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V Shane Pankratz

Publications and source records attributed to V Shane Pankratz.

At least 19 recordsLinked to original sources
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2007

Mammographic breast density as a general marker of breast cancer risk.

Mammographic breast density is a strong risk factor for breast cancer but whether breast density is a general marker of susceptibility or is specific to the location of the eventual cancer is unknown. A study of 372 incident breast cancer cases and 713 matched controls was conducted within the Mayo Clinic mammography screening practice. Mammograms on average 7 years before breast cancer were digitized, and quantitative measures of percentage density and dense area from each side and view were estimated. A regional density estimate accounting for overall percentage density was calculated from both mammogram views. Location of breast cancer and potential confounders were abstracted from medical records. Conditional logistic regression was used to estimate associations, and C-statistics were used to evaluate the strength of risk prediction. There were increasing trends in breast cancer risk with increasing quartiles of percentage density and dense area, irrespective of the side of the breast with cancer (P(trends) < 0.001). Percentage density from the ipsilateral side [craniocaudal (CC): odds ratios (ORs), 1.0 (ref), 1.7, 3.1, and 3.1; mediolateral oblique (MLO): ORs, 1.0 (ref), 1.5, 2.2, and 2.8] and the contralateral side [CC: ORs, 1.0 (ref), 1.8, 2.2, and 3.7; MLO: ORs, 1.0 (ref), 1.6, 1.9, and 2.5] similarly predicted case-control status (C-statistics, 0.64-65). Accounting for overall percentage density, density in the region where the cancer subsequently developed was not a significant risk factor [CC: 1.0 (ref), 1.3, 1.0, and 1.2; MLO: 1.0 (ref), 1.1, 1.0, and 1.1 for increasing quartiles]. Results did not change when examining mammograms 3 years on average before the cancer. Overall mammographic density seems to represent a general marker of breast cancer risk that is not specific to breast side or location of the eventual cancer.

Breast Neoplasms↗
PubMed2006

Associations between measles vaccine immunity and single-nucleotide polymorphisms in cytokine and cytokine receptor genes.

BACKGROUND: Cytokines are key regulators of measles vaccine humoral and cellular immunity. Single-nucleotide polymorphisms (SNPs) that are associated with differences in cytokine levels should also influence measles vaccine-induced immunity. METHODS: We genotyped 118 measles-mumps-rubella-vaccinated subjects for SNPs from 6 cytokine genes (interleukin [IL]-2, IL-4, IL-10, IL-12A, IL-12B, and interferon [IFN]-gamma) and their receptors (IL-2RA, IL-2RB, IL-4RA, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, and IFN-gamma R). Associations of SNPs with measles-specific antibodies, lymphoproliferation, and secreted cytokines were determined using chi2 tests and analyses of covariance. RESULTS: We found significant associations (P<.05) between SNPs in the IL-2, IL-10, and IL-12RB genes and measles vaccine-induced immunity. The IVS1-100G (rs2069762) and the Ex2-34G (rs2069763) SNPs within the IL-2 gene were associated with high antibody and high lymphoproliferative responses, whereas SNPs within the IL-10 and IL-12R genes were associated with low antibody and lymphoproliferative responses to measles. SNPs within the IL-4RA and IL-12B genes varied significantly (P<.05) across immune response measures. Significant associations were also found between SNPs and secreted cytokine levels. CONCLUSIONS: Specific SNPs in the cytokine and cytokine receptor genes are significantly associated with variations in measures of the immune response to measles vaccination. These results need to be further validated in a larger cohort.

Cytokines↗
PubMed2006

Age-related lobular involution and risk of breast cancer.

BACKGROUND: As women age, the lobules in their breasts undergo involution or regression. We investigated whether lobular involution in women with benign breast disease was associated with subsequent breast cancer risk. METHODS: We examined biopsy specimens of 8736 women in the Mayo Benign Breast Disease Cohort from whom biopsy samples were taken between January 1, 1967, and December 31, 1991. Median follow-up for breast cancer outcomes was 17 years. We classified lobular involution in the background breast tissue as none (0% involuted lobules), partial (1%-74%), or complete (> or = 75%). Subsequent breast cancer events and data on other risk factors were obtained from medical records and follow-up questionnaires. To estimate relative risks (RRs), standardized incidence ratios were calculated by use of incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) Registry. All statistical tests were two-sided. RESULTS: Distribution of extent of involution was none among 1627 (18.6%) women, partial among 5197 (59.5%), and complete among 1912 (21.9%). Increased involution was positively associated with increased age and inversely associated with parity (both P<.001). The relative risk for the entire cohort of 8736 women, compared with the Iowa SEER population, was 1.40 (95% CI = 1.30 to 1.51). Risk of breast cancer was associated with the extent of involution (for no involution, RR [i.e., observed versus expected] = 1.88, 95% confidence interval [CI] = 1.59 to 2.21; for partial involution, RR = 1.47, 95% CI = 1.33 to 1.61; and for complete involution, RR = 0.91, 95% CI = 0.75 to 1.10; test for heterogeneity P<.001). Lobular involution modified risk in all subsets (e.g., among women with atypia, for no involution, RR = 7.79, 95% CI = 3.56 to 14.81; for partial involution, RR = 4.06, 95% CI = 3.03 to 5.33; and for complete involution, RR = 1.49, 95% CI = 0.41 to 3.82; P = .003). CONCLUSIONS: In this large cohort of women with benign breast disease, lobular involution was associated with reduced risk of breast cancer. Aberrant involution may be a biologically important phenomenon in breast cancer biology.

Adult↗
PubMed2006

A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype-tagging approaches.

BACKGROUND: Numerous studies point to a positive relationship between elevated levels of estrogens and increased risk of breast. Androgens are converted to estrogens by the aromatase enzyme, which is encoded by the CYP19 gene. We recently published resequencing data on 88 polymorphisms identified in that gene. The hypothesis tested in this study was that polymorphisms, or haplotypes, in CYP19 are related to risk of breast cancer. METHODS: Incident cases of breast cancer were identified through the Division of Medical Oncology at the Mayo Clinic in Rochester, MN. Controls were patients visiting Mayo for an annual medical examination. Controls were frequency matched to cases based on age and region of residence. Tag-polymorphisms were selected using 2 methods: (1) 12 variants using the tag-selection method of Carlson et al. (Am J Hum Genet 74:106-120, 2004); and (2) 12 variants using the haplotype method of Stram (Genet Epidemiol 27:365-374, 2004). Six SNPs were selected by both methods. Genotyping was conducted using SNPStream, TaqMan and RFLP analyses. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Analyses were conducted among all cases and controls, or stratified by estrogen receptor alpha (ER) status and/or menopausal status. RESULTS: A total of 750 cases (60% postmenopausal) and 732 controls (75% postmenopausal) were included. No association with breast cancer risk was detected for individual variants, selected tagSNPs or hap-tag SNPs despite 80% power to detect OR as low as 1.49 for minor allele frequency (MAF) of 0.10. Similarly, stratified analyses based on ER status or menopausal status failed to detect any association with breast cancer risk. CONCLUSION: These analyses suggest that variants of CYP19 are not associated with risk of breast cancer.

Alleles↗
PubMed2006

Human leukocyte antigen haplotypes in the genetic control of immune response to measles-mumps-rubella vaccine.

To elucidate the contribution of human leukocyte antigen (HLA) haplotypes and their genotypic combinations to immune status after measles-mumps-rubella (MMR) vaccination, 346 children 12-18 years of age were studied. The class I A*29-Cw*16-B*44 haplotype was associated with lower levels of immunoglobulin G (IgG) antibody to both measles (P=.08) and mumps (P=.03) viral antigens. The A*26-Cw*12-B*38 haplotype was associated with higher cellular immune responses to measles (P=.02) and mumps (P=.01) vaccine viruses. Subjects with the class II DRB1*03-DQB1*02-DPB1*04 haplotype had higher lymphoproliferative responses to measles virus (P=.01) and mumps virus (P=.006). The DRB1*15/16-DQB1*06-DPB1*03 haplotype was associated with high levels of IgG antibody to measles virus (P=.09) but low levels of IgG antibody to rubella virus (P=.02), whereas DRB1*04-DQB1*03-DPB1*03 was associated with high lymphoproliferative responses to both measles (P=.01) and rubella (P=.002) vaccine viruses. A*26-Cw*12-B*38 was associated with both mumps virus-specific humoral (P=.007) and cell-mediated (P=.01) immune responses after 2 doses of MMR vaccine. Haplotype DRB1*04-DQB1*03-DPB1*03 was associated with both lower rubella virus IgG antibody levels (P=.02) and higher rubella virus-specific lymphoproliferation (P=.002). Better characterization of such HLA profiles could inform and improve the design of novel epitope-rich vaccines and help to predict protective immune responses at the individual and population level.

Adolescent↗
PubMed2006

Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study.

BACKGROUND: It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI). OBJECTIVE: To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI. DESIGN: Prospective cohort study. SETTING: Primary care clinic. PARTICIPANTS: A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort). MAIN OUTCOME MEASURES: Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome). RESULTS: Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3). CONCLUSIONS: Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.

Aged↗
PubMed2006

Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases.

OBJECTIVE: Our objective was to determine whether histologic grade independently contributes to the prognosis of non-small cell lung cancer. METHODS: A total of 5018 hospital-based patients diagnosed from 1997 to 2003 and 712 population-based patients diagnosed from 1984 to 2003 were followed up through the end of 2004. The effect of histologic grade on postdiagnosis survival or postresection recurrence was evaluated by Cox proportional hazards models. Relative risks (RR) were estimated by comparing undifferentiated, poorly differentiated, and moderately differentiated carcinoma with well-differentiated carcinoma. RESULTS: Histologic grade was significantly associated with survival after adjustment for the effects of age, gender, smoking history, tumor stage, histologic cell type, and treatment modality. Patients with undifferentiated carcinoma had an 80% elevated risk of death (RR = 1.83; 95% confidence interval [CI], 1.4-2.4) compared with those with well-differentiated carcinoma; 70% and 40% elevated risks were observed for patients with poorly and moderately differentiated carcinoma, respectively (RR, 1.7 [1.5-2.0] and 1.4 [1.2-1.6]). Similar results were observed for 718 incidence cases in which the relative risks were 1.6 (1.1-2.2) and 1.4 (1.0-1.9) for poorly/undifferentiated carcinoma and moderately differentiated carcinoma, respectively. Patients with less-differentiated carcinoma after tumor resection had a higher risk of recurrence, with adjusted hazard ratios of 2.1 (95% CI: 1.4-2.9) and 1.4 (1.0-1.9) for poorly/undifferentiated and moderately differentiated carcinoma compared with well-differentiated carcinoma. CONCLUSIONS: Histologic grade has significant prognostic value for survival of patients with non-small cell lung cancer. Histologic grade may provide useful information in defining the aggressiveness of tumors and should be considered as an independent factor affecting survival beyond TNM staging.

Aged↗
PubMed2006

Conventional assessment of needle biopsy specimens is more useful than digital image analysis of proliferation and DNA ploidy in prediction of positive surgical margins at radical prostatectomy.

OBJECTIVES: The preoperative prediction of the likelihood of positive surgical margins (+SMs) at radical retropubic prostatectomy (RRP) may be useful for counseling and determining the surgical approach. The aim of this study was to assess the additional value of digital image analysis (DIA) of ploidy and proliferation on needle biopsies, in addition to the known preoperative predictors of +SMs at RRP. METHODS: We identified 454 patients treated by RRP at our institution from 1995 to 1998 for prostate cancer verified by transrectal ultrasound-guided biopsy, with a specimen adequate for DIA. Patients receiving preoperative hormonal therapy were excluded. The clinical features, transrectal ultrasound-guided biopsy findings, and DIA evaluation of MIB-I immunostaining and DNA ploidy were assessed in a multivariate logistic regression model to predict for +SMs at RRP. RESULTS: The mean +/- SD age at treatment was 64.5 +/- 6.5 years, the percentage of positive cores was 40.4% +/- 24.3%, the median prostate-specific antigen level was 6.3 ng/mL (range 0.6 to 112.0), median biopsy Gleason score was 6 (range 4 to 9), and median percentage of diploid nuclei was 67% (range 0% to 100%). Of the 454 patients, 185 (40.7%) had +SMs; this finding was time dependent (1995 to 1996, 45% and 1997 to 1998, 31%; P = 0.004). Univariately, preoperative prostate-specific antigen, biopsy Gleason score, extent of cancer on biopsy, MIB-1 expression, percentage of diploid or nondiploid nuclei, and year of surgery were predictive for +SMs. On multivariate analysis, the preoperative prostate-specific antigen level, biopsy Gleason score, percentage of positive cores, and year of surgery remained significant. CONCLUSIONS: The results of our study have shown that the likelihood of +SMs at RRP is best predicted on the basis of conventional prognostic factors. The DIA features of needle biopsies did not provide additional predictive power.

Adult↗
PubMed2006

Childhood asthma and measles vaccine response.

BACKGROUND: Asthmatic patients have a TH2-predominant milieu that is associated with humoral immunity. However, little is known about whether humoral immune responses to viral antigens differ between asthmatic and nonasthmatic children. OBJECTIVE: To determine whether humoral immune response differs in asthmatic patients vs nonasthmatic patients. METHODS: Measles virus specific IgG antibody levels were determined for the Rochester Family Measles Study cohort (n = 876), a convenience sample of healthy children 5 to 12 years of age in Rochester, MN. We conducted comprehensive medical record reviews of 838 children who were eligible for this study. We determined the child's asthma status at the time of determination of antibody levels by applying predetermined criteria for asthma. Comparisons were made using the 2-sample t test or chi2 test. RESULTS: Of the 838 children, 156 (18.6%) had asthma at the time of the determination of antibody levels and were not taking systemic steroids within 14 days of specimen collection. Among those with a nonequivocal antibody reading, the seropositive response rates were similar in asthmatic patients and nonasthmatic patients (89.7% vs 90.3%, respectively; P = .83). However, the equivocal response rates were slightly higher among asthmatic patients than nonasthmatic patients (6.4% vs 4.7%, respectively). CONCLUSION: Asthmatic children seem to have similar humoral immune responses to measles vaccine as those without asthma. Although the findings reassure health care practitioners, whether this finding is generalizable to other vaccines and whether asthmatic patients with low antibody levels have normal cell-mediated immunity need to be elucidated in future studies.

Antibody Formation↗
PubMed2006

An analysis of breast cancer risk in women with single, multiple, and atypical papilloma.

Breast papillomas may be single or multiple and associated with atypical ductal or lobular hyperplasias (ADH/ALH). The risk of breast carcinoma development in patients with papillomas, particularly those with multiple or atypical lesions, is incompletely defined. Fibrocystic lesions were histopathologically classified in a benign breast disease cohort of 9155 who underwent biopsy from 1967 to 1991, with papilloma assessment in 9108. Individuals with papillomas (N=480) were classified into 4 groups: single papilloma (SP, N=372), single papilloma with ADH or ALH (SP+A, N=54), multiple (>5) papillomas (MP, N=41), and multiple papillomas with ADH or ALH (MP+A, N=13). Those without papillomas were classified as nonproliferative (NP, N=6053), proliferative without atypia (PDWA, N=2308), and ADH/ALH [atypical hyperplasia (AH), N=267]. The relative risk of cancer development within our cohort was compared to that expected in the general population using standardized incidence ratios. The relative risk of breast cancer development associated with SP [2.04, 95% confidence interval (CI) 1.43-2.81] was greater than NP (1.28, 95% CI 1.16-1.42) but similar to PDWA (1.90, 95% CI 1.66-2.16). The risk associated with SP+A (5.11, 95% CI 2.64-8.92) was highly elevated but not substantively different than atypical hyperplasia (4.17, 95% CI 3.10-5.50). Patients with MP are at increased risk compared with PDWA or SP (3.01, 95% CI 1.10-6.55), particularly those with MP+A (7.01, 95% CI 1.91-17.97). There was a marginal increase in breast cancer risk (16%) among patients with proliferative disease if a papilloma was present, but this did not reach statistical significance (P=0.29). The observed frequency of ipsilateral (vs. contralateral) breast cancer development in papilloma subsets was not significantly different than other patient groups. We conclude that SP imparts a cancer risk similar to conventional proliferative fibrocystic change. The presence of papilloma in, or associated with, atypia does not modify the risk connotation of ADH/ALH overall. MP constitutes a proliferative breast disease subset having unique clinical and biologic behavior.

Aged↗
PubMed2006

Impact of self-assessment questions and learning styles in Web-based learning: a randomized, controlled, crossover trial.

PURPOSE: To determine the effect of self-assessment questions on learners' knowledge and format preference in a Web-based course, and investigate associations between learning styles and outcomes. METHOD: The authors conducted a randomized, controlled, crossover trial in the continuity clinics of the Mayo-Rochester internal medicine residency program during the 2003-04 academic year. Case-based self-assessment questions were added to Web-based modules covering topics in ambulatory internal medicine. Participants completed two modules with questions and two modules without questions, with sequence randomly assigned. Outcomes included knowledge assessed after each module, format preference, and learning style assessed using the Index of Learning Styles. RESULTS: A total of 121 of 146 residents (83%) consented. Residents had higher test scores when using the question format (mean +/- standard error, 78.9% +/- 1.0) than when using the standard format (76.2% +/- 1.0, p = .006). Residents preferring the question format scored higher (79.7% +/- 1.1) than those preferring standard (69.5% +/- 2.3, p < .001). Learning styles did not affect scores except that visual-verbal "intermediate" learners (80.6% +/- 1.4) and visual learners (77.5% +/- 1.3) did better than verbal learners (70.9% +/- 3.0, p = .003 and p = .033, respectively). Sixty-five of 78 residents (83.3%, 95% CI 73.2-90.8%) preferred the question format. Learning styles were not associated with preference (p > .384). Although the question format took longer than the standard format (60.4 +/- 3.6 versus 44.3 +/- 3.3 minutes, p < .001), 55 of 77 residents (71.4%, 60.0-81.2%) reported that it was more efficient. CONCLUSIONS: Instructional methods that actively engage learners improve learning outcomes. These findings hold implications for both Web-based learning and "traditional" educational activities. Future research, in both Web-based learning and other teaching modalities, should focus on further defining the effectiveness of selected instructional methods in specific learning contexts.

Cross-Over Studies↗
PubMed2005

Immunologic significance of HLA class I genes in measles virus-specific IFN-gamma and IL-4 cytokine immune responses.

The variability of immune responses modulated by human leukocyte antigen (HLA) genes and secreted cytokines is a significant factor in the development of a protective effect of measles vaccine. We studied the association between type 1 helper T cells (Th1)- and Th2-like cytokine immune responses and HLA class I alleles among 339 schoolchildren who previously received two doses of the measles vaccine. Median values for measles-specific interferon gamma (IFN-gamma) and interleukin-4 (IL-4) cytokines were 40.7 pg/ml [interquartile range (IQR) 8.1-176.7] and 9.7 pg/ml (IQR 2.8-24.3), respectively. Class I HLA-A (*0101 and *3101) and HLA-Cw (*0303 and *0501) alleles were significantly associated with measles-virus-induced IFN-gamma secretion. HLA-A*3101 and Cw*0303 were associated with a higher median IFN-gamma response, while A*0101 and Cw*0501 were associated with lower measles-specific IFN-gamma response. We found limited associations between HLA class I gene polymorphisms and Th2-like (IL-4) immune responses after measles vaccination, indicating that HLA class I molecules may have a limited effect on measles-vaccine-induced IL-4 secretion. Understanding the genetic factors that influence variations in cytokine secretion following measles vaccination will provide insight into the factors that influence both cell-mediated and humoral immunity to measles.

Adolescent↗
PubMed2005

Studies of humoral immunity to preprohypocretin in human leukocyte antigen DQB1*0602-positive narcoleptic subjects with cataplexy.

BACKGROUND: Canine models for narcolepsy have mutations of the hypocretin receptor 2 gene, and preprohypocretin knockout murine lines exhibit narcoleptic-like behaviors. Human narcolepsy with cataplexy is associated with human leukocyte antigen DQB1*0602 and reduced hypocretin levels in cerebrospinal fluid, suggesting an autoimmune diathesis. We tested the hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have immunoglobulin (Ig)G reactive to human preprohypocretin and its cleavage products. METHODS: Serum samples of 41 DQB1*0602-positive narcoleptic subjects with cataplexy and 55 control subjects were studied, as were 19 narcoleptic and 13 control samples of cerebrospinal fluid. We tested for IgG reactive to preprohypocretin and its major cleavage products (including hypocretin 1 and 2), using immunoprecipitation assays (IP), immunofluorescence microscopy (IF) of Chinese hamster ovarian cells expressing preprohypocretin, and Western blots. RESULTS: There was no evidence for IgG reactive to preprohypocretin or its cleavage products in CSF of subjects with narcolepsy as measured by IPs, Western blots, and IF. Although the IP with CSF and the C-terminal peptide showed significant differences by two methods of comparison, the control subjects had higher counts per minute than narcoleptic subjects, which was opposite to our hypothesis. CONCLUSIONS: The hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have IgG reactive to preprohypocretin or its cleavage products was not supported.

Adult↗
PubMed2005

Benign breast disease and the risk of breast cancer.

BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We studied a large group of women with benign breast disease to obtain reliable estimates of this risk. METHODS: We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To estimate relative risks, we compared the number of observed breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry. RESULTS: We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No increased risk was found among women with no family history and nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia. CONCLUSIONS: Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic classification of a benign breast lesion and a family history of breast cancer.

Adult↗
PubMed2005

HLA class II alleles and measles virus-specific cytokine immune response following two doses of measles vaccine.

Measles virus-specific T cells and the production of cytokines play a critical role in the immune response following measles immunization. To understand the genetic factors that influence variation in IFN-gamma and IL-4 responses following measles immunization and to provide insight into the factors influencing both cellular and humoral immunity to measles, we assessed associations between human leukocyte antigen (HLA) class II genes and measles-specific Th1 and Th2-type cytokine responses in peripheral blood lymphocytes from 339 children previously vaccinated with two doses of measles-mumps-rubella vaccine (MMR-II). Median values for measles-specific IFN-gamma and IL-4 secretion levels were 40.73 and 9.71 pg/ml, respectively. The global tests suggested associations between measles-specific IFN-gamma response and alleles of the DRB1 and DQB1 loci (P=0.07 and P=0.02, respectively). Specifically, DRB1*0301, *0901, and *1501 alleles were significantly associated with IFN-gamma secretion. The alleles that suggested evidence of an HLA association with IL-4 secretion were DRB1*0103, *0701, and *1101. Th1 cytokine responses and DQB1 allele associations revealed that the alleles with the strongest association with IFN-gamma secretion were DQB1*0201, *0303, *0402, and *0602. Specific alleles with a suggestive association with low measles-specific Th2 cytokine responses were DQB1*0202 and *0503. In addition, DPB1*0101, *0201, and *0601 alleles provided suggestive evidence of an HLA association with measles-induced IFN-gamma response, while DPB1*0501 was associated with an IL-4 response. These data suggest that IFN-gamma and IL-4 cytokine responses to measles may be genetically restricted in part by HLA class II genes, which in turn can restrict the cellular immune response to measles vaccine.

Adolescent↗