| 1. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 2. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 3. |
- Zheng, Fenglian, et al.
(författare)
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Structural and functional hippocampal alterations in Multiple sclerosis and neuromyelitis optica spectrum disorder
- 2022
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Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 28:5, s. 707-717
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC (p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS (p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS (R = -0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.
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| 4. |
- Fang, Li Tai, et al.
(författare)
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Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing
- 2021
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1151-1160
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking 'tumor-only' or 'matched tumor-normal' analyses. The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.
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| 5. |
- Liu, Zhenzhong, et al.
(författare)
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Study of natural attenuation after acid in situ leaching of uranium mines using isotope fractionation and geochemical data
- 2023
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 865, s. 161033-
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Tidskriftsartikel (refereegranskat)abstract
- Acid in situ leaching (AISL) is a subsurface mining approach suitable for low-grade ores which does not generate tail-ings, and has been adopted widely in uranium mining. However, this technique causes an extremely high concentra-tion of contaminants at post-mining sites and in the surroundings soon after the mining ceases. As a potential AISL remediation strategy, natural attenuation has not been studied in detail. To address this problem, groundwater collected from 26 wells located within, adjacent, upgradient, and downgradient of a post-mining site were chosen to analyze the fate of U(VI), SO42-, delta 34S, and delta 238U, to reveal the main mechanisms governing the migration and atten-uation of the dominant contaminants and the spatio-temporal evolutions of contaminants in the confined aquifer of the post-mining site. The delta 238U values vary from -0.07 %o to 0.09 %o in the post-mining site and from -1.43 %o to 0.03 %o around the post-mining site. The delta 34S values were found to vary from 3.3 %o to 6.2 %o in the post-mining site and from 6.0 %o to 11.0 %o around the post-mining site. Detailed analysis suggests that there are large differences between the range of isotopic composition variation and the range of pollutants concentration distribution, and the es-timated Rayleigh isotope fractionation factor is 0.9994-0.9997 for uranium and 1.0032-1.0061 for sulfur. The isotope ratio of uranium and sulfur can be used to deduce the migration history of the contaminants and the irreversibility of the natural attenuation process in the anoxic confined aquifer. Combining the isotopic fractionation data for U and S with the concentrations of uranium and sulfate improved the accuracy of understanding of reducing conditions along the flow path. The study also indicated that as long as the geological conditions are favorable for redox reactions, natural attenuation could be used as a cost-effective remediation scheme.
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| 6. |
- Xiao, Wenming, et al.
(författare)
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Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing
- 2021
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1141-1150
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Tidskriftsartikel (refereegranskat)abstract
- Recommendations are given on optimal read coverage and selection of calling algorithm to maximize the reproducibility of cancer mutation detection in whole-genome or whole-exome sequencing. Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.
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| 7. |
- Lee, Hanna, et al.
(författare)
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Metabolic phenotype and microbiome of infants fed formula containing Lactobacillus paracasei strain F-19
- 2022
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Ingår i: Frontiers in Pediatrics. - : Frontiers Media S.A.. - 2296-2360. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Early childhood nutrition drives the development of the gut microbiota. In contrast to breastfeeding, feeding infant formula has been shown to impact both the gut microbiota and the serum metabolome toward a more unfavorable state. It is thought that probiotics may alter the gut microbiota and hence create a more favorable metabolic outcome. To investigate the impact of supplementation with Lactobacillus paracasei spp. paracasei strain F-19 on the intestinal microbiota and the serum metabolome, infants were fed a formula containing L. paracasei F19 (F19) and compared to a cohort of infants fed the same standard formula without the probiotic (SF) and a breast-fed reference group (BF). The microbiome, as well as serum metabolome, were compared amongst groups. Consumption of L. paracasei F19 resulted in lower community diversity of the gut microbiome relative to the SF group that made it more similar to the BF group at the end of the intervention (4 months). It also significantly increased lactobacilli and tended to increase bifidobacteria, also making it more similar to the BF group. The dominant genus in the microbiome of all infants was Bifidobacterium throughout the intervention, which was maintained at 12 months. Although the serum metabolome of the F19 group was more similar to the group receiving the SF than the BF group, increases in serum TCA cycle intermediates and decreases in several amino acids in the metabolome of the F19 group were observed, which resulted in a metabolome that trended toward the BF group. Overall, L. paracasei F19 supplementation did not override the impact of formula-feeding but did impact the microbiome and the serum metabolome in a way that may mitigate some unfavorable metabolic impacts of formula-feeding.
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| 8. |
- Lee, Hanna, et al.
(författare)
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Milk Fat Globule Membrane as a Modulator of Infant Metabolism and Gut Microbiota : A Formula Supplement Narrowing the Metabolic Differences between Breastfed and Formula-Fed Infants
- 2021
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Ingår i: Molecular Nutrition & Food Research. - : Wiley-VCH Verlagsgesellschaft. - 1613-4125 .- 1613-4133. ; 65:3
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Tidskriftsartikel (refereegranskat)abstract
- Scope Milk fat globule membrane (MFGM) is an important component of milk that has previously been removed in the manufacture of infant formulas, but has recently gained attention owing to its potential to improve immunological, cognitive, and metabolic health. The goal of this study is to determine whether supplementing MFGM in infant formula would drive desirable changes in metabolism and gut microbiota to elicit benefits observed in prior studies. Methods and Results The serum metabolome and fecal microbiota are analyzed using H-1 NMR spectroscopy and 16S rRNA gene sequencing respectively in a cohort of Chinese infants given a standard formula or a formula supplemented with an MFGM-enriched whey protein fraction. Supplementing MFGM suppressed protein degradation pathways and the levels of insulinogenic amino acids that are typically enhanced in formula-fed infants while facilitating fatty acid oxidation and ketogenesis, a feature that may favor brain development. MFGM supplementation did not induce significant compositional changes in the fecal microbiota but suppressed microbial diversity and altered microbiota-associated metabolites. Conclusion Supplementing MFGM in a formula reduced some metabolic gaps between formula-fed and breastfed infants.
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| 9. |
- Li, Xiaonan, et al.
(författare)
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Serum cytokine patterns are modulated in infants fed formula with probiotics or milk fat globule membranes : A randomized controlled trial
- 2021
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Proteins and lipids of milk fat globule membrane (MFGM) and probiotics are immunomodulatory. We hypothesized that Lactobacillus paracasei ssp. paracasei strain F19 (F19) would augment vaccine antibody and T helper 1 type immune responses whereas MFGM would produce an immune response closer to that of breastfed (BF) infants.Objective: To compare the effects of supplementing formula with F19 or bovine MFGM on serum cytokine and vaccine responses of formula-fed (FF) and BF infants.Design: FF infants were randomized to formula with F19 (n = 195) or MFGM (n = 192), or standard formula (SF) (n = 194) from age 21±7 days until 4 months. A BF group served as reference (n = 208). We analyzed seven cytokines (n = 398) in serum at age 4 months using magnetic bead-based multiplex technology. Using ELISA, we analyzed anti-diphtheria IgG (n = 258) and anti-poliovirus IgG (n = 309) concentrations in serum before and after the second and third immunization, respectively.Results: Compared with SF, the F19 group had greater IL-2 and lower IFN-γ concentrations (p<0.05, average effect size 0.14 and 0.39). Compared with BF, the F19 group had greater IL-2, IL-4 and IL-17A concentrations (p<0.05, average effect size 0.42, 0.34 and 0.26, respectively). The MFGM group had lower IL-2 and IL-17A concentrations compared with SF (p<0.05, average effect size 0.34 and 0.31). Cytokine concentrations were comparable among the MFGM and BF groups. Vaccine responses were comparable among the formula groups.Conclusions: Contrary to previous studies F19 increased IL-2 and lowered IFN-γ production, suggesting that the response to probiotics differs across populations. The cytokine profile of the MFGM group approached that of BF infants, and may be associated with the previous finding that infectious outcomes for the MFGM group in this cohort were closer to those of BF infants, as opposed to the SF group. These immunomodulatory effects support future clinical evaluation of infant formula with F19 or MFGM.
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| 10. |
- Li, Yongmei, et al.
(författare)
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Update to the Newly Developed Expression for the Stability Ratio of Colloidal Dispersions
- 2023
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 39:15, s. 5284-5293
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Tidskriftsartikel (refereegranskat)abstract
- The colloidal stability, one of the basic and important properties of a colloidal dispersion, is commonly evaluated in terms of the stability ratio. In this study, a recently developed expression for the stability ratio is updated, by reformulating the fraction of successful collisions leading to secondary minimum coagulation. The updated formula reinterprets the statistical meaning of the fraction of successful collisions leading to primary or secondary minimum coagulation, ensuring that the total fraction of successful collisions is always less than or equals to 1. It was shown to be superior to the available expressions in accounting for the contribution of the primary and secondary minimum coagulations on the stability ratio. It can well interpret the stability of colloidal dispersions of spherical particles; moreover, it is of great potential to be applied to colloidal dispersions of plate-like particles. In addition, this formula is found to be consistent with the concept of the critical coagulation concentration and well interpret the effects of particle size, counterion valence, surface potential, and Hamaker constant on the colloidal stability.
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