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Biomedical subjects

David J Hunter

Publications and source records attributed to David J Hunter.

At least 145 records · Page 8Linked to original sources
PubMed2003

Polymorphisms in DNA double-strand break repair genes and breast cancer risk in the Nurses' Health Study.

Genetic polymorphisms in double-strand break repair genes may influence DNA repair capacity and, in turn, confer predisposition to breast cancer. We prospectively assessed the associations of candidate polymorphisms G31479A (R188H) in XRCC2, A4541G (5'-UTR), A17893G (IVS5-14) and C18067T (T241 M) in XRCC3, and C299T (5'-UTR) and T1977C (D501D) in Ligase IV with breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n=1004; controls, n=1385). We observed no overall associations of these six genotypes with breast cancer risk. Four common haplotypes in XRCC3 accounted for 99% of the chromosomes of the present study population. We observed that Ligase IV 1977C carriers were at increased breast cancer risk if they had a first degree family history of breast cancer (test for interaction, P=0.01). We observed that the XRCC2 R188H polymorphism modified the association of plasma alpha-carotene level and breast cancer risk (test for ordinal interaction, P=0.03); the significantly decreased risk seen overall for women in the highest quartile of plasma alpha-carotene was only present among 188H non-carriers (the top quartile versus the bottom quartile; multivariate odds ratio, 0.55; 95% confidence interval, 0.40-0.75). No significant interactions were seen between any of these polymorphisms and duration or dose of cigarette smoking. The gene-environment interaction data suggest that the subtle effects of some of these variants on breast cancer risk may be magnified in the presence of certain exposures.

Adult↗
PubMed2003

Polymorphic variation at the -202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk.

Previous reports have suggested an association between circulating IGFBP-3 levels and the risk of premenopausal breast cancer, and a single nucleotide polymorphism (SNP) in the promoter region of IGFBP-3 (nucleotide -202) was shown to influence transcription. There is prior evidence that the action of antiproliferative agents such as retinoids and selective estrogen receptor modulators (SERMs) act in part by upregulating IGFBP3 gene expression. We identified 677 women with incident breast cancer and 834 matched controls from the Nurses' Health Study (NHS) and genotyped them at the -202 locus. For 943 of these women, we had previously measured IGF-I and IGFBP-3 plasma levels, and for 861 of these subjects, plasma retinol levels were available. Age-adjusted mean circulating IGFBP-3 levels were highest in the individuals with the AA genotype and decreased significantly in a stepwise manner in the presence of 1 or 2 copies of the C allele (4,426 ng/ml, 4,060 ng/ml and 3,697 ng/ml, respectively). We found a positive relation between age-adjusted IGFBP-3 levels and plasma retinol (14% difference in IGFBP-3 in top vs. bottom tertiles of retinol, p for trend < 0.001; Spearman correlation coefficient r = 0.25), which was similar across genotypes at the -202 IGFBP3 locus (interaction term, F = 0.10, p = 0.91). Breast cancer risk was not significantly related to genotype at the -202 locus in our prospective analyses. We confirmed a relation between the -202 IGFBP3 polymorphism and IGFBP-3 serum levels and observed a positive correlation between circulating retinol levels and circulating IGFBP-3 levels, providing further evidence that retinoids may influence IGF physiology. Our data do not demonstrate a significant influence of this locus on breast cancer risk, but we cannot exclude a minor influence or an influence confined to subgroups.

Adult↗
PubMed2003

Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass.

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a critical regulator of adipogenesis. PPAR gamma+/- mice are resistant to high-fat diet-induced obesity and thus PPAR gamma may mediate physiological responses to dietary fat in other mammals. The aim of this study was to determine whether the human PPAR gamma proline to alanine substitution polymorphism (Pro12Ala) modifies the association between dietary fat and adiposity and plasma lipids. Subjects (n=2141) were controls selected for three case-control studies nested within the Nurses' Health Study, a large ongoing prospective cohort study. Associations between intake of total fat, fat subtypes and BMI were different in PPAR gamma 12Ala variant allele-carriers compared with non-carriers. Among homozygous wild-type Pro/Pro individuals, those in the highest quintile of total fat intake, had significantly higher mean body mass index (BMI) compared with those in the lowest quintile (27.3 versus 25.4 kg/m2, respectively; P-trend<0.0001) whereas among 12Ala variant allele-carriers there was no significant trend observed between dietary fat intake and BMI (P-trend=0.99; P-interaction=0.003). In contrast, intake of monounsaturated fat was not associated with BMI among homozygous wild-type women but was inversely associated with BMI among 12Ala variant allele-carriers (mean in lowest quintile=27.6 versus mean in highest quintile=25.5 kg/m2; P-trend=0.006; P-interaction=0.003). The relationship between dietary fat intake and plasma lipid concentrations also differed according to PPAR gamma genotype. These data suggest that PPAR gamma genotype is an important factor in physiological responses to dietary fat in humans.

Alleles↗
PubMed2003

A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk.

Biological and epidemiological data suggest that progesterone has an important role in mammary tumorigenesis. Because the effects of progesterone require the progesterone receptor (PGR), which exists in two isoforms, PR-A and PR-B, we sought to determine whether the functional polymorphism, +331 G/A, which causes an increase in the expression of the hPR-B isoform, is related to breast cancer risk. Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 990 cases and 1,364 controls and observed a statistically significant increased risk of breast cancer among carriers of the +331 A allele (odds ratio, 1.33; 95% confidence interval, 1.01-1.74) compared with subjects with the GG genotype. We also observed a potential interaction between genotype and body mass index (BMI) among postmenopausal women, with the highest risk (odds ratio, 2.30; 95% confidence interval, 1.02-5.21) among obese women (BMI >/=30 kg/m(2)) with the GA or AA genotype compared with lean (BMI <25 kg/m(2)) women with the GG genotype. Our findings suggest that the increased production of hPR-B by the +331 G/A polymorphism may predispose women to breast cancer development through increased hPR-B-dependent stimulation of mammary cell growth.

Adult↗
PubMed2003

Premenopausal fat intake and risk of breast cancer.

BACKGROUND: International comparisons and case-control studies have suggested a positive relation between dietary fat intake and breast cancer risk, but prospective studies, most of them involving postmenopausal women, have not supported this association. We conducted a prospective analysis of the relation between dietary fat intake and breast cancer risk among premenopausal women enrolled in the Nurses' Health Study II. METHODS: Dietary fat intake and breast cancer risk were assessed among 90 655 premenopausal women aged 26 to 46 years in 1991. Fat intake was assessed with a food-frequency questionnaire at baseline in 1991 and again in 1995. Breast cancers were self-reported and confirmed by review of pathology reports. Multivariable relative risks (RRs) and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. RESULTS: During 8 years of follow-up, 714 women developed incident invasive breast cancer. Relative to women in the lowest quintile of fat intake, women in the highest quintile of intake had a slight increased risk of breast cancer (RR = 1.25, 95% CI = 0.98 to 1.59; P(trend) =.06). The increase was associated with intake of animal fat but not vegetable fat; RRs for the increasing quintiles of animal fat intake were 1.00 (referent), 1.28, 1.37, 1.54, and 1.33 (95% CI = 1.02 to 1.73; P(trend) =.002). Intakes of both saturated and monounsaturated fat were related to modestly elevated breast cancer risk. Among food groups contributing to animal fat, red meat and high-fat dairy foods were each associated with an increased risk of breast cancer. CONCLUSIONS: Intake of animal fat, mainly from red meat and high-fat dairy foods, during premenopausal years is associated with an increased risk of breast cancer.

Adult↗
PubMed2003

Genetic contribution to cartilage volume in women: a classical twin study.

OBJECTIVE: A classical twin study was performed to assess the relative contribution of genetic and environmental factors to cartilage volume. METHODS: The subjects were 136 adult female twins: 31 monozygotic and 37 dizygotic twin pairs. The subjects had a T2-weighted fat-saturated sagittal gradient echo MRI performed of their right knee. Femoral, tibial and patella cartilage volumes were measured using 3D Slicer, a piece of software that facilitates semi-automatic segmentation, generation of three-dimensional surface models and quantitative analysis. The intraclass correlations were calculated, and maximum-likelihood model fitting was used to estimate genetic and environmental variance components. All variables were adjusted for age, BMI and femoral condyle size. RESULTS: The intraclass correlations for all of the cartilage volumes assessed were higher in monozygotic than dizygotic twin pairs. The heritabilities (95% confidence intervals) obtained from model fitting were: femoral, 61% (36-77%); tibial, 76% (56-87%); patella, 66% (47-79%); and total cartilage volume, 73% (51-85%). CONCLUSION: This study provides evidence for the importance of genetic factors in determining cartilage volume. Identifying heritability is the first step on the way to finding specific genes, which may improve our insight in the pathophysiology of cartilage disorders including the etiology of complex diseases such as osteoarthritis.

Aged↗
PubMed2003

Night-shift work and risk of colorectal cancer in the nurses' health study.

Exposure to light at night suppresses the physiologic production of melatonin, a hormone that has antiproliferative effects on intestinal cancers. Although observational studies have associated night-shift work with an increased risk of breast cancer, the effect of night-shift work on the risk of other cancers is not known. We prospectively examined the relationship between working rotating night shifts and the risk of colorectal cancers among female participants in the Nurses' Health Study. We documented 602 incident cases of colorectal cancer among 78 586 women who were followed up from 1988 through 1998. Compared with women who never worked rotating night shifts, women who worked 1-14 years or 15 years or more on rotating night shifts had multivariate relative risks of colorectal cancer of 1.00 (95% confidence interval [CI] = 0.84 to 1.19) and 1.35 (95% CI = 1.03 to 1.77), respectively (P(trend) =.04). These data suggest that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women.

Adult↗
PubMed2003

Meat, fish and egg intake and risk of breast cancer.

Intakes of animal protein, meat, and eggs have been associated with breast cancer incidence and mortality in ecological studies, but data from long-term prospective studies are limited. We therefore examined these relationships in the Nurses' Health Study. We followed 88,647 women for 18 years, with 5 assessments of diet by food frequency questionnaire, cumulatively averaged and updated over time. We calculated the relative risks (RR) and 95% confidence intervals (95% CI) for risk of developing invasive breast cancer, over categories of nutrient and food intake. During follow-up, 4,107 women developed invasive breast cancer. Compared to the lowest quintile of intake, the RR and 95% CI for the highest quintile of intake were 1.02 (0.92-1.14) for animal protein, 0.93 (0.83-1.05) for red meat and 0.89 (0.79-1.00) for all meat. Results did not differ by menopausal status or family history of breast cancer. We found no evidence that intake of meat or fish during mid-life and later was associated with risk of breast cancer.

Adult↗
PubMed2003

Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer.

BACKGROUND: In several epidemiologic investigations, folate intake has appeared to reduce the elevated risk of breast cancer associated with moderate alcohol consumption. However, data relating plasma folate levels to breast cancer risk are sparse. We investigated the association between plasma folate and other vitamins with breast cancer in a prospective, nested case-control study. METHODS: Blood samples were obtained during 1989 and 1990 from 32 826 women in the Nurses' Health Study who were followed through 1996 for the development of breast cancer. We identified 712 breast cancer case patients and selected 712 individually matched control subjects. Dietary information was obtained using food frequency questionnaires given in 1980, 1984, 1986, and 1990. Logistic regression was used to estimate the relative risks (RRs) of breast cancer (after adjustment for potential risk factors), and a generalized linear model was used to calculate the Pearson correlation coefficients between plasma estimates of folate, vitamin B(6), vitamin B(12), and homocysteine, and intakes of folate, vitamin B(6), and vitamin B(12). All statistical tests were two-sided. RESULTS: The multivariable RR comparing women in the highest quintile of plasma folate with those in the lowest was 0.73 (95% confidence interval [CI] = 0.50 to 1.07; P(trend) =.06). The inverse association between plasma folate and breast cancer risk was highly statistically significant among women consuming at least 15 g/day (i.e., approximately 1 drink/day) of alcohol (multivariable RR = 0.11, 95% CI = 0.02 to 0.59 for highest versus lowest quintile) in contrast with that of women consuming less than 15 g/day (multivariable RR = 0.72, 95% CI = 0.49 to 1.05). The multivariable RR comparing women in the highest quintile of plasma vitamin B(6) levels with those in the lowest quintile was 0.70 (95% CI = 0.48 to 1.02; P(trend) =.09). Plasma vitamin B(12) levels were inversely associated with breast cancer risk among premenopausal women (multivariable RR = 0.36, 95% CI = 0.15 to 0.86 for highest versus lowest quintile) but not among postmenopausal women. Plasma homocysteine was not associated with breast cancer risk. CONCLUSIONS: Higher plasma levels of folate and possibly vitamin B(6) may reduce the risk of developing breast cancer. Achieving adequate circulating levels of folate may be particularly important for women at higher risk of developing breast cancer because of higher alcohol consumption.

Adult↗
PubMed2003

Major dietary patterns and the risk of colorectal cancer in women.

BACKGROUND: Several foods and nutrients have been implicated in the development of colon and rectal cancers. In this study, we prospectively assessed the associations between major dietary patterns and the risks of these 2 cancers in women. METHODS: Using dietary information collected in 1984, 1986, 1990, and 1994 from 76 402 women aged 38 to 63 years without a history of cancer in 1984, we conducted factor analysis and identified 2 major dietary patterns: "prudent" and "Western." We calculated factor scores for each participant and examined prospectively the associations between dietary patterns and colon and rectal cancer risks. RESULTS: The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains, while the Western pattern, by higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains. During 12 years of follow-up, we identified 445 cases of colon cancer and 101 cases of rectal cancer. After adjusting for potential confounders, we observed a relative risk for colon cancer of 1.46 (95% confidence interval, 0.97-2.19) when comparing the highest with the lowest quintiles of the Western pattern (P value for trend across quintiles, .02). The prudent pattern had a nonsignificant inverse association with colon cancer (relative risk for fifth quintile compared with the first, 0.71; 95% confidence interval, 0.50-1.00; P for trend across quintiles, .31). We did not observe any significant association between dietary patterns and rectal cancer. CONCLUSION: We found a significant positive association between the Western dietary pattern and the risk of colon cancer.

Adult↗
PubMed2003

Vitamin and carotenoid intake and risk of squamous cell carcinoma of the skin.

Our objective was to examine prospectively the intake of vitamins A (including retinol and total vitamin A), C and E; folate; total carotene; and several individual carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin and lutein/zeaxanthin) in relation to incidence of SCC of the skin in 2 large cohorts of men and women. We used a prospective cohort study design with up to 14 years of follow-up in women and 10 years in men. Diet was measured with FFQs every 2-4 years; cases of SCC of the skin were ascertained on biennial questionnaires and confirmed by medical records. Participants were female nurses and male health professionals, from the Nurses' Healthy Study and the Health Professionals Follow-up Study in the United States, without a history of any cancer in 1982 (n = 85,944 women) and 1986 (n = 43,867 men). Follow-up response was achieved for over 90% of potential person-years. Relative risks and 95% confidence intervals for development of SCC of the skin are reported. We recorded 369 cases of SCC in women and 305 cases in men. After multivariate adjustment for various known behavioral, sun-exposure and sun-sensitivity risk factors for SCC, there were no significant inverse associations between these dietary factors and SCC incidence. No evidence was found that vitamins A, C and E; folate; or carotenoids play an important protective role against incident SCC.

Adult↗
PubMed2003

Parallel preparative high-performance liquid chromatography with on-line molecular mass characterization.

High-throughput chemistry (HTC) is now an integral part of the lead discovery process in many pharmaceutical and related chemical companies. As this process becomes refined or improved, with the integration of systems with enhanced capabilities, and the requirement for quality compounds of high purity increases, purification is often considered a bottleneck. Although a wide range of purification techniques is available, high-performance liquid chromatography (HPLC) is usually the preferred method of purification to produce high-purity compounds. Parallel preparative HPLC with robust UV-guided fraction collection has been shown to reduce the bottleneck and complement the parallel synthesis systems. However, despite the success of this technique, post-purification analysis of fractions to identify the target compound adds an additional level of complexity. This paper describes the interfacing of the Biotage Parallex with the MUX interface on a single quadrupole mass spectrometer, thus combining robust UV-guided fractionation with on-line MS characterization.

Chromatography, High Pressure Liquid↗
PubMed2003

The role of bone metabolism in osteoarthritis.

Bone is not structurally normal in osteoarthritis (OA). Periarticular bone in OA has increased turnover, decreased bone mineral content and stiffness, and decreased trabecular numbers. The increased turnover of collagen, in particular, may affect the biomechanical competence of bone and is driven by a number of processes, including osteoblast phenotypic expression, chondrocyte apoptosis, matrix metalloproteinases, and growth factors. This turnover is reflected in alterations in biomarkers and bone mineral density (BMD). High BMD at non-joint sites is associated with an increased risk of OA; however, low BMD and high bone turnover appears to be associated with more rapid progression. These alterations in bone turnover offer new therapeutic opportunities.

Biomarkers↗
PubMed2003

Polymorphisms in steroid hormone pathway genes and mammographic density.

Mammographic density has been linked with exposure to endogenous and exogenous steroid hormones, and increased breast cancer risk. Variation in breast density may be due, in part, to polymorphisms in steroid hormone biosynthesis, metabolism and signaling genes. We conducted cross-sectional analyses within the Nurses' Health Study (n = 538), to investigate variation in mammographic breast density, by 10 polymorphisms in eight candidate genes (CYP17, CYP19, CYP1A1, CYP1B1, COMT, UGT1A1, AR, and AIB1). Breast density was assessed using a computer-assisted technique. We evaluated whether associations between variant alleles of these genes and breast density differed by menopause and postmenopausal hormone (PMH) use. Polymorphisms in CYP17, CYP19, CYP1B1, COMT CYP1A1, or AR were not associated consistently with breast density among premenopausal or postmenopausal women. Premenopausal women with the 7/7 UGT1A1 genotype had lower breast density (difference compared to the 6/6 genotype of: -16.5% density; p = 0.04). In contrast, postmenopausal women with the 7/7 UGT1A1 genotype had greater breast density compared to those with the 6/6 genotype (+6.2% density; p = 0.05); this association was strongest among current PMH users (+13.0% density; p = 0.03). In analyses limited to postmenopausal women, breast density was also greater among women carrying short AIB1 alleles (< or = 26 glutamine repeats; +4.1% density; p = 0.04). Most of the variants in the candidate breast cancer genes evaluated in this study are not strong predictors of breast density. However, our findings of differences in associations for UGT1A1 and AIB1 genotypes with breast density by menopausal status needs additional corroboration.

Adult↗
PubMed2003

Association of NAT2 and smoking in relation to breast cancer incidence in a population-based case-control study (United States).

OBJECTIVE: To evaluate the potential interaction between N-acetyltransferase 2 (NAT2) and smoking in breast cancer incidence. METHODS: The data are derived from a population-based case-control study of women aged 20-69 years who were residents of Massachusetts or Wisconsin during 1997-1998. Incident cases of invasive breast cancer were identified through state tumor registries and age-similar controls were selected at random from population lists. Telephone interviews were conducted to obtain information on known and suspected risk factors including smoking history. Women provided oral mucosal DNA through the mail for genetic studies. RESULTS: A total of 791 cases and 797 controls were included in the analysis. Overall, smoking was modestly associated with breast cancer risk (multivariate odds ratio (OR) for ever smoking: 1.37; 95% confidence interval (CI): 1.12-1.69), and there was a trend in risk for greater pack-years of smoking among postmenopausal women (p for trend = 0.02). Overall, NAT2 was not related to invasive breast cancer (multivariate OR: 1.1 1; 95% CI: 0.90-1.36). Associations of smoking with breast cancer tended to be somewhat stronger among the women with the slow acetylator genotype for NAT2: when compared to those who never smoked and were rapid acetylators, the OR for ever smoking was 1.50 (95% CI: 1.11-2.02) in slow acetylators, and OR: 1.24 (95% CI: 0.91-1.70) in rapid acetylators. However, tests for multiplicative interaction were not significant in case-control comparisons, or in case-only analyses. CONCLUSION: Results of the study are compatible with the majority of previous studies that indicate little or no association of NAT2, smoking, or their interaction with the occurrence of breast cancer.

Adult↗
PubMed2003

Multiple displacement amplification prior to single nucleotide polymorphism genotyping in epidemiologic studies.

We assessed the whole genome amplification strategy, known as multiple displacement amplification (MDA), for use with the TaqMan genotyping platform for DNA samples derived from two case-control studies nested in the Nurses' Health Study and the Physicians' Health Study. Our objectives were to (1) quantify DNA yield from samples of varying starting concentrations and (2) assess whether MDA products give an accurate representation of the original genomic sequence. Multiple displacement amplification yielded a mean 23000-fold increase in DNA quantity and genotyping results demonstrate 99.95% accuracy across six SNPs from four genes for 352 samples included in this study. These results suggest that MDA will provide a sufficiently robust amplification of limiting samples of genomic DNA that can be used for SNP genotyping in large case-control studies of complex diseases.

Base Sequence↗