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- Alberts, R, et al.
(författare)
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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:8, s. 1517-1524
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Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
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| 3. |
- Skrastad, R. B., et al.
(författare)
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Risk assessment for preeclampsia in nulliparous women at 11-13weeks gestational age: prospective evaluation of two algorithms
- 2015
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Ingår i: BJOG: An International Journal of Obstetrics & Gynaecology. - : Wiley. - 1471-0528 .- 1470-0328. ; 122:13, s. 1781-1788
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo evaluate two algorithms for prediction of preeclampsia in a population of nulliparous women in Norway. DesignProspective screening study. SettingNational Centre for Fetal Medicine in Trondheim, Norway. PopulationFive hundred and forty-one nulliparous women. MethodsThe women were examined between 11(+0) and 13(+6)weeks with interviews for maternal characteristics and measurements of mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein A and placental growth factor. The First Trimester Screening Program version 2.8 by The Fetal Medicine Foundation (FMF) was compared with the Preeclampsia Predictor TM version 1 revision 2 by Perkin Elmer (PREDICTOR). Main outcome measuresPrediction of preeclampsia requiring delivery before 37weeks, before 42weeks and late preeclampsia (delivery after 34weeks). ResultsThe performance of the two algorithms was similar, but quite poor, for prediction of preeclampsia requiring delivery before 42weeks with an area under the curve of 0.77 (0.67-0.87) and sensitivity 40% (95% CI 19.1-63.9) at a fixed 10% false positive rate for FMF and 0.74 (0.63-0.84) and sensitivity 30% (95% CI 11.9-54.3) at a fixed 10% false positive rate for PREDICTOR. The FMF algorithm for preeclampsia requiring delivery <37weeks had an area under the curve of 0.94 (0.86-1.0) and sensitivity of 80% (95% CI 28.4-99.5) at a 10% fixed false positive rate. ConclusionsFetal Medicine Foundation and PREDICTOR algorithms had similar and only modest performance in predicting preeclampsia. The results indicate that the FMF algorithm is suitable for prediction of preterm preeclampsia.
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| 4. |
- Wang, J., et al.
(författare)
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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:11, s. 1396-1406
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Tidskriftsartikel (refereegranskat)abstract
- Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr(-/-) mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 x 10(-8)) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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