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RATIONALE - Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.
OBJECTIVES - Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.
METHODS - Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects.
MEASUREMENTS AND MAIN RESULTS - Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans.
CONCLUSIONS - Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.
PURPOSE - Physical activity, a protective factor for breast cancer, increases the level of DNA methylation. Fibroblast growth factor receptor 2 (FGFR2), a confirmed breast cancer susceptibility gene, is predisposed to be methylated. Therefore, DNA methylation related genes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and DNA methyltransferase (DNMT), together with physical activity and FGFR2, may interact with each other to effect breast cancer risk.
METHODS - A total of 839 incident breast cancer cases and 863 age-matched controls from Guangzhou, China were included in this study. We used questionnaires to assess physical activity in metabolic equivalent (MET)-h/week/year and a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform to ascertain genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models.
RESULTS - Exercise activity and FGFR2 rs2981582 were confirmed to be associated with breast cancer risk, and were found to significantly interact (P for multiplicative and additive interactions = 0.045 and 0.021, respectively). Women who had CT/TT genotypes of FGFR2 rs2981582 and experienced exercise activity <3 MET-h/week/year had significantly increased risk (OR = 3.15, 95% CI = 2.28-4.35) compared to women with CC genotype and ≥ 3 MET-h/week/year. There was also a significant interaction between FGFR2 rs2981582 and MTHFR rs1801133 on breast cancer risk (P for multiplicative and additive interactions = 0.039 and 0.023, respectively).
CONCLUSION - We found both a gene-environment (FGFR2-exercise activity) and a gene-gene (FGFR2-MTHFR) interaction on breast cancer risk. Our results suggest that environmental factors, such as physical activity, may be able to counteract genetic susceptibility to breast cancer.
Copyright © 2014 Elsevier Ltd. All rights reserved.
RATIONALE - Most genomic studies of lung function have used phenotypic data derived from a single time-point (e.g., presence/absence of disease) without considering the dynamic progression of a chronic disease.
OBJECTIVES - To characterize lung function change over time in subjects with asthma and identify genetic contributors to a longitudinal phenotype.
METHODS - We present a method that models longitudinal FEV1 data, collected from 1,041 children with asthma who participated in the Childhood Asthma Management Program. This longitudinal progression model was built using population-based nonlinear mixed-effects modeling with an exponential structure and the determinants of age and height.
MEASUREMENTS AND MAIN RESULTS - We found ethnicity was a key covariate for FEV1 level. Budesonide-treated children with asthma had a slight but significant effect on FEV1 when compared with those treated with placebo or nedocromil (P < 0.001). A genome-wide association study identified seven single-nucleotide polymorphisms nominally associated with longitudinal lung function phenotypes in 581 white Childhood Asthma Management Program subjects (P < 10(-4) in the placebo ["discovery"] and P < 0.05 in the nedocromil treatment ["replication"] group). Using ChIP-seq and RNA-seq data, we found that some of the associated variants were in strong enhancer regions in human lung fibroblasts and may affect gene expression in human lung tissue. Genetic mapping restricted to genome-wide enhancer single-nucleotide polymorphisms in lung fibroblasts revealed a highly significant variant (rs6763931; P = 4 × 10(-6); false discovery rate < 0.05).
CONCLUSIONS - This study offers a strategy to explore the genetic determinants of longitudinal phenotypes, provide a comprehensive picture of disease pathophysiology, and suggest potential treatment targets.
BACKGROUND - The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney.
OBJECTIVE - We hypothesized that polymorphisms in KCNJ1, SLC12A1, and 7 other genes may modify the association between calcium intake and colorectal neoplasia risk.
METHODS - We conducted a 2-phase study in 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study.
RESULTS - In phase I, we identified 5 single-nucleotide polymorphisms (SNPs) that significantly interacted with calcium intake in adenoma risk. In phase II, rs2855798 in KCNJ1 was replicated. In combined analysis of phases I and II, the P values for interactions between calcium intake and rs2855798 were 1 × 10(-4) for all adenoma and 5 × 10(-3) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with no variant allele but was significantly associated with a 41% reduced adenoma risk among those who carried at least 1 variant allele in KCNJ1. The corresponding reduction in risk of multiple or advanced adenomas was 52% among those with at least 1 variant allele. The P values for interactions between calcium intake and combined SNPs from the KCNJ1 and SLC12A1 genes were 7.5 × 10(-5) for adenoma and 9.9 × 10(-5) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with nonvariant alleles in 2 genes but was significantly associated with a 34% reduced adenoma risk among those who carried a variant allele in 1 of the genes. The corresponding reduction in risk of multiple or advanced adenomas was 64% among those with variant alleles in both genes.
CONCLUSION - These findings, if confirmed, will be critical for the development of personalized prevention strategies for colorectal cancer.
© 2014 American Society for Nutrition.
OBJECTIVE - To assess correlations between cruciferous vegetable intake and urinary isothiocyanate (ITC) level, in addition to glutathione S-transferase (GST) genotypes and other individual factors.
DESIGN - The study included cohort participants whose urinary ITC levels had been previously ascertained. Urinary ITC was assessed using HPLC. Usual dietary intake of cruciferous vegetables was assessed using a validated FFQ and total dietary ITC intake was calculated. Recent cruciferous vegetable intake was determined. GST genotypes were assessed using duplex real-time quantitative PCR assays. Spearman correlations were calculated between the covariates and urinary ITC levels and linear regression analyses were used to calculate the mean urinary ITC excretion according to GST genotype.
SETTING - Urban city in China.
SUBJECTS - The study included 3589 women and 1015 men from the Shanghai Women's and Men's Health Studies.
RESULTS - Median urinary ITC level was 1.61 nmol/mg creatinine. Self-reported usual cruciferous vegetable intake was weakly correlated with urinary ITC level (r s=0.1149; P<0.0001), while self-reported recent intake was more strongly correlated with urinary ITC (r s=0.2591; P<0.0001). Overall, the GST genotypes were not associated with urinary ITC level, but significant differences according to genotype were observed among current smokers and participants who provided an afternoon urine sample. Other factors, including previous gastrectomy or gastritis, were also related to urinary ITC level.
CONCLUSIONS - The study suggests that urinary secretion of ITC may provide additional information on cruciferous vegetable intake and that GST genotypes are related to urinary ITC level only in some subgroups.
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.
RATIONALE - Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers.
OBJECTIVES - To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations.
METHODS - Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays.
MEASUREMENTS AND MAIN RESULTS - We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype.
CONCLUSIONS - Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.
Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed peripheral neuropathy. The identification of genetic predictors of increased risk might suggest novel therapeutic targets for such patients. In AIDS Clinical Trials Group protocol 384, antiretroviral-naïve patients were randomized to d4T/didanosine (ddI)- or zidovudine/lamivudine-containing regimens. Data from d4T/ddI recipients were analyzed for genome-wide associations (approximately 1 million genetic loci) with new onset distal sensory peripheral neuropathy. Analyses involved 254 patients (49 % White, 34 % Black, 17 % Hispanic), comprising 90 peripheral neuropathy cases (32 grade 1, 35 grade 2, 23 grade 3) and 164 controls. After correcting for multiple comparisons, no polymorphism was consistently associated with neuropathy among all patients, among White, Black, and Hispanic patients analyzed separately, both in genome-wide analyses (threshold, P < 5.0 × 10(-8)) and focused on 46 neuropathy-associated genes (threshold, P < 3.5 × 10(-5)). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P = 8.4 × 10(-4)), in LITAF among Blacks (rs13333308, P = 6.0 × 10(-6)), and in NEFL among Hispanics (rs17763685, P = 5.6 × 10(-6)). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect.
Mitochondrial toxicity is implicated in some treatment-limiting antiretroviral therapy complications, and reports of mitochondrial dysfunction in untreated HIV infection suggest antiretroviral therapy independent effects of HIV. Several studies have explored associations between mtDNA haplogroups (patterns of mtDNA polymorphisms) and outcomes of HIV infection and/or antiretroviral therapy, but findings have been inconsistent. We systematically reviewed published studies examining mtDNA haplogroups in HIV-infected persons to summarize reported outcome associations, and to highlight potential future research directions. We identified 21 articles published from 2005-2013. Multiple different phenotypes were studied; most were antiretroviral therapy associated metabolic outcomes (e.g. lipodystrophy, insulin resistance, and dyslipidemia). Haplogroup H was associated with the most outcomes, including AIDS progression, CD4 T-cell recovery, cirrhosis (in hepatitis C coinfection), and metabolic outcomes. This review is the first to focus on the emerging area of mtDNA haplogroups in HIV, and summarizes the published literature on associations between mtDNA haplogroups and clinical outcomes in populations of European and African descent. Several reported associations require replication and ideally biological verification before definitive conclusions can be drawn, but research in this area has the potential to explain outcome disparities and impact clinical management of patients.
PURPOSE - To assess the associations between cruciferous vegetable (CV) intake, GST gene polymorphisms, and colorectal cancer (CRC) in a population of Chinese men.
METHODS - Using incidence density sampling, CRC cases (N = 340) diagnosed before December 31, 2010 within the Shanghai Men's Health Study were matched to noncases (N = 673). CV intake was assessed from a food frequency questionnaire and by isothiocyanate levels from spot urine samples. GSTM1 and GSTT1 were categorized as null (0 copies) versus non-null (1 or 2 copies). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association between CV intake and GST gene variants with CRC, and statistical interactions were evaluated.
RESULTS - CRC risk was not associated with CV intake, whether measured by self-report or by urinary isothiocyanate nor with GST gene variants. No statistical interactions were detected between CV intake and GST gene variants on the odds of CRC. Stratifying by timing of urine sample collection and excluding CRC cases diagnosed in the first 2 years did not materially alter the results.
CONCLUSIONS - This study provides no evidence supporting the involvement of CV intake in the development of CRC in Chinese men.
Copyright © 2014 Elsevier Inc. All rights reserved.