| 41. |
- Lascorz, Jesus, et al.
(författare)
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Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility
- 2010
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 31:9, s. 1612-1619
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Tidskriftsartikel (refereegranskat)abstract
- Genetic susceptibility accounts for similar to 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P-trend = 2.2 x 10(-16), ORper allele = 1.34, 95% CI 1.11-1.61).
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| 42. |
- Lascorz, Jesus, et al.
(författare)
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Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer
- 2012
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis. Methods: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort). Results: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were similar to 2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model). Conclusions: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed.
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| 43. |
- Næss, Sigrid, et al.
(författare)
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Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.
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| 44. |
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| 45. |
- Pattaro, Cristian, et al.
(författare)
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A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level
- 2010
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 11, s. 41-
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Tidskriftsartikel (refereegranskat)abstract
- Background Serum creatinine (SCR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in SCR level is explicable by genetic factors. Methods We performed a meta-analysis of genome-wide association studies of SCR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts'). Results After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10-6 and 1.7 × 10-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated. Conclusions While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level.
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| 46. |
- Petersson, Joel, et al.
(författare)
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Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash
- 2009
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 46:8, s. 1068-1075
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Tidskriftsartikel (refereegranskat)abstract
- Recently, it has been suggested that the supposedly inert nitrite anion is reduced in vivo to form bioactive nitric oxide with physiological and therapeutic implications in the gastrointestinal and cardiovascular systems. Intake of nitrate-rich food such as vegetables results in increased levels of circulating nitrite in a process suggested to involve nitrate-reducing bacteria in the oral cavity. Here we investigated the importance of the oral microflora and dietary nitrate in regulation of gastric mucosal defense and blood pressure. Rats were treated twice daily with a commercial antiseptic mouthwash while they were given nitrate-supplemented drinking water. The mouthwash greatly reduced the number of nitrate-reducing oral bacteria and as a consequence, nitrate-induced increases in gastric NO and circulating nitrite levels were markedly reduced. With the mouthwash the observed nitrate-induced increase in gastric mucus thickness was attenuated and the gastroprotective effect against an ulcerogenic compound was lost. Furthermore, the decrease in systemic blood pressure seen during nitrate supplementation was now absent. These results suggest that oral symbiotic bacteria modulate gastrointestinal and cardiovascular function via bioactivation of salivary nitrate. Excessive use of antiseptic mouthwashes may attenuate the bioactivity of dietary nitrate.
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| 47. |
- Petersson, J, et al.
(författare)
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Importance and regulation of the colonic mucus barrier in a mouse model of colitis.
- 2011
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Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 300:2
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Tidskriftsartikel (refereegranskat)abstract
- The colonic mucus layer serves as an important barrier and prevents colonic bacteria from invading the mucosa and cause inflammation. The regulation of colonic mucus secretion is poorly understood. The aim of this study was to investigate the role of the mucus barrier in induction of colitis. Furthermore, regulation of mucus secretion by luminal bacterial products was studied. The colon of anesthetized Muc2(-/-), Muc1(-/-), wild-type (wt), and germ-free mice was exteriorized, the mucosal surface was visualized, and mucus thickness was measured with micropipettes. Colitis was induced by DSS (dextran sodium sulfate, 3%, in drinking water), and disease activity index (DAI) was assessed daily. The colonic mucosa of germ-free and conventionally housed mice was exposed to the bacterial products LPS (lipopolysaccharide) and PGN (peptidoglycan). After DSS induction of colitis, the thickness of the firmly adherent mucus layer was significantly thinner after 5 days and onward, which paralleled the increment of DAI. Muc2(-/-) mice, which lacked firmly adherent mucus, were predisposed to colitis, whereas Muc1(-/-) mice were protected with significantly lower DAI by DSS compared with wt mice. The mucus barrier increased in Muc1(-/-) mice in response to DSS, whereas significantly fewer T cells were recruited to the inflamed colon. Mice housed under germ-free conditions had an extremely thin adherent colonic mucus layer, but when exposed to bacterial products (PGN or LPS) the thickness of the adherent mucus layer was quickly restored to levels observed in conventionally housed mice. This study demonstrates a correlation between decreasing mucus barrier and increasing clinical symptoms during onset of colitis. Mice lacking colonic mucus (Muc2(-/-)) were hypersensitive to DSS-induced colitis, whereas Muc1(-/-) were protected, probably through the ability to increase the mucus barrier but also by decreased T cell recruitment to the afflicted site. Furthermore, the ability of bacteria to regulate the thickness of the colonic mucus was demonstrated.
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| 48. |
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| 49. |
- Reinisch, Walter, et al.
(författare)
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Clinical Practice of Adalimumab and Infliximab Biosimilar Treatment in Adult Patients With Crohn's Disease
- 2021
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Ingår i: Inflammatory Bowel Diseases. - : Lippincott-Raven Publishers. - 1078-0998 .- 1536-4844. ; 27:1, s. 106-122
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Tidskriftsartikel (refereegranskat)abstract
- The introduction of tumor necrosis factor (TNF) inhibitors has significantly changed the treatment landscape in Crohn's disease (CD). The overall therapeutic achievements with TNF inhibitors such as infliximab, adalimumab, and certolizumab pegol paved the way to push the boundaries of treatment goals beyond symptomatic relief and toward cessation of objective signs of inflammation, including endoscopic remission. Even though these agents are widely used for the treatment of moderate to severe CD, heterogeneity still exists in translating evidence-based guidelines on the use of anti-TNF agents into actual treatment algorithms in CD. This might be due to several reasons including disparities in health expenditure policies; lack of harmonization between countries; and variations in assessment of disease severity, use of disease monitoring tools, or application of treatment targets by physicians. With the advent of biosimilars, patent-free versions of reference biologics are now available to minimize health inequalities in drug availability. In this context, this article aims to provide practical clinical guidance for the use of infliximab and adalimumab biosimilars in patients with moderate to severe CD by outlining different clinical scenarios that patients may encounter during their treatment journey.
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| 50. |
- Salmela, Elina, et al.
(författare)
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Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe
- 2008
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Ingår i: PLOS ONE. - San Fransisco : Public library of science. - 1932-6203. ; 3:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations.Principal Findings: In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (F(ST) = 0.0040, p < 10(-4)), also between Eastern and Western Finland (F(ST) = 0.0032, p < 10(-3)). The latter indicated the existence of a relatively strong autosomal substructure within the country, similar to that observed earlier with smaller numbers of markers. The Germans and British were less differentiated than the Swedes, Western Finns and especially the Eastern Finns who also showed other signs of genetic drift. This is likely caused by the later founding of the northern populations, together with subsequent founder and bottleneck effects, and a smaller population size. Furthermore, our data suggest a small eastern contribution among the Finns, consistent with the historical and linguistic background of the population.Significance: Our results warn against a priori assumptions of homogeneity among Finns and other seemingly isolated populations. Thus, in association studies in such populations, additional caution for population structure may be necessary. Our results illustrate that population history is often important for patterns of genetic variation, and that the analysis of hundreds of thousands of SNPs provides high resolution also for population genetics.
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