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- Mahajan, Anubha, et al.
(författare)
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Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 636-646
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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| 2. |
- Carlander, C., et al.
(författare)
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Assessing cervical intraepithelial neoplasia as an indicator disease for HIV in a low endemic setting: a population-based register study
- 2017
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Ingår i: Bjog-an International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 124:11, s. 1680-1687
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To analyse whether the prevalence of undiagnosed HIV among (1) all women in Sweden and (2) migrant women, diagnosed with cervical intraepithelial neoplasia grade 2 or worse CIN2+ reaches the threshold of 0.1%, which has been suggested to be cost-effective for HIV testing. Design Population-based register study. Setting Counties of Stockholm and Gothenburg, Sweden, 1990-2014. Population All women, born between 1940 and 1990, with at least one cervical cytology or histology registered in the Swedish National Cervical Screening Register (NKCx). Methods Data were collected from the NKCx and the Swedish National HIV register. The proportion of women with undiagnosed HIV among women with CIN2+ compared with women with a normal/mildly abnormal cytology/histology was assessed. Results The proportion of undiagnosed HIV was higher among all women with CIN2+ than among those without CIN2+: 0.06% (95% CI 0.04-0.08) versus 0.04% (95% CI 0.04-0.04); P = 0.017). Among migrant women, the proportion of undiagnosed HIV was higher among those with CIN2+ than among those without [0.30% (95% CI 0.20-0.43) versus 0.08% (95% CI 0.07-0.10); P < 0.001] and exceeded 0.1%, suggesting the cost-effectiveness of HIV testing. Women with undiagnosed HIV at the time of CIN2+ had a significantly lower nadir CD4+ T-cell count, as a measure of immunosuppression, compared with women without CIN2+ before HIV diagnosis ( median nadir CD4, 95 cells/mm(3) versus 210 cells/mm(3); P < 0.01). Conclusions HIV testing should be performed in migrant women with unknown HIV status diagnosed with CIN2+.
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