Improved two-step testing of genome-wide gene-environment interactions.

Two-step tests for gene-environment ( G × E $G\times E$ ) interactions exploit marginal single-nucleotide polymorphism (SNP) effects to improve the power of a genome-wide interaction scan. They combine a screening step based on marginal effects used to "bin" SNPs for weighted hypothesis testing in the second step to deliver greater power over single-step tests while preserving the genome-wide Type I error. However, the presence of many SNPs with detectable marginal effects on the trait of interest can reduce power by "displacing" true interactions with weaker marginal effects and by adding to the number of tests that need to be corrected for multiple testing. We introduce a new significance-based allocation into bins for Step-2 G × E $G\times E$ testing that overcomes the displacement issue and propose a computationally efficient approach to account for multiple testing within bins. Simulation results demonstrate that these simple improvements can provide substantially greater power than current methods under several scenarios. An application to a multistudy collaboration for understanding colorectal cancer reveals a G × Sex interaction located near the SMAD7 gene.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.

BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

A Unified Model for the Analysis of Gene-Environment Interaction.

Gene-environment (G × E) interaction is important for many complex traits. In a case-control study of a disease trait, logistic regression is the standard approach used to model disease as a function of a gene (G), an environmental factor (E), G × E interaction, and adjustment covariates. We propose an alternative model with G as the outcome and show how it provides a unified framework for obtaining results from all of the common G × E tests. These include the 1-degree-of-freedom (df) test of G × E interaction, the 2-df joint test of G and G × E, the case-only and empirical Bayes tests, and several 2-step tests. In the context of this unified model, we propose a novel 3-df test and demonstrate that it provides robust power across a wide range of underlying G × E interaction models. We demonstrate the 3-df test in a genome-wide scan of G × sex interaction for childhood asthma using data from the Children's Health Study (Southern California, 1993-2001). This scan identified a strong G × sex interaction at the phosphodiesterase gene 4D locus (PDE4D), a known asthma-related locus, with a strong effect in males (per-allele odds ratio = 1.70; P = 3.8 × 10-8) and virtually no effect in females. We describe a software program, G×EScan (University of Southern California, Los Angeles, California), which can be used to fit standard and unified models for genome-wide G × E studies.

Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study.

PURPOSE: There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women. METHODS: The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels. RESULTS: When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95% CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95% CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups. CONCLUSIONS: Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis.

PURPOSE: We assessed survival after radical prostatectomy, intensity modulated radiation therapy or conformal radiation therapy vs no local therapy for metastatic prostate cancer adjusting for patient comorbidity, androgen deprivation therapy and other factors. MATERIALS AND METHODS: We identified men 66 years old or older with metastatic prostate cancer treated with radical prostatectomy, intensity modulated radiation therapy, conformal radiation therapy or no local therapy in the SEER-Medicare linked database from 2004 to 2009. Multivariable Cox proportional hazards models before and after inverse propensity score weighting were used to assess all cause and prostate cancer specific mortality. Competing risk regression analysis was done to assess prostate cancer specific mortality. RESULTS: Of 4,069 men with metastatic prostate cancer radical prostatectomy in 47, intensity modulated radiation therapy in 88 and conformal radiation therapy in 107 were selected as local therapy vs no local therapy in 3,827. Radical prostatectomy was associated with a 52% decrease (HR 0.48, 95% CI 0.27-0.85) in the risk of prostate cancer specific mortality after adjusting for sociodemographics, primary tumor characteristics, comorbidity, androgen deprivation therapy and bone radiation within 6 months of diagnosis. Intensity modulated radiation therapy was associated with a 62% decrease (HR 0.38, 95% CI 0.24-0.61) in the risk of prostate specific cancer specific mortality. Conformal radiation therapy was not associated with improved survival compared to no local therapy. Propensity score weighting yielded comparable results. Competing risk analysis revealed a 42% and 57% decrease (SHR 0.58, 95% CI 0.35-0.95 and SHR 0.43, 95% CI 0.27-0.68, respectively) in the risk of prostate cancer specific mortality for radical prostatectomy and intensity modulated radiation therapy. CONCLUSIONS: Local therapy with radical prostatectomy and intensity modulated radiation therapy but not with conformal radiation therapy was associated with a survival benefit in men with metastatic prostate cancer. This finding warrants prospective evaluation in clinical trials.

Realities and myths of the Teresken Syndrome--an evaluation of the exploitation of dwarf shrub resources in the Eastern Pamirs of Tajikistan.

In the Eastern Pamirs extensive livestock herding is the predominant land use option and dwarf shrubs - teresken (Krascheninnikovia ceratoides) and to a lesser extent wormwood (Artemisia spp.) - are an important source of thermal energy and are crucial forage plants, particularly in winter. For the post-Soviet period, many papers and reports suggest rapidly increasing exploitation rates with sometimes alarming figures for degradation. Conventional knowledge about the Pamirs pinpoints the frightening and irreversible extraction of teresken as a dwindling resource causing land degradation - termed the 'Teresken Syndrome'. However, these publications are based on limited empirical evidence. This paper discusses the socio-economic role of dwarf shrubs as fuel and forage - today and in the past - and provides an overview of the extent of dwarf shrub distribution and degraded areas. Although our observations confirm extensive dwarf shrub exploitation, general assumptions of severe desertification as a result of dwarf shrub extraction do not yield reliable scenarios. The effects of harvesting on the vegetation cover vary widely depending on extraction practices and yields of different dwarf shrub-dominated formations. Furthermore, considerable and increasing shares of energy needs are satisfied by animal manure and imported coal. On the other hand, for low-income households harvesting dwarf shrubs is an important and reliable option to ensure both their own household energy supply and an income source. We argue that the term 'Teresken Syndrome', which was introduced after the emergency replacement of Soviet coal supplies by dwarf shrubs in the 1990s, is not appropriate anymore to describe the current use of natural resources in the Eastern Pamirs. However, under the current economic circumstances the nexus remains that the Pamir people are caught in the dilemma of using dwarf shrubs as energy and as forage resource. However, the observed negotiation practices concerning competitive use between dwarf shrub extractors and herders could be developed into community-based management schemes of this common pool resource.

Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS: 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS: 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION: PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING: Carraresi Foundation and others.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Introduction: Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. Methods: We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Results: Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Discussion: Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

High-resolution assessment of the carrying capacity and utilization intensity in mountain rangelands with remote sensing and field data.

Dry rangelands provide resources for half of the world's livestock, but degradation due to overgrazing is a major threat to system sustainability. Existing carrying capacity assessments are limited by low spatiotemporal resolution and high generalization, which hampers applied ecological management decisions. This paper provides an example for deriving the carrying capacity and utilization levels for cold drylands at a new level of detail by including major parts of the transhumance system. We combined field data on vegetation biomass and communities, forage quality, productivity, livestock species and quantities, grazing areas and their spatiotemporal variations with Sentinel-2 and MODIS snow cover satellite imagery to develop maps of forage requirements and availability. These products were used to calculate carrying capacity and grazing potential in the Pamir-Hindukush Mountains. Results showed high spatial variability of utilization rates between 5% and 77%. About 30% of the area showed unsustainable grazing above the carrying capacity. Utilization rates displayed strong spatial differences with unsustainable grazing in winter pastures and at lower elevations, and low rates at higher altitudes. The forage requirements of wild herbivores (ungulates and marmots) were estimated to be negligible compared to livestock, with one tenth of the biomass consumption and no increase in unsustainably grazed pastures due to the wider distribution of animals. The assessment was sensitive to model parameterization of forage requirements and demand, whereby conservative scenarios, i.e. lower fodder availability or higher fodder requirements of livestock due to climate and altitude effects, increased the area with unsustainable grazing practices to 50%. The presented approach enables an in-depth evaluation of the carrying capacity and corresponding management actions. It includes new variables relevant for transhumance systems, such as the combination of forage quantity and quality or accessibility restrictions due to snow, and shows utilization patterns at high spatial resolutions. Regional maps allow the identification of unsustainable utilization areas, such as winter pastures in this study.

Correlates of COVID-19 vaccination status among college students.

Objectives: Despite the widespread availability of COVID-19 vaccines in the United States, vaccine hesitancy remains high among certain groups. This study examined the correlates of being unvaccinated among a sample of students attending a single university (N = 2900) during the spring and summer of 2021, when the campus had been closed for over a year and students were preparing to return to in-person learning. Methods: Students responded to an email invitation and completed electronic surveys. Results: In multivariable logistic regression analyses, students were more likely to be unvaccinated if they were African American, identified with any political affiliation other than Democrat, were undergraduates or international students, had not traveled outside the Los Angeles during the pandemic, and/or had previously been ill with COVID-19. Conclusion: Findings indicate that culturally resonant educational interventions, and possibly vaccine requirements, are needed to promote vaccination among university students.

The neonicotinoid thiacloprid leads to multiple defects during early embryogenesis of the South African clawed frog (Xenopuslaevis).

There is increasing concern about the health effects of pesticides that pollute natural waters. In particular, the use of neonicotinoids, such as thiacloprid (THD), is causing unease. THD is considered non-toxic to non-target vertebrates. Studies classify THD as carcinogenic, toxic to reproduction, and therefore harmful to the environment. A detailed study of possible THD effects during the amphibian embryogenesis is needed because leaching can introduce THD into aquatic environments. We incubated stage 2 embryos of the South African clawed frog in various THD concentrations (0.1-100 mg/L) at 14 °C to study the potential effects of a one-time THD contamination of waters on the early embryogenesis. We showed that THD has, indeed, negative effects on the embryonic development of the X. laevis. A treatment with THD led to a reduced embryonic body length and mobility. Furthermore, a treatment with THD resulted in smaller cranial cartilages, eyes and brains, and the embryos had shorter cranial nerves and an impaired cardiogenesis. On a molecular basis, THD led to a reduced expression of the brain marker emx1 and the heart marker mhcα. Our results underly the importance of a strict and efficient monitoring of the regulatory levels and application areas of THD.

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.

BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.

Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

COVID-19 booster vaccine attitudes and behaviors among university students and staff in the United States: The USC Trojan pandemic research Initiative.

Although authorized mRNA COVID-19 vaccines (BNT162b2 by BioNTech/Pfizer and mRNA-1273 by Moderna) significantly reduce morbidity and mortality, recent evidence suggests that immunity wanes over time, and that a booster dose could further reduce COVID-19 transmission and severe illness. However, research examining attitudes on booster willingness in diverse populations is needed. This study examined COVID-19 booster vaccine attitudes and behaviors among university students and staff in the fall of 2021. In our sample, 96.2% of respondents indicated willingness to get a COVID-19 booster shot at least once per year. In both bivariate and multivariate analyses higher trust in science was associated with having higher odds of booster willingness. Those who identify as Black, on average, reported trusting science less than other racial/ethnic groups. Our findings demonstrate high willingness to receive a COVID-19 booster shot and highlight the importance of educational messages and initiatives that focus on building trust in science to increase willingness to get the COVID-19 booster. More research is needed to better understand the impact of cultural beliefs on booster willingness and vaccine hesitancy. This understanding will help determine what messages and populations to target to increase booster willingness in the future.

Characteristics associated with COVID-19 vaccination status among staff and faculty of a large, diverse University in Los Angeles: The Trojan Pandemic Response Initiative.

Objective: This study examined characteristics associated with being unvaccinated among a sample of university staff and faculty prior to university campus reopening for in-person learning in 2021. Methods: Staff and faculty responded to an email invitation to complete an online survey. Survey questions included demographic data (race/ethnicity, age, sex), COVID-19 knowledge and behaviors, employment specific data including division and subdivision (healthcare vs. non-healthcare related division); and self-reported vaccination status. A multivariable logistic regression analysis was performed to determine significant characteristics associated with the likelihood of being unvaccinated for COVID-19. Results: Participants identifying as Asian and Asian American (aOR = 1.44, 95% CI: 1.06, 1.96), Hispanic/Latinx (aOR = 1.73, 95% CI: 1.21, 2.49) or Multicultural/Other (aOR = 1.72, 95% CI: 1.24, 2.38) had greater odds of being unvaccinated compared to Non-Hispanic White participants. Other characteristics associated with greater likelihood of being unvaccinated included working as a university staff member (vs. faculty) (aOR = 1.69, 95% CI: 1.24. 2.30), decrease in income (aOR = 1.34, 95% CI:1.05, 1.71), inability to work remotely (aOR = 1.48, 95% CI:1.13, 1.93) and not traveling outside of the Los Angeles area (aOR = 1.46, 95% CI: 1.16, 1.83). Political affiliation as an Independent (aOR = 1.39, 95% CI:1.04, 1.85) or as something else (aOR = 3.84, 95% CI: 2.72, 5.41) were more likely to be unvaccinated compared to participants identifying as Democrat. Conclusions: Several factors associated with racial and social disparities may delay the uptake of COVID-19 vaccination. This study highlights the need for targeted educational interventions to promote vaccination among university staff and faculty.