Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis

Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions.     

High serum riboflavin is associated with the risk of sporadic colorectal cancer

BackgroundExperimental results indicate that riboflavin is involved in tumorigenesis. Data regarding the relationship between riboflavin and colorectal cancer (CRC) are limited, and findings vary between observational studies.DesignThis was a case–control retrospective study.ObjectiveThis study aimed to evaluate the associations between serum riboflavin level and sporadic CRC risk.MethodsIn total, 389 participants were enrolled in this study – including 83 CRC patients without family history and 306 healthy controls – between January 2020 and March 2021 at the Department of Colorectal Surgery and Endoscope Center at Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Age, sex, body mass index, history of polyps, disease conditions (e.g., diabetes), medications, and eight other vitamins were used as confounding factors. Adjusted smoothing spline plots, subgroup analysis, and multivariate logistic regression analysis were conducted to estimate the relative risk between serum riboflavin levels and sporadic CRC risk. After fully adjusting for the confounding factors, an increased risk of colorectal cancer was suggested for individuals with higher levels of serum riboflavin (OR = 1.08 (1.01, 1.15), p = 0.03) in a dose–response relationship.ConclusionsOur results support the hypothesis that higher levels of riboflavin may play a role in facilitating colorectal carcinogenesis. The finding of high levels of circulating riboflavin in patients with CRC warrants further investigation.     

DNA repair gene 8-oxoguanine DNA glycosylase Ser326Cys polymorphism and colorectal cancer risk in a Kashmiri population

8-Oxoguanine DNA glycosylase (OGG1) is one of the important base excision repair enzymes that repair 8-oxoguanine lesion incorporated within the DNA of an individual by reactive oxygen species. The aim of this study was to detect the role of OGG1 Ser326Cys polymorphism in susceptibility to colorectal cancer (CRC) in a Kashmiri population. We investigated the genotype distribution of the OGG1 gene in 114 CRC cases in comparison with 200 healthy subjects. There was no significant association between OGG1 Ser326Cys polymorphism and CRC, but the homozygous Cys/Cys variant genotype was associated with an increased risk of colon cancer (p<0.05). This study suggests that the OGG1 polymorphism is not associated with the risk of development of CRC in the Kashmiri population in general but modulates the risk of cancer development in colon via interaction with many dietary factors.     

Intake of dietary fats and colorectal cancer risk: Prospective findings from the UK Dietary Cohort Consortium

Introduction: Epidemiologic evidence for an association between colorectal cancer (CRC) risk and total dietary fat, saturated fat (SF), monounsaturated fat (MUFA) and polyunsaturated fat (PUFA) is inconsistent. Previous studies have used food frequency questionnaires (FFQ) to assess diet, but data from food diaries may be less prone to severe measurement error than data from FFQ. Methods: We conducted a case–control study nested within seven prospective UK cohort studies, comprising 579 cases of incident CRC and 1996 matched controls. Standardized dietary data from 4- to 7-day food diaries and from FFQ were used to estimate odds ratios for CRC risk associated with intake of fat and subtypes of fat using conditional logistic regression. We also calculated multivariate measurement error corrected odds ratios for CRC using repeated food diary measurements. Results: We observed no associations between intakes of total dietary fat or types of fat and CRC risk, irrespective of whether dietary data were obtained using food diaries or FFQ. Conclusion: Our results do not support the hypothesis that intakes of total dietary fat, SF, MUFA or PUFA are linked to risk of CRC.     

Baseline alcohol consumption,type of alcoholic beverage and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition-Norfolk study

Excessive alcohol consumption has been associated with increased risk of colorectal cancer (CRC). However, the effect of modest alcohol consumption or of particular types of beverages on CRC risk remains unclear. We examined whether consumption of total alcohol or specific types of alcoholic beverages relate to overall or site-specific CRC risk in a prospective population study of 24,244 participants and 407 incident CRC cases after 11 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Consumption of specific alcoholic beverages at baseline was collected using a detailed health and lifestyle questionnaire. Total alcohol consumption was not associated with CRC risk before or after adjustment for age, sex, weight, height, and smoking status (HR: 0.80, 95% CI: 0.51–1.26 for alcohol consumption of ≥21 units/week compared with non-drinkers), and further adjustment for education level, exercise, family history of CRC, and dietary factors did not significantly alter the risk estimates (HR: 0.70, 95% CI: 0.44–1.13). No significant associations were observed between consumption of specific alcoholic beverages (beer, sherry, or spirits) and CRC risk when compared with non-drinkers after adjustment for lifestyle and dietary factors. Daily consumption of ≥1 unit of wine appeared inversely related to CRC risk (HR: 0.61, 95% CI: 0.40–0.94). No evidence was found for sex-specific relationships, and further exclusion of cases incident within 3 years of baseline did not change the associations observed. In this population-based UK cohort, we did not find any significant adverse effect of alcohol over the moderate range of intake on colorectal cancer risk.     

Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis

There is still insufficient data about the risk-benefit profile about recommending non-aspirin, non-steroidal anti-inflammatory drugs (NA-NSAIDs) for colorectal cancer (CRC) prevention, especially in people aged 40 years or older. This study specifically addressed the association between regular NA-NSAIDs use and CRC risk in the population aged 40 years or older, performing a comprehensive systematic review and meta-analysis of all published studies on this topic until April 2018, by a search of PubMed, Scopus and Web of science databases and clinical trial registries. Two reviewers independently selected studies based on predefined inclusion criteria and assessed study quality using the Newcastle-Otawa scale. The data was combined with the random effects model. Potential heterogeneity was calculated as Q statistic and I² value. A total of 23 studies involving more than 1 million subjects contributed to the analysis. Pooled odds ratio (OR) of NA-NSAIDs effects on CRC risk was 0.74 (0.67-0.81), I² = 75.9%, p < 0.001. Heterogeneity was explained by a number of variables including the quality of the studies. Significant protective effects of NA-NSAIDs use were found for women (risk reduction of 19%), higher doses (risk reduction of 18%), distal colon cancer (risk reduction of 22%) and white people (risk reduction from 31% to 41%). From the results NA-NSAIDs use appears to be CRC chemopreventive for a specific subgroup of the population.     

Association between XRCC1 and XRCC3 polymorphisms and colorectal cancer risk: a meta-analysis of 23 case–control studies

Several potential functional polymorphisms in the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln (rs25487), Arg194Trp (rs1799782), Arg280His (rs25489) and X-ray repair cross-complementing group 3 (XRCC3) T241M (rs861539) have been implicated in colorectal cancer (CRC) risk, but the results are conflicting. Here, we performed a meta-analysis of 23 published case control datasets and assessed genetic heterogeneity between those datasets. All the case–control studies published from January 2000 to June 2012 on the association between those polymorphisms and CRC risk were identified by searching the electronic literature Medline. Statistical analysis was performed with the software programs Review Manager (version 4.2). For overall CRC, no significant association was observed, the pooled odds ratios for XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 T241M were 1.02 (95 % CI: 0.93, 1.12), 1.03 (95 % CI: 0.94, 1.14), 0.98 (95 % CI: 0.85, 1.13) and 1.03 (95 % CI: 0.85, 1.26), respectively. Furthermore, no significant association was observed in subgroup analyses based on ethnicity. The results suggested that these four SNPs evaluated are not associated with risk of CRC.     

Assortative mating and within-spouse pair comparisons

Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias.     

Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

Selenium (Se), a dietary trace metal essential for human health, is incorporated into ~25 selenoproteins including selenoprotein S (SelS) and the 15-kDa selenoprotein (Sep15) both of which have functions in the endoplasmic reticulum protein unfolding response. The aim of this study was to investigate whether genetic variants in such selenoprotein genes are associated with altered risk of colorectal cancer (CRC). A Korean population of 827 patients with CRC and 733 healthy controls was genotyped for 7 SNPs in selenoprotein genes and one SNP in the gene encoding manganese superoxide dismutase using Sequenom technology. Multivariate logistic regression analysis showed that after adjustment for lifestyle factors three SNP variants were associated with altered disease risk. There was a mean odds ratio of 2.25 [95% CI 1.13,4.48] in females homozygous TT for rs34713741 in SELS with the T variant being associated with higher risk of rectal cancer, and odds ratios of 2.47 and 2.51, respectively, for rs5845 and rs5859 in SEP15 with the minor A and T alleles being associated with increased risk of male rectal cancer. The data indicate that the minor alleles for rs5845, rs5859 and rs34713741 are associated with increased rectal cancer risk and that the effects of the three SNPs are dependent on gender. The results highlight potential links between Se, the function of two selenoproteins involved in the protein unfolding response and CRC risk. Further studies are required to investigate whether the effects of the variants on CRC risk are also modulated by dietary Se intake.     

Dietary inflammatory index and inflammatory gene interactions in relation to colorectal cancer risk in the Bellvitge colorectal cancer case–control study

Chronic inflammation is an important factor in colorectal carcinogenesis. However, evidence on the effect of pro-inflammatory and anti-inflammatory foods and nutrients is scarce. Moreover, there are few studies focusing on diet–gene interactions on inflammation and colorectal cancer (CRC). This study was designed to investigate the association between the novel dietary inflammatory index (DII) and CRC and its potential interaction with polymorphisms in inflammatory genes. Data from the Bellvitge Colorectal Cancer Study, a case–control study (424 cases with incident colorectal cancer and 401 hospital-based controls), were used. The DII score for each participant was obtained by multiplying intakes of dietary components from a validated dietary history questionnaire by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Data from four important single nucleotide polymorphisms located in genes thought to be important in inflammation-associated CRC: i.e., interleukin (IL)-4, IL-6, IL-8, and peroxisome proliferator-activated receptor-γ (PPARG) were analyzed. A direct association was observed between DII score and CRC risk (OR_{Q4 vs. Q1} 1.65, 95 % CI 1.05–2.60, and P trend 0.011). A stronger association was found with colon cancer risk (OR_{Q4 vs. Q1} 2.24, 95 % CI 1.33–3.77, and P trend 0.002) than rectal cancer risk (OR_{Q4 vs. Q1} 1.12, 95 % CI 0.61–2.06, and P trend 0.37). DII score was inversely correlated with SNP rs2243250 in IL-4 among controls, and an interaction was observed with CRC risk. Neither correlation nor interaction was detected for other inflammatory genes. Overall, high-DII diets are associated with increased risk of CRC, particularly for colon cancer, suggesting that dietary-mediated inflammation plays an important role in colorectal carcinogenesis.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0447-x) contains supplementary material, which is available to authorized users.     

Colorectal cancer risk factors in the detection of advanced adenoma and colorectal cancer

Several risk factors for colorectal cancer (CRC) have been identified. If individuals with risk factors are more likely to harbor cancer or it precursors screening programs should be targeted toward this population. We evaluated the predictive value of colorectal cancer risk factors for the detection of advanced colorectal adenoma in a population based CRC colonoscopy screening program. Data were collected in a multicenter trial conducted in the Netherlands, in which 6600 asymptomatic men and women between 50 and 75 years were randomly selected from a population registry. They were invited to undergo a screening colonoscopy. Based on a review of the literature CRC risk factors were selected. Information on risk factors was obtained from screening attendees through a questionnaire. For each CRC risk factor, we estimated its odds ratio (OR) relative to the presence of advanced neoplasia as detected at colonoscopy. Of the 1426 screening participants who underwent a colonoscopy, 1236 (86%) completed the risk questionnaire. 110 participants (8.9%) had advanced neoplasia. The following risk factors were significantly associated with advanced neoplasia detected by colonoscopy: age (OR: 1.06 per year; 95% CI: 1.03–1.10), calcium intake (OR: 0.99 per mg; 95% CI: 0.99–1.00), positive CRC family history (OR: 1.55 per first degree family member; 95%CI: 1.11–2.16) and smoking (OR: 1.75; 95%CI: 1.09–2.82). Elderly screening participants, participants with lower calcium intake, a CRC family history, and smokers are at increased risk of harboring detectable advanced colorectal neoplasia at screening colonoscopy.     

Development and preliminary validation of the cancer family impact scale for colorectal cancer

AIM: The aim of our study was to develop a measure of how a family history of colorectal cancer (CRC) affects families from the viewpoint of unaffected family members. METHOD: Using data from 1,285 participants (637 families) in the Johns Hopkins Colon Cancer Genetic Testing study, we developed and validated The Cancer Family Impact Scale (CFIS), an instrument for use in studies investigating relationships among family factors and CRC prevention behaviors when family history is a risk factor. RESULTS: Through exploratory factor analysis (EFA) using a 50% random sample of participants, we identified 5 latent constructs among 18 items: (1) NEGATIVE: negative effects of cancer on the family; (2) POSITIVE: positive effects of cancer on the family; (3) COMMUNICATE: how families communicate about cancer; (4) FLOW: how information about cancer is conveyed in families; and (5) NORM: how individuals react to family norms about cancer. Confirmatory factor analysis (CFA) on the same sample showed the CFIS to have a reasonably good fit (chi(2) = 389.97, degree of freedom (df ) = 122, root mean square error of approximation = 0.06 [0.05-0.07], comparative fit index = 0.90, Tucker-Lewis index = 0.88, goodness of fit index = 0.94), and findings were cross-validated on the remaining 50% of the participants. The reliability of the scale was alpha = 0.65. CONCLUSIONS: The CFIS could be used to clarify the role that family factors play in the association between CRC family history and CRC prevention behaviors, and also aid in the development and evaluation of family-based cancer prevention interventions.     

Pre-diagnostic telomere length and colorectal cancer risk

BackgroundProgressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent.MethodsWe examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336).ResultsWe did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest) = 1.36 (0.85, 2.17), P-trend = 0.27; OR (95% CI) per 1 SD decrease in TL = 1.12 (0.92, 1.36)].ConclusionsOur prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.     

The association between dietary intakes of methionine,choline and betaine and breast cancer risk: A systematic review and meta-analysis

Background and aimThis study evaluates the associations between dietary intakes and circulating blood levels of methionine, choline or betaine and breast cancer risk, which remains currently unclear.MethodsSystematic searches for observational epidemiological studies were performed of the MEDLINE, Embase, and Web of Science databases through July, 2022. Two review authors independently screened titles and abstracts against the eligibility criteria at a first stage, and screened full texts of potentially eligible records at a second stage, followed by data extraction from qualified studies. Quality of evidence was assessed using the Newcastle-Ottawa scale quality assessment tool. Risk estimates were calculated using random-effects meta-analysis.ResultsIn total, 21 studies were selected for qualitative analyses and 18 studies were included in the meta-analyses. Random-effects analysis combining prospective cohort (N = 8) or case–control studies (N = 10) showed little evidence of an association between dietary intake of methionine or betaine and the risk of breast cancer. However, inconclusive evidence for a significant inverse association between choline intake and breast cancer risk was found in case–control studies (odds ratio [OR] estimates for highest vs. lowest intakes = 0.38; 95 % CI: 0.16–0.86) but not in prospective cohort studies (hazard ratio [HR] estimates for highest vs. lowest intakes = 1.01; 95 % CI: 0.92–1.12).ConclusionThis study did not suggest an effect of dietary intake of methionine, choline, nor betaine on breast cancer risk, mainly due to the lack of precision of the combined risk estimates as few studies are available. To overcome this uncertainty, more well-designed studies with relevant individual-level covariates are needed.     

Start codon FokI and intron 8 BsmI variants in the vitamin D receptor gene and susceptibility to colorectal cancer

Epidemiological evidence suggests the protective effect of vitamin D against colorectal cancer (CRC) and the polymorphisms in vitamin D receptor (VDR) gene may influence the development of CRC. In this study the possible association of VDR FokI and BsmI gene polymorphisms with CRC risk was examined. A total of 904 subjects, including 452 cases with CRC and 452 controls were enrolled in this study. All 904 subjects were genotyped for VDR FokI and BsmI gene polymorphisms by PCR-RFLP method. We observed no significant difference in genotype and allele frequencies between the cases with CRC and controls for the both FokI and BsmI polymorphisms either before or after adjustment for confounding factors including age, BMI, sex, and smoking status. Furthermore, no evidence for effect modification of the association VDR gene FokI and BsmI variants and CRC by BMI, sex, or tumor site was observed. In addition, there was no significant difference in genotype and allele frequencies between the normal weight (BMI <25 kg/m²) cases with CRC and overweight/obese (BMI ≥25 kg/m²) cases with CRC for the two SNPs. Our results do not lend support to the hypothesis that VDR gene FokI and BsmI polymorphisms are associated with the risk of CRC. However, further studies are required to confirm this finding.     

Childhood energy intake and adult mortality from cancer: the Boyd Orr Cohort Study.

OBJECTIVE: To examine the relation between energy intake in childhood and adult mortality from cancer. STUDY DESIGN: Cohort study. SETTING: 16 rural and urban centres in England and Scotland. SUBJECTS: 3834 people who took part in Lord Boyd Orr''s Carnegie survey of family diet and health in prewar Britain between 1937 and 1939 who were followed up with the NHS, central register. Standardised methods were used to measure household dietary intake during a one week period. MAIN OUTCOME MEASURES: Cancer mortality. RESULTS: Significant associations between childhood energy intake and cancer mortality were seen when the confounding effects of social variables were taken into account in proportional hazards models (relative hazard for all cancer mortality 1.15 (95% confidence interval 1.06 to 1.24), P = 0.001, for every MJ increase in adult equivalent daily intake in fully adjusted models). This effect was essentially limited to cancers not related to smoking (relative hazard 1.20; 1.07 to 1.34; P = 0.001), with similar effects seen in men and women. CONCLUSION: This positive association between childhood energy intake and later cancer is consistent with animal evidence linking energy restriction with reduced incidence of cancer and the association between height and human cancer, implying that higher levels of energy intake in childhood increase the risk of later development of cancer. This evidence for long term effects of early diet confirm the importance of optimal nutrition in childhood and suggest that the unfavourable trends seen in the incidence of some cancers may have their origins in early life.     

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.     

Standard errors for attributable risk for simple and complex sample designs

Adjusted attributable risk (AR) is the proportion of diseased individuals in a population that is due to an exposure. We consider estimates of adjusted AR based on odds ratios from logistic regression to adjust for confounding. Influence function methods used in survey sampling are applied to obtain simple and easily programmable expressions for estimating the variance of AR. These variance estimators can be applied to data from case-control, cross-sectional, and cohort studies with or without frequency or individual matching and for sample designs with subject samples that range from simple random samples to (sample) weighted multistage stratified cluster samples like those used in national household surveys. The variance estimation of AR is illustrated with: (i) a weighted stratified multistage clustered cross-sectional study of childhood asthma from the Third National Health and Examination Survey (NHANES III), and (ii) a frequency-matched case-control study of melanoma skin cancer.