched poverty a modifiable determinant of ethnic health inequities.

Subclinical Cardiac Dysfunction is Associated with Reduced Cardiorespiratory Fitness and Cardiometabolic Risk Factors in Firefighters.

BACKGROUND: Past studies have documented the ability of cardiopulmonary exercise testing to detect cardiac dysfunction in symptomatic patients with coronary artery disease. Firefighters are at high risk for work-related cardiac events. This observational study investigated the association of subclinical cardiac dysfunction detected by cardiopulmonary exercise testing with modifiable cardiometabolic risk factors in asymptomatic firefighters. METHODS: As part of mandatory firefighter medical evaluations, study subjects were assessed at 2 occupational health clinics serving 21 different fire departments. Mixed effects logistic regression analyses were used to estimate odds ratios (ORs) and account for clustering by fire department. RESULTS: Of the 967 male firefighters (ages 20-60 years; 84% non-Hispanic white; 14% on cardiovascular medications), nearly two-thirds (63%) had cardiac dysfunction despite having normal predicted cardiorespiratory fitness (median peak VO2 = 102%). In unadjusted analyses, cardiac dysfunction was significantly associated with advanced age, obesity, diastolic hypertension, high triglycerides, low high-density lipoprotein (HDL) cholesterol, and reduced cardiorespiratory fitness (all P values < .05). After adjusting for age and ethnicity, the odds of having cardiac dysfunction were approximately one-third higher among firefighters with obesity and diastolic hypertension (OR = 1.39, 95% confidence interval [CI] = 1.03-1.87 and OR = 1.36, 95% CI = 1.03-1.80) and more than 5 times higher among firefighters with reduced cardiorespiratory fitness (OR = 5.41, 95% CI = 3.29-8.90). CONCLUSION: Subclinical cardiac dysfunction detected by cardiopulmonary exercise testing is a common finding in career firefighters and is associated with substantially reduced cardiorespiratory fitness and cardiometabolic risk factors. These individuals should be targeted for aggressive risk factor modification to increase cardiorespiratory fitness as part of an outpatient prevention strategy to improve health and safety.

Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture.

BACKGROUND: The risk of arterial diseases may be elevated among family members of individuals having multifocal fibromuscular dysplasia (FMD). We sought to investigate the risk of arterial diseases in families of individuals with FMD. METHODS: Family histories for 73 probands with FMD were obtained, which included an analysis of 463 total first-degree relatives focusing on FMD and related arterial disorders. A polygenic risk score for FMD (PRSFMD) was constructed from prior genome-wide association findings of 584 FMD cases and 7139 controls and evaluated for association with an abdominal aortic aneurysm (AAA) in a cohort of 9693 AAA cases and 294 049 controls. A previously published PRSAAA was also assessed among the FMD cases and controls. RESULTS: Of all first degree relatives of probands, 9.3% were diagnosed with FMD, aneurysms, and dissections. Aneurysmal disease occurred in 60.5% of affected relatives and 5.6% of all relatives. Among 227 female first-degree relatives of probands, 4.8% (11) had FMD, representing a relative risk (RR)FMD of 1.5 ([95% CI, 0.75-2.8]; P=0.19) compared with the estimated population prevalence of 3.3%, though not of statistical significance. Of all fathers of FMD probands, 11% had AAAs resulting in a RRAAA of 2.3 ([95% CI, 1.12-4.6]; P=0.014) compared with population estimates. The PRSFMD was found to be associated with an AAA (odds ratio, 1.03 [95% CI, 1.01-1.05]; P=2.6×10-3), and the PRSAAA was found to be associated with FMD (odds ratio, 1.53 [95% CI, 1.2-1.9]; P=9.0×10-5) as well. CONCLUSIONS: FMD and AAAs seem to be sex-dimorphic manifestations of a heritable arterial disease with a partially shared complex genetic architecture. Excess risk of having an AAA according to a family history of FMD may justify screening in family members of individuals having FMD.

Extent and distribution of linkage disequilibrium in the Old Order Amish.

Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02-0.09, and for autosomal SNPs 10-20 kb apart with common alleles (minor allele frequency > or =0.05), the LD measure r(2) was at least 0.8 for 15 and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA ( approximately 88%) at r(2) > or =0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations.

Computerized image analysis: texture-field orientation method for pectoral muscle identification on MLO-view mammograms.

PURPOSE: To develop a new texture-field orientation (TFO) method that combines a priori knowledge, local and global information for the automated identification of pectoral muscle on mammograms. METHODS: The authors designed a gradient-based directional kernel (GDK) filter to enhance the linear texture structures, and a gradient-based texture analysis to extract a texture orientation image that represented the dominant texture orientation at each pixel. The texture orientation image was enhanced by a second GDK filter for ridge point extraction. The extracted ridge points were validated and the ridges that were less likely to lie on the pectoral boundary were removed automatically. A shortest-path finding method was used to generate a probability image that represented the likelihood that each remaining ridge point lay on the true pectoral boundary. Finally, the pectoral boundary was tracked by searching for the ridge points with the highest probability lying on the pectoral boundary. A data set of 130 MLO-view digitized film mammograms (DFMs) from 65 patients was used to train the TFO algorithm. An independent data set of 637 MLO-view DFMs from 562 patients was used to evaluate its performance. Another independent data set of 92 MLO-view full field digital mammograms (FFDMs) from 92 patients was used to assess the adaptability of the TFO algorithm to FFDMs. The pectoral boundary detection accuracy of the TFO method was quantified by comparison with an experienced radiologist's manually drawn pectoral boundary using three performance metrics: The percent overlap area (POA), the Hausdorff distance (Hdist), and the average distance (AvgDist). RESULTS: The mean and standard deviation of POA, Hdist, and AvgDist were 95.0 +/- 3.6%, 3.45 +/- 2.16 mm, and 1.12 +/- 0.82 mm, respectively. For the POA measure, 91.5%, 97.3%, and 98.9% of the computer detected pectoral muscles had POA larger than 90%, 85%, and 80%, respectively. For the distance measures, 85.4% and 98.0% of the computer detected pectoral boundaries had Hdist within 5 and 10 mm, respectively, and 99.4% of computer detected pectoral muscle boundaries had AvgDist within 5 mm from the radiologist's manually drawn boundaries. CONCLUSIONS: The pectoral muscle on DFMs can be detected accurately by the automated TFO method. The preliminary study of applying the same pectoral muscle identification algorithm to FFDMs without retraining demonstrates that the TFO method is reasonably robust against the differences in the image properties between the digitized and digital mammograms.

Dynamic multiple thresholding breast boundary detection algorithm for mammograms.

PURPOSE: Automated detection of breast boundary is one of the fundamental steps for computer-aided analysis of mammograms. In this study, the authors developed a new dynamic multiple thresholding based breast boundary (MTBB) detection method for digitized mammograms. METHODS: A large data set of 716 screen-film mammograms (442 CC view and 274 MLO view) obtained from consecutive cases of an Institutional Review Board approved project were used. An experienced breast radiologist manually traced the breast boundary on each digitized image using a graphical interface to provide a reference standard. The initial breast boundary (MTBB-Initial) was obtained by dynamically adapting the threshold to the gray level range in local regions of the breast periphery. The initial breast boundary was then refined by using gradient information from horizontal and vertical Sobel filtering to obtain the final breast boundary (MTBB-Final). The accuracy of the breast boundary detection algorithm was evaluated by comparison with the reference standard using three performance metrics: The Hausdorff distance (HDist), the average minimum Euclidean distance (AMinDist), and the area overlap measure (AOM). RESULTS: In comparison with the authors' previously developed gradient-based breast boundary (GBB) algorithm, it was found that 68%, 85%, and 94% of images had HDist errors less than 6 pixels (4.8 mm) for GBB, MTBB-Initial, and MTBB-Final, respectively. 89%, 90%, and 96% of images had AMinDist errors less than 1.5 pixels (1.2 mm) for GBB, MTBB-Initial, and MTBB-Final, respectively. 96%, 98%, and 99% of images had AOM values larger than 0.9 for GBB, MTBB-Initial, and MTBB-Final, respectively. The improvement by the MTBB-Final method was statistically significant for all the evaluation measures by the Wilcoxon signed rank test (p < 0.0001). CONCLUSIONS: The MTBB approach that combined dynamic multiple thresholding and gradient information provided better performance than the breast boundary detection algorithm that mainly used gradient information.

Sequence variation in the mitochondrial gene cytochrome c oxidase subunit I and prostate cancer in African American men.

BACKGROUND: Previous studies have found associations between mitochondrial DNA (mtDNA) mutations and several cancer types. Recently, we found that mutations in the mtDNA gene cytochrome c oxidase subunit 1 (COI) were both linked to and associated with prostate cancer (PCa) in Caucasian men. Here we examine the association between COI mutations and PCa in African American men. METHODS: The entire COI gene was directly sequenced in 132 PCa cases and 135 controls from the Flint Men's Health Study, a community-based sample of African American men with and without PCa. Associations between all variants and PCa were evaluated. RESULTS: We identified 102 COI single nucleotide polymorphisms (SNPs), including 15 missense variants. Overall, the presence of one or more COI missense variants was not significantly associated with PCa. Individually, two SNPs (T6221C and T7389C) were significantly associated with prostate cancer (P < 0.05) and in strong linkage disequilibrium with each other (r(2) > 0.6). CONCLUSIONS: Of the two significantly associated SNPs, one is a synonymous substitution and the other is part of the African-specific mitochondrial haplogroup (L). Additional research will be needed to determine the clinical relevance of these associations in African populations.

PedMine--a simulated annealing algorithm to identify maximally unrelated individuals in population isolates.

UNLABELLED: In family-based genetic studies, it is often useful to identify a subset of unrelated individuals. When such studies are conducted in population isolates, however, most if not all individuals are often detectably related to each other. To identify a set of maximally unrelated (or equivalently, minimally related) individuals, we have implemented simulated annealing, a general-purpose algorithm for solving difficult combinatorial optimization problems. We illustrate our method on data from a genetic study in the Old Order Amish of Lancaster County, Pennsylvania, a population isolate derived from a modest number of founders. Given one or more pedigrees, our program automatically and rapidly extracts a fixed number of maximally unrelated individuals. AVAILABILITY: http://www.hg.med.umich.edu/labs/douglaslab/software.html (version 1.0.0).

Chromosome 8q24 markers: risk of early-onset and familial prostate cancer.

Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.

Mammographic breast density--evidence for genetic correlations with established breast cancer risk factors.

Previous twin and family studies indicate that the familial aggregation of breast density is due (in part) to genetic factors. Whether these genetic influences are shared with other breast cancer risk factors, however, is not known. Using standard film-screen mammography, we screened 550 women, including 611 pairs of sisters, from the Old Order Amish population of Lancaster County, Pennsylvania. We digitized mammograms and quantified the dense and nondense areas of the breast using a computer-assisted method. Information about other breast cancer risk factors was collected via questionnaires and a physical exam. Using pedigree-based variance component methods, we estimated the genetic contributions to several breast cancer risk factors, including breast density, and evaluated the evidence for shared genetic influences between them. After adjusting for covariates, genetic effects accounted for >33% of the total variance of each risk factor (P < 0.001), including breast density, and the dense and nondense areas of the breast were significantly genetically correlated with parity [genetic correlation (rho(G)) = -0.47; P = 0.013] and age at menarche (rho(G) = -0.38; P = 0.008), respectively. The nondense area of the breast and, in turn, breast density, expressed as a ratio of dense area to total area, were also genetically correlated with most measures of adiposity but in opposite directions (rho(G) > or = 0.75; P < 10(-7) for nondense area). We conclude that the genetic components that influence breast density are not independent of the genetic components that influence other breast cancer risk factors. This shared genetic architecture should be considered in future genetic studies of breast density.

The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study.

BACKGROUND: The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions. METHODS: The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy. RESULTS: The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes. CONCLUSIONS: Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.

Genetic influences on blood pressure response to the cold pressor test: results from the Heredity and Phenotype Intervention Heart Study.

OBJECTIVES: Blood pressure (BP) response to the cold pressor test (CPT) has been found to predict the development of hypertension and cardiovascular disease in prospective studies. The determinants of BP response to the CPT, including the role of genetic factors, however, are largely unknown. Additionally, to our knowledge, no study has examined the genetics of BP recovery from the CPT, including whether shared genetic factors influence both reactivity and recovery. METHODS: As part of the Heredity and Phenotype Intervention Heart Study, we administered a 2.5 min hand CPT to 835 participants from 18 extended Amish families. We estimated the heritability of BP reactivity and recovery (measured by the incremental area under the curve) and the genetic correlations between baseline, reactivity, and recovery BP phenotypes. RESULTS: After adjusting for relevant covariates, including baseline BP, the heritability estimates for both systolic BP (SBP) and diastolic BP (DBP) reactivity and recovery differed significantly from zero (P < 0.01), with 12-25% of the total variation in BP response attributable to additive genetic effects. The genetic correlations between baseline DBP and response phenotypes were not significantly different from zero, whereas the genetic correlation between DBP reactivity and recovery (0.74) was significantly different from zero and 1 (P < 0.005). The genetic correlation between SBP reactivity and recovery was similar (0.81; P < 0.05). CONCLUSION: We conclude that, independent of baseline BP, BP response to CPT is heritable, and that both shared and unshared genetic factors influence BP reactivity and recovery, thus stressing the importance of identifying genetic variants that influence both traits.

'Dipping our toes in the research pool': novice researchers in a collaborative project.

A study into research capacity at two universities offered opportunities to both novice and experienced researchers. Here, Julie Douglas and three novice researchers, Yvonne Flood, Sara Morris and Claire Rushton, reflect on their involvement in the collaborative project and how it contributed to individual and institutional development.

Association between germline variation in the FHIT gene and prostate cancer in Caucasians and African Americans.

Many studies have established that loss of heterozygosity and/or altered expression of the fragile histidine triad (FHIT) gene is a common event in a number of tumor types including prostate carcinoma. Encompassing the most active fragile site in the human genome, FRA3B, FHIT has become the model fragile site-associated tumor suppressor gene. In a recent study, linkage and association between germline genetic variation in FHIT (specifically single nucleotide polymorphism rs760317) and prostate cancer were reported. We sought to confirm this finding in two independent samples: (a) a family-based sample of 817 men with (n = 434) and without (n = 383) prostate cancer from 323 Caucasian families, and (b) a community-based case-control sample of African American men with (n = 133) and without (n = 342) prostate cancer. Using a family-based association test, rs760317 was associated with prostate cancer in Caucasians (P = 0.031), with a reduction in the risk of prostate cancer among carriers of the minor allele (odds ratio, 0.66; 95% confidence interval, 0.42-1.04; P = 0.074). African American carriers experienced a similar risk reduction (odds ratio, 0.63; 95% confidence interval, 0.42-0.96; P = 0.032). These results are remarkably consistent across ethnic samples but are in opposition to results from the original study, which showed an association between the minor allele of rs760317 and an increased risk of prostate cancer. Taken together, the consistently significant but flipped association between single nucleotide polymorphism rs760317 and prostate cancer in three independent samples suggests that rs760317 may be in linkage disequilibrium with one or more prostate cancer susceptibility variants in or near FHIT.

Common variation in the BRCA1 gene and prostate cancer risk.

Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding (and including) the BRCA1 gene. We also used the Genotype-Identity-by-Descent Sharing Test to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln(356)Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (P = 0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval, 1.21-4.20). Notably, BRCA1 Gln(356)Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, Genotype-Identity-by-Descent Sharing Test results suggest that Gln(356)Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (P = 0.022). Thus, we have identified a common, nonsynonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.