Mendelian randomization with incomplete measurements on the exposure in the Hispanic Community Health Study/Study of Latinos.

Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for the computation of the estimator. Simulation studies show that the proposed method performs well in making inference on the causal effect. We apply our method to the Hispanic Community Health Study/Study of Latinos, a community-based prospective cohort study, and estimate the causal effect of several metabolites on phenotypes of interest.

Blood pressure and expression of microRNAs in whole blood.

BACKGROUND: Blood pressure (BP) is a complex, multifactorial clinical outcome driven by genetic susceptibility, behavioral choices, and environmental factors. Many molecular mechanisms have been proposed for the pathophysiology of high BP even as its prevalence continues to grow worldwide, increasing morbidity and marking it as a major public health concern. To address this, we evaluated miRNA profiling in blood leukocytes as potential biomarkers of BP and BP-related risk factors. METHODS: The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined in 2008. On two days separated by 1-2 weeks, we examined three BP measures: systolic, diastolic, and mean arterial pressure measured at both pre- and post-work exams for blood NanoString nCounter miRNA profiles. We used covariate-adjusted linear mixed-effect models to examine associations between BP and increased miRNA expression in both pooled and risk factor-stratified analyses. RESULTS: Overall 43 miRNAs were associated with pre-work BP (FDR<0.05). In stratified analyses different but overlapping groups of miRNAs were associated with pre-work BP in truck drivers, high-BMI participants, and usual alcohol drinkers (FDR<0.05). Only four miRNAs were associated with post-work BP (FDR<0.05), in ever smokers. CONCLUSION: Our results suggest that many miRNAs were significantly associated with BP in subgroups exposed to known hypertension risk factors. These findings shed light on the underlying molecular mechanisms of BP, and may assist with the development of a miRNA panel for early detection of hypertension.

DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study.

Oxidative stress (OS) is a primary mechanism of carcinogenesis, and methylation of genes related to it may play a role in cancer development. In this study, we examined the prospective association between blood DNA methylation of four oxidative stress genes and cancer incidence. Our study population included a total of 582 participants in the Normative Aging Study (NAS) who had blood drawn during 1-4 visits from 1999-2012 (mean follow up 9.0 years). Promoter DNA methylation of CRAT, iNOS, OGG1 and GCR in blood leukocytes was measured using pyrosequencing. We used Cox regression models to examine prospective associations between cancer incidence and both methylation at the baseline visit and methylation rate of changes over time. Baseline OGG1 methylation was associated with higher risk of all-cancer (HR: 1.43, 95% CI: 1.15-1.78) and prostate cancer (HR: 1.52, 95% CI: 1.03-2.25) incidence. Compared with participants remaining cancer-free, those who eventually developed cancer had significantly accelerated CRAT methylation (p = 0.04) and decelerated iNOS methylation (p<0.01) over time prior to cancer diagnosis. Accelerated CRAT methylation was associated with higher all-cancer incidence (HR: 3.88, 95% CI: 1.06-14.30), whereas accelerated iNOS methylation was associated with lower all-cancer incidence (HR: 0.08, 95% CI 0.02-0.38). Our results suggest that methylation and its dynamic change over time in OS-related genes, including OGG1, CRAT and iNOS, may play an important role in carcinogenesis. These results can potentially facilitate the development of early detection biomarkers and new treatments for a variety of cancers.

Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines.

Inter-individual variation in cytosine modifications has been linked to complex traits in humans. Cytosine modification variation is partially controlled by single nucleotide polymorphisms (SNPs), known as modified cytosine quantitative trait loci (mQTL). However, little is known about the role of short tandem repeat polymorphisms (STRPs), a class of structural genetic variants, in regulating cytosine modifications. Utilizing the published data on the International HapMap Project lymphoblastoid cell lines (LCLs), we assessed the relationships between 721 STRPs and the modification levels of 283,540 autosomal CpG sites. Our findings suggest that, in contrast to the predominant cis-acting mode for SNP-based mQTL, STRPs are associated with cytosine modification levels in both cis-acting (local) and trans-acting (distant) modes. In local scans within the ±1 Mb windows of target CpGs, 21, 9, and 21 cis-acting STRP-based mQTL were detected in CEU (Caucasian residents from Utah, USA), YRI (Yoruba people from Ibadan, Nigeria), and the combined samples, respectively. In contrast, 139,420, 76,817, and 121,866 trans-acting STRP-based mQTL were identified in CEU, YRI, and the combined samples, respectively. A substantial proportion of CpG sites detected with local STRP-based mQTL were not associated with SNP-based mQTL, suggesting that STRPs represent an independent class of mQTL. Functionally, genetic variants neighboring CpG-associated STRPs are enriched with genome-wide association study (GWAS) loci for a variety of complex traits and diseases, including cancers, based on the National Human Genome Research Institute (NHGRI) GWAS Catalog. Therefore, elucidating these STRP-based mQTL in addition to SNP-based mQTL can provide novel insights into the genetic architectures of complex traits.

Longitudinal Study of DNA Methylation of Inflammatory Genes and Cancer Risk.

BACKGROUND: Chronic inflammation plays a key role in cancer etiology. DNA methylation modification, one of the epigenetic mechanisms regulating gene expression, is considered a hallmark of cancer. Human and animal models have identified numerous links between DNA methylation and inflammatory biomarkers. Our objective was to prospectively and longitudinally examine associations between methylation of four inflammatory genes and cancer risk. METHODS: We included 795 Normative Aging Study participants with blood drawn one to four times from 1999 to 2012 (median follow-up, 10.6 years). Promoter DNA methylation of IL6, ICAM-1, IFN, and TLR2 in blood leukocytes was measured using pyrosequencing at multiple CpG sites and averaged by gene for data analysis. We used Cox regression models to examine prospective associations of baseline and time-dependent methylation with cancer risk and compared mean methylation differences over time between cancer cases and cancer-free participants. RESULTS: Baseline IFN hypermethylation was associated with all-cancer (HR, 1.49; P = 0.04) and prostate cancer incidence (HR, 1.69; P = 0.02). Baseline ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, respectively). In our time-dependent analyses, IFN hypermethylation was associated with all-cancer (HR, 1.79; P = 0.007) and prostate cancer (HR, 1.57; P = 0.03) incidence; and ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, respectively). We detected significant ICAM-1 hypermethylation in cancer cases (P = 0.0003) 10 to 13 years prediagnosis. CONCLUSION: Hypermethylation of IFN and ICAM-1 may play important roles in early carcinogenesis, particularly that of prostate cancer. IMPACT: These methylation changes could inform the development of early detection biomarkers and potential treatments of inflammation-related carcinogenesis.

Characterization of genome-wide H3K27ac profiles reveals a distinct PM2.5-associated histone modification signature.

BACKGROUND: Current studies of environmental health suggest a link between air pollution components, such as particulate matter (PM), and various diseases. However, the specific genes and regulatory mechanisms implicated in PM-induced diseases remain largely unknown. Epigenetic systems such as covalent modification of histones in chromatin may mediate environmental factors in gene regulation. Investigating the relationships between PM exposure and histone modification status may help understand the mechanisms underlying environment-associated health conditions. METHODS: In this study, we obtained genome-wide profiles of H3K27ac (histone 3 lysine 27 acetylation), known to be an active gene regulatory histone modification marker, in blood samples collected from four Chinese individuals exposed to high or low PM2.5 (particles with diameters up to 2.5 µm). RESULTS: The genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) data indicated a comprehensive differential H3K27ac landscape across the individual genomes, which was associated with high PM2.5. Moreover, a substantial number of these PM2.5-associated differential H3K27ac markers were in genes involved in immune cell activation, potentially linking these epigenetic changes with air pollution-induced immune and inflammatory responses. CONCLUSIONS: Our study provides the first genome-wide characterization of H3K27ac profiles in individuals subjected to different exposure levels of PM2.5. Future systematic investigations of the relationships between air pollutants and histone modifications in large population samples are warranted to elucidate the contributions of histone modifications to environment-associated diseases.

Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort.

BACKGROUND: Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence. METHODS: We included 792 Normative Aging Study participants with 1-4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis. FINDINGS: Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference = 0.017); all participants had similar age-adjusted BTL 8-14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p = 0.003) and four (p = 0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured ≤ 4 years pre-diagnosis with any (OR = 3.27, p < 0.001) and prostate cancers (OR = 6.87, p < 0.001). INTERPRETATION: Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker.