Faculty Bibliography
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543
Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer
BACKGROUND:The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS/METHODS:We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS:We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS:Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.
PMID: 38408508
ISSN: 1569-8041
CID: 5664602
Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
PMCID:11053150
PMID: 38670944
ISSN: 2041-1723
CID: 5657882
Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US
Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, β-diversity, and taxonomic and functional pathway abundance by SES. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by β-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Prevotella copri and Catenibacterium sp000437715, and decreasing abundance of Dysosmobacter welbionis in terms of their high log-fold change differences. In addition, nativity and race/ethnicity have emerged as ecosocial factors that also influence the gut microbiota. Together, these results showed that lower SES was strongly associated with compositional and taxonomic measures of the gut microbiome, and may contribute to shaping the gut microbiota.
PMID: 38467678
ISSN: 2055-5008
CID: 5645682
Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US
Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger U.S. studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of several individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, β-diversity, and taxonomic and functional pathway abundance by socioeconomic status. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by β-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Genus Catenibacterium and Prevotella copri. The significant association between SES and gut microbiota remained even after considering the race/ethnicity in this racially diverse cohort. Together, these results showed that lower socioeconomic status was strongly associated with compositional and taxonomic measures of the gut microbiome, suggesting that SES may shape the gut microbiota.
PMID: 37131763
ISSN: 2693-5015
CID: 5738092
International journal of cardiology. Cardiovascular risk & prevention. 2023:19.DOI: 10.1016/j.ijcrp.2023.200217
PM2.5 and cardiovascular diseases: State-of-the-Art review
Air pollution, especially exposure to particulate matter 2.5 (PM2.5), has been associated with an increase in morbidity and mortality around the world. Specifically, it seems that PM2.5 promotes the development of cardiovascular risk factors such as hypertension and atherosclerosis, while being associated with an increased risk of cardiovascular diseases, including myocardial infarction (MI), stroke, heart failure, and arrhythmias. In this review, we seek to elucidate the pathophysiological mechanisms by which exposure to PM2.5 can result in adverse cardiovascular outcomes, in addition to understanding the link between exposure to PM2.5 and cardiovascular events. It is hypothesized that PM2.5 functions via 3 mechanisms: increased oxidative stress, activation of the inflammatory pathway of the immune system, and stimulation of the autonomic nervous system which ultimately promote endothelial dysfunction, atherosclerosis, and systemic inflammation that can thus lead to cardiovascular events. It is important to note that the various cardiovascular associations of PM2.5 differ regarding the duration of exposure (short vs long) to PM2.5, the source of PM2.5, and regulations regarding air pollution in the area where PM2.5 is prominent. Current strategies to reduce PM2.5 exposure include personal strategies such as avoiding high PM2.5 areas such as highways or wearing masks outdoors, to governmental policies restricting the amount of PM2.5 produced by organizations. This review, by highlighting the significant impact between PM2.5 exposure and cardiovascular health will hopefully bring awareness and produce significant change regarding dealing with PM2.5 levels worldwide.
PMCID:10585625
PMID: 37869561
ISSN: 2772-4875
CID: 5736232
Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
PMID: 37783704
ISSN: 2041-1723
CID: 5609492
Grain, Gluten, and Dietary Fiber Intake Influence Gut Microbial Diversity: Data from the Food and Microbiome Longitudinal Investigation
UNLABELLED:< 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity. SIGNIFICANCE:Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.
PMCID:10035461
PMID: 36968219
ISSN: 2767-9764
CID: 5594522
A microbial causal mediation analytic tool for health disparity and applications in body mass index
BACKGROUND:Emerging evidence suggests the potential mediating role of microbiome in health disparities. However, no analytic framework can be directly used to analyze microbiome as a mediator between health disparity and clinical outcome, due to the non-manipulable nature of the exposure and the unique structure of microbiome data, including high dimensionality, sparsity, and compositionality. METHODS:Considering the modifiable and quantitative features of the microbiome, we propose a microbial causal mediation model framework, SparseMCMM_HD, to uncover the mediating role of microbiome in health disparities, by depicting a plausible path from a non-manipulable exposure (e.g., ethnicity or region) to the outcome through the microbiome. The proposed SparseMCMM_HD rigorously defines and quantifies the manipulable disparity measure that would be eliminated by equalizing microbiome profiles between comparison and reference groups and innovatively and successfully extends the existing microbial mediation methods, which are originally proposed under potential outcome or counterfactual outcome study design, to address health disparities. RESULTS:Through three body mass index (BMI) studies selected from the curatedMetagenomicData 3.4.2 package and the American gut project: China vs. USA, China vs. UK, and Asian or Pacific Islander (API) vs. Caucasian, we exhibit the utility of the proposed SparseMCMM_HD framework for investigating the microbiome's contributions in health disparities. Specifically, BMI exhibits disparities and microbial community diversities are significantly distinctive between reference and comparison groups in all three applications. By employing SparseMCMM_HD, we illustrate that microbiome plays a crucial role in explaining the disparities in BMI between ethnicities or regions. 20.63%, 33.09%, and 25.71% of the overall disparity in BMI in China-USA, China-UK, and API-Caucasian comparisons, respectively, would be eliminated if the between-group microbiome profiles were equalized; and 15, 18, and 16 species are identified to play the mediating role respectively. CONCLUSIONS:The proposed SparseMCMM_HD is an effective and validated tool to elucidate the mediating role of microbiome in health disparity. Three BMI applications shed light on the utility of microbiome in reducing BMI disparity by manipulating microbial profiles. Video Abstract.
PMID: 37496080
ISSN: 2049-2618
CID: 5592392
Noise Exposure and Cardiovascular Health
Noise is considered an environmental stressor adversely affecting well-being and quality of life, inter-individual communications, and attention and cognitive function and inducing emotional responses, corresponding to noise annoyance. In addition, noise exposure is associated with non-auditory effects including worsening mental health, cognitive impairments, and adverse birth outcomes, sleep disorders, and increased annoyance. An accumulating body of evidence has indicated that traffic noise is also associated with CVD, through multiple pathways. It has been shown that psychological stress and mental health disorders such as depression and anxiety have a negative impact on the development of cardiovascular diseases and outcomes. Likewise, reduced sleep quality and/or duration has been reported to increase sympathetic nervous system activity, which can predispose to conditions like hypertension and diabetes mellitus, known risk factors for CVD. Finally, there seems to be a disruption in the hypothalamic-pituitary-axis secondary to noise pollution that also results in an increased risk of CVD. The World Health Organization has estimated that the number of DALYs (disability-adjusted life-years) lost resulting from environmental noise in Western Europe ranges from 1 to 1.6 million, making noise the second major contributor to the burden of disease in Europe, only after air pollution. Thus, we sought to explore the relationship between noise pollution and risk of CVD.
PMID: 37422031
ISSN: 1535-6280
CID: 5539582
Nonlinear low dose hematotoxicity of benzene; a pooled analyses of two studies among Chinese exposed workers
BACKGROUND:Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems. METHODS:Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers. RESULTS:Supra-linear exposure response associations were observed between air benzene concentrations (range ∼ 0.1 - 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints. DISCUSSION:We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis.
PMID: 37290291
ISSN: 1873-6750
CID: 5533562
