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INTRODUCTION: 65%-70% of colorectal cancer (CRC) cases are considered sporadic; they arise under the influence of environmental factors in individuals lacking a family history of CRC. Low-risk genetic variants are believed to contribute to CRC risk, in tandem with lifestyle factors.

METHODS: Six hundred sixteen nonfamilial Swedish CRC cases with at least 1 of the following 5 risk factors: smoking, excessive alcohol consumption, physical inactivity, adherence to an unhealthy diet, and excess body weight were included in this study. A control group consisting of 1,642 healthy individuals was used. Cases and controls were genotyped from blood samples at the Centre for Inherited Disease Research at Johns Hopkins University within the Colorectal Transdisciplinary Study research collaboration, using the Illumina Infinium OncoArray-500 K BeadChip. Five separate genome-wide haplotype association analyses were performed, one for each risk factor. Logistic regression models were used to estimate associations between haplotypes (exposure) and CRC (outcome) in cases with lifestyle risk factors vs controls. Haplotypes with an odds ratio >1 were considered candidate risk markers, denoting an area of interest in the genome. A significance threshold of P < 5 x 10(-8) was used.

RESULTS: We found 17 haplotype regions significantly associated with CRC in cases vs controls. Several regions included genes linked to inflammation and tumor promotion.

DISCUSSION: We concluded that having certain genetic variants was associated with an increased risk of CRC compared with healthy controls among cases with known lifestyle risk factors. The interplay of lifestyle and genetic risk factors calls for further elucidation.

Background

How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death.

Methods

We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men.

Findings

The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass.

Interpretation

These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease.

This study explored the association between celiac disease (CeD) and Dupuytren's contracture (DC) using data from the Swedish ESPRESSO cohort. We analyzed 49,699 CeD patients and 245,267 matched controls, identifying 1420 incident DC cases. CeD patients had a 1.21-fold increased risk of DC compared to controls, with a more pronounced risk in women and older individuals. Further research is needed to understand the underlying mechanisms of this relationship.

Background

Many currently proposed diets for inflammatory bowel disease (IBD) focus on increasing plant-based foods, although a vegetarian diet can still contain products such as emulsifiers and refined grains that are believed to negatively impact IBD incidence and progression. To better inform dietary management in IBD, we investigated the association between plant-based diets and the incidence and complications of IBD.

Methods

We leveraged data from the UK Biobank (UKB, 2009–2022) including 187,888 participants free of IBD at baseline and the European Prospective Investigation into Cancer and Nutrition (EPIC, 1991–2010) cohort including 341,539 individuals free of IBD across centres among Denmark, France, Germany, Greece, Italy, the Netherlands, Sweden and UK. Healthy and unhealthy diets were characterised using plant-based diet indexes (PDIs); in individual participants, these were based on the 24-h dietary recalls for UKB and food frequency questionnaires for EPIC. The primary outcome was the incidence of IBD; secondary outcomes evaluated endpoints of disease prognosis (IBD-related surgery, diabetes, cardiovascular diease, and all-cause mortality). Cox regression was applied to estimate hazard ratios (HRs).

Findings

In the UKB (925 incident IBD, median follow-up 11.6 years, IQR 1.3 years), higher adherence to healthy PDI was associated with a lower IBD risk (HR 0.75, 95% CI 0.60–0.94), while higher alignment to an unhealthy PDI associated with an increased risk (HR 1.48, 95% CI 1.21–1.82) when comparing extreme quintiles of PDIs. Among individuals with established IBD, healthy PDI was inversely associated (HR 0.50, 95% CI 0.30–0.83) and unhealthy PDI was positively associated (HR 2.12, 95% CI 1.30–3.44) with need for IBD-related surgery. We did not observe significant associations between PDIs and risk of cardiovascular disease, diabetes mellitus or mortality. In the EPIC study (548 incident IBD, median follow-up 14.5 years, IQR 7.0 years), the HR of incident IBD for healthy PDI was 0.71 (95% CI 0.59–0.85) and for unhealthy PDI was 1.54 (95% CI 1.30–1.84).

Interpretation

We provide evidence that the composition of a plant-based diet may be an important determinant of the risk of developing IBD, and of disease course after diagnosis. Further research is needed to explore the mechanistic pathways linking plant-based diets and IBD incidence and prognosis.

Background

Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited.

Objective

The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC.

Design

The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study.

Participants/setting

There were 842149 men followed for up to 9 to 22 years between 1985 and 2009 across studies.

Main outcome measures

The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score >= 8 or poorly differentiated/undifferentiated) and PC mortality.

Statistical analysis performed

Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models.

Results

Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P <= .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366).

Conclusions

Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Background

High levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease (CVD); however, the effects of Lp(a)-lowering therapy in combination with low-density lipoprotein cholesterol (LDL-C)-lowering treatment or lifestyle improvements on CVD risk remain unexplored.

Methods

We conducted a factorial Mendelian randomization study among 385 917 participants in the UK Biobank. Separate genetic scores were constructed to proxy the effects of Lp(a) lowering, LDL-C lowering through different targets [HMG-CoA reductase, NPC1-like intracellular cholesterol transporter 1, proprotein convertase subtilisin/kexin Type 9, and low-density lipoprotein receptor (LDLR)], as well as improvements in body mass index (BMI), systolic blood pressure (SBP), and lifestyle factors (cigarette smoking, alcohol consumption, and physical activity).

Results

Genetically predicted lower Lp(a) levels were associated with a decreased risk of CVD and CVD-specific mortality. Per 50-mg/dl, the hazard ratio ranged from 0.73 [95% confidence interval (CI): 0.73, 0.73] for peripheral artery disease (PAD) to 0.95 (95% CI: 0.92, 0.99) for venous thromboembolism. In factorial analyses exploring combined exposure to low-level Lp(a) and low-level LDL-C, there was no consistent evidence for departure from an additive model for any outcome (P_interaction > .05), with the exception of the analysis using the LDLR score and PAD (P_interaction = .006). In factorial analyses exploring combination therapies integrating Lp(a) lowering with interventions on BMI, SBP, and lifestyle factors, there was no evidence for departure from an additive model in any analysis (P_interaction > .05).

Conclusions

Our study suggests that Lp(a) lowering will have a similar magnitude for reducing cardiovascular events whether it is considered alone, or in conjunction with LDL-C reduction or lifestyle improvements.

Background The causes of bladder cancer are not completely understood. Our objective was to identify blood proteins and modifiable causal risk factors for bladder cancer by combining genome-wide association study (GWAS) and Mendelian randomization (MR) analyses.Methods We first performed a GWAS meta-analysis of 6984 bladder cancer case patients and 708 432 control individuals from 3 European databases. Next, we conducted 2-sample MR and colocalization analyses using data from the present GWAS and published GWAS meta-analyses on plasma proteins and modifiable factors.Results Genome-wide association study meta-analysis uncovered 17 bladder cancer susceptibility loci, of which 3 loci were novel. Genes were enriched in pathways related to the metabolic and catabolic processes of xenobiotics and cellular detoxification. Proteome-wide MR analysis based on cis-acting genetic variants revealed that higher plasma levels of glutathione S-transferases were strongly associated with a reduced risk of bladder cancer. There is strong evidence of colocalization between GSTM1 and bladder cancer. Finally, multivariable MR analyses of suspected risk factors for bladder cancer revealed independent causal associations between smoking and adiposity, particularly abdominal obesity, and risk of bladder cancer.Conclusions Findings from this large-scale GWAS and multivariable MR analyses highlight the key role of detoxification processes, particularly glutathione S-transferase 1, as well as smoking and abdominal obesity in bladder cancer etiology.

Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins.

Background: and Aims Total carbohydrate intake has been inconsistently associated with inflammatory bowel disease (IBD) risk in previous epidemiological studies. We aimed to evaluate the effects of glycemic index and glycemic load, 2 main indicators for measuring the quality and quantity of carbohydrates, on the risk of IBD subtypes (ie, Crohn's disease [CD] and ulcerative colitis [UC]).

Methods: We included 121 148 UK Biobank participants without IBD at baseline, and collected dietary information from a validated web-based 24-hour dietary recall questionnaire. Overall dietary glycemic index and glycemic load were estimated. Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Substitution analyses were conducted to test associations after replacing medium- or high-glycemic-index foods with low-glycemic-index foods.

Results: During a median follow-up of 10.6 years, 133 incident CD and 335 incident UC cases were identified. Dietary glycemic index was associated with UC but not CD. The HR of UC was 1.13 (95% CI, 1.01-1.27) per 1-SD increment and 1.46 (95% CI, 1.07-1.99) for the highest versus lowest quartile of glycemic index. Replacing medium or medium- and high-glycemic-index foods with low-glycemic-index foods was associated with a lower risk of UC. No significant associations were found between dietary glycemic load with risk of CD and UC.

Conclusions: A higher dietary glycemic index, but not glycemic load, is associated with an increased risk of UC, underscoring the importance of considering glycemic index in dietary recommendations for UC prevention.