Modifier Of Association Research Articles

Accelerated aging as a modifier of associations between traffic-related air pollution and blood pressure

Accelerated aging as a modifier of associations between traffic-related air pollution and blood pressure

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation

BackgroundHuman leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). MethodsIn a secondary analysis from a previous study, 166,256 adult KTRs in 2000–2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1–3, and 4–6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. ResultsCompared with 0 HLA-mm, 1–3 HLA-mm was not associated, and 4–6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94–1.17 and HR = 1.11, 95% CI = 1.00–1.34, respectively]. Both 1–3 HLA-mm and 4–6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08–1.18) and (HR = 1.16, 95% CI = 1.09–1.22), respectively]. KTR's history of pre-transplant cancer, age 50–64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1–3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1–3 and 4–6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. ConclusionDirect association between SOM and the degree of HLA mismatching is equivocal and limited to the 4–6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Allostatic Load as a Modifier of Associations Between Metals and Blood Pressure

BACKGROUND AND AIM: Disadvantaged populations are often co-exposed to high levels of metals and psychological stressors. While limited research suggests that stress may increase susceptibility to lead cardiotoxicity, the influence of stress on other metals remains unexplored. We examined whether allostatic load (AL), a measure of chronic stress, modifies associations between metals (cadmium, mercury, arsenic, antimony, cesium, cobalt, molybdenum, thallium, tungsten, uranium, or lead) and blood pressure (BP). METHODS: We analyzed cross-sectional data on 11 blood and urinary metal biomarkers and systolic and diastolic BP in 5,022 adults (20+ years) participating in NHANES 2003-2010 using linear regression models. We assessed whether associations were modified by AL using interaction terms and stratified analyses. Because there is no scientific consensus on how to measure AL, we compared four different approaches to dichotomize participants into high and low AL based on seven stress biomarkers. Final models for each metal were adjusted for age, sex, race/ethnicity, BMI, education level, serum cotinine, urinary creatinine (to account for urinary dilution), and other confounding metals (e.g., lead). RESULTS: For diastolic BP, we observed no significant interactions between any metals and AL, but stratified analyses indicated that blood lead and urinary cobalt were significantly associated with higher BP in the high AL group only. These results were robust to the method used to define AL. For systolic BP, we observed the opposite trend: blood lead and urinary cobalt were associated with higher BP in the low AL group but not the high AL group, though results varied by AL definition. CONCLUSIONS: AL may modify the association between certain metals and BP in adults. As results may differ by method used to define AL, future research should use multiple approaches to operationalize AL until consensus is reached on the most appropriate definition. KEYWORDS: Metals, Stress, Blood Pressure, Allostatic Load

Mental Health Outcomes in Barcelona: The Interplay between Gentrification and Greenspace.

Greenspace is widely related to mental health benefits, but this relationship may vary by social group. Gentrification, as linked to processes of unequal urban development and conflict, potentially impacts health outcomes. This study explores the relationships between greenspace and mental health and between gentrification and mental health associations. It also further examines gentrification as an effect modifier in the greenspace–mental health association and SES as an effect modifier in the gentrification-mental health association. We used cross-sectional Barcelona (Spain) data from 2006, which included perceived mental health status and self-reported depression/anxiety from the Barcelona Health Survey. Greenspace exposure was measured as residential access to (1) all greenspace, (2) greenways and (3) parks in 2006. Census-tract level gentrification was measured using an index including changes in sociodemographic indicators between 1991 and 2006. Logistic regression models revealed that only greenways were associated with better mental health outcomes, with no significant relationship between mental health and parks or all greenspace. Living in gentrifying neighborhoods was protective for depression/anxiety compared to living in non-gentrifying neighborhoods. However, only residents of gentrifiable census tracts benefited from the exposure to greenways. SES was not found to be an effect modifier in the association between gentrification and mental health. Future research should tackle this study’s limitations by incorporating a direct measure of displacement in the gentrification status indicator, accounting for qualitative aspects of greenspace and user’s perceptions. Gentrification may undermine the health benefits provided by greenspace interventions.

Genetic risk of obesity as a modifier of associations between neighbourhood environment and body mass index: an observational study of 335 046 UK Biobank participants

BackgroundThere is growing recognition that recent global increases in obesity are the product of a complex interplay between genetic and environmental factors. However, in gene-environment studies of obesity, ‘environment’ usually...

Anionic Polymerization of Butadiene Using Lithium/Potassium Multi-metallic Systems: Influence on Polymerization Control and Polybutadiene Microstructure

Thermal, mechanical, and viscoelastic properties of polybutadiene-based rubber materials are highly dependent on polybutadiene microstructure. The use of polar modifier in association with alkyllithium is a well-known method to obtain polybutadiene with a high vinyl content. Another approach is to use bimetallic initiating species such as alkyllithium combined to heavier alkali metal alkoxide (RONa, ROK…). The polymerization control is nevertheless not achieved and several parameters were found to influence it. Using bimetallic initiating systems based on alkyllithium and a potassium alkoxide, alkyllithium structure, initiator preformation time, and initiator composition were identified as parameters influencing the anionic polymerization process of butadiene and/or polybutadiene microstructure. In addition, the use of trimetallic systems based on alkyllithium, potassium alkoxide, and alkylaluminum was investigated in order to prevent side reactions regardless of the [K]/[Li] ratio and of the initiator preformation time.

Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study.

Prenatal phthalate exposure is associated with altered male reproductive tract development, and in particular, shorter anogenital distance (AGD). AGD, a sexually dimorphic index of prenatal androgen exposure, may also be altered by prenatal stress. How these exposures interact to impact AGD is unknown. Here, we examine the extent to which associations between prenatal phthalate exposure and infant AGD are modified by prenatal exposure to stressful life events (SLEs). Phthalate metabolites [including those of diethylhexyl phthalate (DEHP) and their molar sum (ΣDEHP)] were measured in first trimester urine from 738 pregnant women participating in The Infant Development and the Environment Study (TIDES). Women completed questionnaires on SLEs, and permitted infant AGD measurements at birth. Subjects were classified as 'lower' and 'higher' stress (0 first trimester SLEs vs. 1+).We estimated relationships between phthalate concentrations and AGD (by infant sex and stress group) using adjusted multiple regression interaction models. In the lower stress group, first trimester ΣDEHP was inversely associated with two measures of male AGD: anoscrotal distance (AGD-AS; β = -1.78; 95% CI -2.97, -0.59) and anopenile distance (AGD-AP; β = -1.61; 95% CI -3.01, -0.22). By contrast, associations in the higher stress group were mostly positive and non-significant in male infants. No associations were observed in girls. Associations between prenatal phthalate exposure and altered genital development were only apparent in sons of mothers who reported no SLEs during pregnancy. Prenatal stress and phthalates may interact to shape fetal development in ways that have not been previously explored.

Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.

Subsequent malignant neoplasms (SMNs) are associated with significant morbidity and are a major cause of premature mortality among cancer survivors. Several large studies have demonstrated a strong association between the radiation and/or chemotherapy used to treat primary cancer and the risk of developing SMNs. However, for any given therapeutic exposure, the risk of developing an SMN varies between individuals. Genomic variation can potentially modify the association between therapeutic exposures and SMN risk and may explain the observed interindividual variability. In this review, the author provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related SMNs and discusses the methodological challenges in undertaking an endeavor to develop a deeper understanding of the molecular underpinnings of therapy-related SMNs, such as an appropriate study design, the identification of an adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, clinical validation of the phenotype, and the selection of an appropriate approach or platform for genotyping. Understanding the factors that can modify the risk of treatment-related SMNs is critical to developing targeted intervention strategies and optimizing risk-based health care for cancer survivors.

Abstract B79: Tobacco smoking, polymorphisms in xenobiotic metabolism enzyme genes, and prostate cancer risk and survival

Abstract Introduction: The association between tobacco smoking and prostate cancer (PCa) risk and progression remains unclear. This study examined the association between tobacco smoking and risk of localized and advanced PCa, PCa-specific mortality, and overall mortality in African-American, Hispanic and non-Hispanic White men. Polymorphisms in xenobiotic metabolism enzyme genes were further examined as possible modifiers of associations with smoking. Methods: Using data from the California Collaborative Prostate Cancer Study, a multiethnic population-based case-control study conducted in Los Angeles County (631 advanced and 533 localized cases; 594 controls) and the San Francisco Bay Area (568 advanced and 208 localized cases; 545 controls), we evaluated associations between tobacco smoking and risk of localized and advanced PCa using conditional logistic regression. Cox proportional hazards regression models and Kaplan Meier curves with log-rank tests were used to assess associations with PCa-specific and all-cause mortality. Median follow-up time for cases was 8.8 years (IQR: 6.2-9.9). We also investigated the role of 12 metabolism enzyme single nucleotide polymorphisms from 7 genes as potential modifiers of the relationship between tobacco smoking and PCa risk and progression using interaction models. Results: After adjusting for age, PCa family history, body mass index, alcohol consumption, intake of meat cooked at high temperature, and use of snuffing/chewing tobacco, non-Hispanic Whites who were former smokers had an increased risk of localized PCa when compared to never smokers (OR=1.52, 95%CI: 1.11-2.09, p<0.01). Risk increased with younger age at first tobacco use (p-trend<0.01), duration of tobacco smoking (p-trend=0.01), number of daily cigarettes smoked (p-trend=0.02), and cigarette pack-years (p-trend=0.03). Current smoking was associated with an increased risk of advanced PCa (OR=1.41, 95%CI: 1.02-1.94, p=0.037) among non-Hispanic Whites, but a decreased risk among Hispanics (OR=0.48, 95%CI: 0.23-0.99, p=0.047). No significant trends were seen for any of the smoking variables among Hispanics or African-Americans. A CYP1A2 polymorphism (rs7662551) modified the relationship between smoking status and PCa risk; the addition of each C-allele increased risk for localized (p-interaction=0.01) and advanced (p-interaction=0.03) PCa, particularly among current smokers. Tobacco smoking was not associated with PCa-specific mortality. For all-cause mortality, increased risk was associated with current smoking, duration of smoking, cigarette pack-years, and young age at first smoking. Kaplan Meier survival probabilities for current smokers were 77% from all-cause mortality and 89% from PCa-specific mortality. Conclusions: We observed that tobacco smoking was associated with risk of localized and advanced PCa primarily among Non-Hispanic Whites. Moreover, we observed that tobacco smoking was associated with all-cause mortality, albeit no associations were observed for PCa-specific mortality. Genetic variation in CYP1A2 seems to modify the relationship of tobacco smoking status and PCa risk, but not mortality. Citation Format: Ahva Shahabi, Roman Corral, Chelsea Catsburg, Amit D. Joshi, Jocelyn Koo, Esther M. John, Sue A. Ingles, Mariana C. Stern. Tobacco smoking, polymorphisms in xenobiotic metabolism enzyme genes, and prostate cancer risk and survival. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B79.

Abstract 034: Gestational Diabetes Mellitus Pregnancy is Associated with Subsequent Atherosclerosis in Women During Midlife: CARDIA.

Background: Women who develop gestational diabetes mellitus (GDM) during pregnancy have a 7-fold greater risk of type 2 diabetes and 2.5-times greater risk of the metabolic syndrome several years after delivery than women without a history of GDM. Yet, little is known about whether GDM status contributes to early subclinical atherosclerosis after pregnancy. We hypothesize that a history of GDM is a predictor of early atherosclerosis in women during mid-life. Methods: We examined 883 women (47% Black), aged 18-30 years at enrollment in 1985-1986 (baseline) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Women selected for this analysis delivered 1 or more live births (total of 1,572 births) during the 20-year follow-up, reported GDM status for pregnancies, had no history of heart disease, and had common carotid intima media thickness (maximum ccIMT; average of the maximum wall thickness of the respective carotid artery segment based on 4 ultrasonic measurements for the common carotid arteries) obtained after 20 years of follow-up in 2005–2006. Results: We classified 121 (14%) women as GDM, and 762 women as non-GDM. Among GDM and non-GDM groups, average age at last birth was 31 years, and average age at the year 20 exam was 44 years. Multivariable linear regression models estimated mean (95%CI) ccIMT (mm) among GDM and non-GDM groups adjusted for baseline parity and follow-up covariates including number of post-baseline births, smoking, education, hypertension status, lipid-lowering medication use, and menopausal status. Unadjusted and fully adjusted mean ccIMT was higher for GDM versus non-GDM groups: (0.791 vs 0.758; p=0.002), and (0.813 vs 0.787;p=0.011), respectively. Adjustment for baseline BMI (a mediator of both GDM and IMT), modestly attenuated the difference in ccIMT means between GDM (0.799) and non-GDM (0.781); p=0.084. Race and age did not act as confounders or as effect modifiers of associations, and BMI was not an effect modifier. Addition of weight gain, and pregnancy-related hypertension during 20 years of follow-up in separate models had little impact on these findings. Conclusions: Among women of reproductive age, GDM during pregnancy may unmask future risk of subclinical atherosclerosis during midlife. Development of GDM during pregnancy serves as an important harbinger of future cardiometabolic diseases in young women long before disease onset.

Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk

Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n = 35), steroid hormone metabolism (HOR, n = 13), and oxidative phosphorylation (OXP, n = 90) pathways. Unconditional logistic regression was used to estimate OR and 95% CI between genotype and case status. Overall significance of each gene and pathway was evaluated by using Fisher's method to combine SNP-level evidence. At the SNP level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. Interindividual variation involving BIO was most strongly associated with EOC risk (empirical P = 0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for nongenetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P > 0.10). We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC.

Age at exposure to ionising radiation and cancer mortality among Hanford workers: follow up through 1994

Background: Studies of workers at the plutonium production factory in Hanford, WA have led to conflicting conclusions about the role of age at exposure as a modifier of associations between...

Heterogeneity in associations between macronutrient intake and lipoprotein profile in individuals with type 2 diabetes.

To evaluate associations between macronutrient intake and lipoprotein profile among individuals with type 2 diabetes who participated in the San Luis Valley Diabetes Study (SLVDS) or the Insulin Resistance Atherosclerosis Study (IRAS). Diet was assessed by 24-h recall in the SLVDS (n = 421) and by validated food frequency interview in the IRAS (n = 437). Analyses adjusted for kilocalories, age, sex, and other covariates were conducted separately for the two study groups. For the SLVDS, repeated observations were included in mixed model analyses (865 observations). For the IRAS, standard regression analyses were conducted. Recent weight history and time of diabetes diagnosis were evaluated as possible modifiers of associations between nutrient intake and lipoprotein profile. Higher reported intake of total dietary fat was related to significantly higher levels of LDL cholesterol (P < 0.05) in both studies and in all subgroups. Reported intake of total and saturated fat was associated positively with total cholesterol, although statistical significance was not reached for all subgroups. Higher reported carbohydrate intake was associated with increased triglyceride concentrations (P < 0.01) only among individuals with previously undiagnosed diabetes in the SLVDS (n = 69) and only among individuals who gained weight (> 5 lb, n = 87) during the previous year in the IRAS. Toward the goal of optimizing the lipoprotein profile of individuals with diabetes, these results emphasize the potential importance of reducing fat intake while recognizing that individualized approaches to diet are important to minimize the risk of cardiovascular disease.