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  • American Medical Association (AMA)  (2)
  • 1
    Online Resource
    Online Resource
    Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
    American Medical Association (AMA) ; 2023
    In:  JAMA Cardiology Vol. 8, No. 7 ( 2023-07-01), p. 674-
    Details
    In: JAMA Cardiology, American Medical Association (AMA), Vol. 8, No. 7 ( 2023-07-01), p. 674-
    Abstract: A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood. Objective To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy. Design, Setting, and Participants This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023. Exposures The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes. Results A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5] , 28.7 [5.6], 29.7 [7.0] , and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits ( NPPA , NPR3 , PLCE1 , TNS2 , FURIN , RGL3 , and PREX1 ). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta ( PGR , TRPC6 , ACTN4 , and PZP ), remodeling of uterine spiral arteries ( NPPA , NPPB , NPR3 , and ACTN4 ), kidney function ( PLCE1 , TNS2 , ACTN4 , and TRPC6 ), and maintenance of proteostasis in pregnancy serum ( PZP ). Conclusions and Relevance The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.
    Type of Medium: Online Resource
    ISSN: 2380-6583
    URL: Article
    DOI: 10.1001/jamacardio.2023.1312
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration
    American Medical Association (AMA) ; 2023
    In:  JAMA Ophthalmology Vol. 141, No. 5 ( 2023-05-01), p. 449-
    Details
    In: JAMA Ophthalmology, American Medical Association (AMA), Vol. 141, No. 5 ( 2023-05-01), p. 449-
    Abstract: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases. Objective To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants Using International Classification of Diseases, Ninth ( ICD-9 ) and Tenth ( ICD-10 ) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022. Main Outcomes and Measures Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study. Results A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5 ) and 3 novel loci were identified (near CD34/46 , NOTCH4 , and PREX1 ). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million] , 7.3 [0.6] vs 4.7 [3.7] ; P  = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P   & amp;lt; 7.1 × 10 −20 ). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P  = 7.4 × 10 −10 ). This association may have been mediated by loci containing complement genes. Conclusions and Relevance In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.
    Type of Medium: Online Resource
    ISSN: 2168-6165
    URL: Article
    DOI: 10.1001/jamaophthalmol.2023.0706
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    Location Call Number Limitation Availability
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