| 1. |
- Aglago, Elom K., et al.
(författare)
-
A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
-
Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 2. |
- Carreras-Torres, Robert, et al.
(författare)
-
Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation, and immune response
- 2023
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 315-328
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Jiang, Lan, et al.
(författare)
-
Heparin mimetics as potential intervention for COVID-19 and their bio-manufacturing
- 2023
-
Ingår i: SYNTHETIC AND SYSTEMS BIOTECHNOLOGY. - : KEAI PUBLISHING LTD. - 2405-805X. ; 8:1, s. 11-19
-
Forskningsöversikt (refereegranskat)abstract
- The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy. Moreover, after more than 2 years, many populations are still under pressure of infection. Thus, a broader perspective in developing antiviral strategies is still of great importance. Inspired by the observed multiple benefits of heparin in the treatment of thrombosis, the potential of low molecular weight heparin (LMWH) for the treatment of COVID-19 have been explored. Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients, accordingly reducing lethality. Furthermore, several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of heparin and heparin mimetics in viral infection. These clinical observations and designed studies argue for the potential to develop heparin mimetics as anti-SARS-CoV-2 drug candidates. In this review, we summarize the properties of heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection, focusing on the perspectives of developing heparin mimetics via chemical synthesis, chemoenzymatic synthesis, and bioengineered production by microbial cell factories. The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.
|
|
| 4. |
- Li, Dongqing, et al.
(författare)
-
miR-19a/b and miR-20a promote wound healing by regulating the inflammatory response of keratinocytes
- 2021
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:3, s. 659-671
-
Tidskriftsartikel (refereegranskat)abstract
- Persistent and impaired inflammation impedes tissue healing and is characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. Here we show that in human wound-edge keratinocytes, the expression of miR-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, is upregulated during wound repair. However, their levels are lower in chronic ulcers than acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound-edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines/cytokines by keratinocytes. Thus, as crucial regulators of wound inflammation, lack of miR-19a/b and miR-20a may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.
|
|
| 5. |
- Tian, Yu, et al.
(författare)
-
Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
- 2024
-
Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130:10, s. 1687-1696
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 6. |
- Tian, Yu, et al.
(författare)
-
Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
- 2022
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:8, s. 1135-1148
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
|
|
| 7. |
- Tsilidis, Konstantinos K., et al.
(författare)
-
Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent : a Mendelian randomization study
- 2021
-
Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 113:6, s. 1490-1502
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
|
|
| 8. |
- Xia, Zhiyu, et al.
(författare)
-
Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.
- 2020
-
Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:10, s. 3563-3573
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ).CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
|
|
| 9. |
- Zhang, Tianji, et al.
(författare)
-
Interacting polymer-modification enzymes in heparan sulfate biosynthesis
- 2023
-
Ingår i: Carbohydrate Polymers. - : Elsevier. - 0144-8617 .- 1879-1344. ; 299
-
Tidskriftsartikel (refereegranskat)abstract
- Glucuronyl 5-epimerase (Hsepi) converts D-glucuronic acid (GlcA) into L-iduronic acid (IdoA) units, through a mechanism involving reversible abstraction of a proton at C5 of hexuronic acid residues. Incubations of a [4GlcA beta 1-4GlcNSO3 alpha 1-]n precursor substrate with recombinant enzymes in a D2O/H2O medium enabled an isotope exchange approach to the assessment of functional interactions of Hsepi with hexuronyl 2-O-sulfotrans-ferase (Hs2st) and glucosaminyl 6-O-sulfotransferase (Hs6st), both involved in the final polymer-modification steps. Enzyme complexes were supported by computational modeling and homogeneous time resolved fluores-cence. GlcA and IdoA D/H ratios related to product composition revealed kinetic isotope effects that were interpreted in terms of efficiency of the coupled epimerase and sulfotransferase reactions. Evidence for a func-tional Hsepi/Hs6st complex was provided by selective incorporation of D atoms into GlcA units adjacent to 6-O -sulfated glucosamine residues. The inability to achieve simultaneous 2-O-and 6-O-sulfation in vitro supported topologically separated reactions in the cell. These findings provide novel insight into the roles of enzyme in-teractions in heparan sulfate biosynthesis.
|
|
| 10. |
- Gu, Yeqing, et al.
(författare)
-
Consumption of ultraprocessed food and development of chronic kidney disease : the Tianjin Chronic Low-Grade Systemic Inflammation and Health and UK Biobank Cohort Studies
- 2023
-
Ingår i: The American journal of clinical nutrition. - : Elsevier BV. - 1938-3207 .- 0002-9165. ; 117:2, s. 373-382
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundMany ultraprocessed food (UPF)-derived by-products may play a role in the development of chronic kidney disease (CKD). Although several studies have assessed the association of UPFs with kidney function decline or CKD in various countries, no evidence has been shown in China and the United Kingdom.ObjectivesThis study aims to evaluate the association between UPF consumption and risk of CKD in 2 large cohort studies from China and the United Kingdom.MethodsIn total, 23,775 and 102,332 participants without baseline CKD were enrolled in the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) and UK Biobank cohort studies, respectively. Information on UPF consumption was obtained from a validated food frequency questionnaire in the TCLSIH and 24-h dietary recalls in the UK Biobank cohort. CKD was defined as an estimated glomerular filtration rate of ResultsAfter a median follow-up of 4.0 and 10.1 y, the incidence rates of CKD were around 1.1% and 1.7% in the TCLSIH and UK Biobank cohorts, respectively. The multivariable hazard ratio [95% confidence interval] of CKD across increasing quartiles (quartiles 1–4) of UPF consumption were 1 (reference), 1.24 (0.89, 1.72), 1.30 (0.91, 1.87), and 1.58 (1.07, 2.34) (P for trend = 0.02) in the TCLSIH cohort and 1 (reference), 1.14 (1.00, 1.31), 1.16 (1.01, 1.33), and 1.25 (1.09, 1.43) (P for trend < 0.01) in the UK Biobank cohort, respectively.ConclusionsOur finding indicated that higher UPF consumption is associated with a higher risk of CKD. Moreover, restricting UPF consumption may potentially benefit the prevention of CKD. Further clinical trials are required to clarify the causality.
|
|
