Linkage analysis of obesity phenotypes in pre- and post-menopausal women from a United States mid-western population.

Background: Obesity has a strong genetic influence, with some variants showing stronger associations among women than men. Women are also more likely to distribute weight in the abdomen following menopause. We investigated whether genetic loci link with obesity-related phenotypes differently by menopausal status.

Independent association of lobular involution and mammographic breast density with breast cancer risk.

Background: Lobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk.

Methods: To evaluate whether lobular involution and MBD are independently associated with breast cancer risk in women with benign breast disease, we performed a nested cohort study among women (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, and December 31, 1991 and a mammogram available within 6 months of the diagnosis. Women were followed up for an average of 13.

Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease.

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative.

Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment.

Background: The mechanisms of immune response are structured within a highly complex regulatory system. Genetic associations with variation in the immune response to rubella vaccine have typically been assessed one locus at a time. We simultaneously assessed the associations between 726 SNPs tagging 84 candidate immune response genes and rubella-specific antibody levels.

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals).

Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.

Objective: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria.

Methods: We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria.

Extended LTA, TNF, LST1 and HLA gene haplotypes and their association with rubella vaccine-induced immunity.

Background: Recent studies have suggested the importance of HLA genes in determining immune responses following rubella vaccine. The telomeric class III region of the HLA complex harbors several genes, including lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes, located between the class I B and class II DRB1 loci. Apart from HLA, little is known about the effect of this extended genetic region on HLA haplotypic backgrounds as applied to immune responses.

Polyunsaturated fatty acids and reduced odds of MCI: the Mayo Clinic Study of Aging.

Mono- and polyunsaturated fatty acids (MUFA, PUFA) have been associated with a reduced risk of dementia. The association of these fatty acids with mild cognitive impairment (MCI) is not fully established. The objective of the study was to investigate the cross-sectional association of dietary fatty acids with MCI in a population-based sample.

Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia.

Purpose: Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia.

Pseudoangiomatous stromal hyperplasia and breast cancer risk.

Background: Pseudoangiomatous stromal hyperplasia (PASH) is a benign localized fibrotic lesion in which clusters of spindle cells form cleftlike spaces, resembling ectatic vessels. Its relationship to breast cancer risk has not been characterized.

Materials And Methods: Histological presence of PASH was evaluated by review of archival slides in a single institution cohort of women who underwent benign excisional breast biopsy from 1967 to 1991.

Replication of CLU, CR1, and PICALM associations with alzheimer disease.

Objective: To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease.

Design: Follow-up case-control association study.

Setting: The Mayo Clinics at Jacksonville, Florida, and Rochester, Minnesota.

Aromatase immunoreactivity is increased in mammographically dense regions of the breast.

Mammographic breast density (MBD) is one of the strongest risk factors for breast cancer. Unfortunately, the biologic basis underlying this association is unknown. This study compared aromatase expression or immunoreactivity (IR) in core biopsies from mammographically dense versus non-dense regions of the breast to examine whether estrogen synthesis in the breast is associated with MBD and one possible mechanism through which MBD may influence breast cancer.

Centrosome-related genes, genetic variation, and risk of breast cancer.

Centrosome amplification has been detected in premalignant lesions and in situ tumors in the breast and in over 70% of invasive breast tumors, and has been associated with aneuploidy and tumor development. Based on these observations, the contribution of commonly inherited genetic variation in candidate genes related to centrosome structure and function to breast cancer risk was evaluated in an association study. Seven-hundred and 82 single nucleotide polymorphisms (SNPs) from 101 centrosomal genes were analyzed in 798 breast cancer cases and 843 controls from the Mayo Clinic Breast Cancer Study to assess the association between these SNPs (both individually and combined) and risk of breast cancer in this population.

Vegetables, unsaturated fats, moderate alcohol intake, and mild cognitive impairment.

Background/aims: To investigate associations of the Mediterranean diet (MeDi) components and the MeDi score with mild cognitive impairment (MCI).

Methods: Participants (aged 70-89 years) were clinically evaluated to assess MCI and dementia, and completed a 128-item food frequency questionnaire.

Results: 163 of 1,233 nondemented persons had MCI.

Genome-wide analysis of genetic loci associated with Alzheimer disease.

Context: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

Objectives: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

Design, Setting, And Participants: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS.

Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.

Background: Small-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined radiation and chemotherapy is the standard of care; however, treatment outcomes vary. Variability in the rate at which chemotherapy agents are metabolized and in the capacity of repairing DNA damage has been hypothesized to be partly responsible for the treatment response variation.

Methylation markers for small cell lung cancer in peripheral blood leukocyte DNA.

Introduction: Small cell lung cancer (SCLC) is the most aggressive form of lung malignancy.

Methods: To identify and validate potential DNA methylation markers for risk assessment and disease detection, we examined peripheral blood leukocyte DNA specimens for methylation differences between SCLC cases and controls. We tested 1505 CpG sites using the Illumina Beadchip assay and validated 9 CpG sites using pyrosequencing technology.

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers.

Association between mammographic density and age-related lobular involution of the breast.

Purpose: Mammographic density and lobular involution are both significant risk factors for breast cancer, but whether these reflect the same biology is unknown. We examined the involution and density association in a large benign breast disease (BBD) cohort.

Patients And Methods: Women in the Mayo Clinic BBD cohort who had a mammogram within 6 months of BBD diagnosis were eligible.

Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.

Background: Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue. We aimed to unravel the genetic basis of lung cancer in never smokers.

Methods: We did a four-stage investigation.

Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease.

Background: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels.

Methods: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD.

Predominant inflammatory cytokine secretion pattern in response to two doses of live rubella vaccine in healthy vaccinees.

We conducted a population-based study on 738 schoolchildren who received two doses of rubella vaccine in order to determine cytokine secretion patterns and their associations with demographic and clinical variables. The results showed a robust rubella-specific inflammatory cytokine response characterized by high median [inter-quartile range (IQR)] secretion levels (in pg/mL) of IL-6 [3681.0 (3160.

Cystic fibrosis transmembrane conductance regulator gene mutation and lung cancer risk.

The cystic fibrosis transmembrane conductance regulator (CFTR) holds an important role in retaining lung function, but its association with lung cancer is unclear. A case-control study was conducted to determine the possible associations of the genetic variants in the CFTR gene with lung cancer risk. Genotypes of the most common deletion DeltaF508, one functional SNP, and eight tag SNPs in the CFTR gene were determined in 574 lung cancer patients and 679 controls.

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease.

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).

Methodology/principal Findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants.

2'-5'-Oligoadenylate synthetase single-nucleotide polymorphisms and haplotypes are associated with variations in immune responses to rubella vaccine.

Interferon-induced antiviral genes are crucial players in innate antiviral defense and potential determinants of immune response heterogeneity. We selected 114 candidate single-nucleotide polymorphisms (SNPs) from 12 antiviral genes using an LD tagSNP selection approach and genotyped them in a cohort of 738 school children immunized with two doses of rubella vaccine. Associations between SNPs/haplotypes and rubella virus-specific immune measures were assessed using linear regression methodologies.