Browsing by Author "Sheng, Xin"

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    Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease
    (Oxford University Press, 2022) Laster, Marciana L.; Rowan, Bryce; Chen, Hua-Chang; Schwantes-An, Tae-Hwi; Sheng, Xin; Friedman, Peter A.; Ikizler, T. Alp; Sinshiemer, Janet S.; Ix, Joachim H.; Susztak, Katalin; de Boer, Ian H.; Kestenbaum, Bryan; Hung, Adriana; Moe, Sharon M.; Perwad, Farzana; Robinson-Cohen, Cassianne; Medicine, School of Medicine
    Context: Chronic kidney disease (CKD) causes multiple interrelated disturbances in mineral metabolism. Genetic studies in the general population have identified common genetic variants associated with circulating phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). Objective: In this study we aimed to discover genetic variants associated with circulating mineral markers in CKD. Methods: We conducted candidate single-nucleotide variation (SNV) analysis in 3027 participants in the multiethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNVs and circulating levels of mineral markers. Results: SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites. The strongest associations (P < .001) were at rs4074995 (RGS14) for phosphate (0.09 mg/dL lower per minor allele) and FGF23 (8.6% lower), and at rs1801725 (CASR) for calcium (0.12 mg/dL higher). In addition, the prevalence of hyperparathyroidism differed by rs4074995 (RGS14) genotype (chi-square P < .0001). Differential inheritance by race was noted for the minor allele of RGS14. Expression quantitative loci (eQTL) analysis showed that rs4074995 was associated with lower RGS14 gene expression in glomeruli (P = 1.03 × 10-11) and tubules (P = 4.0 × 10-4). Conclusion: We evaluated genetic variants associated with mineral metabolism markers in a CKD population. Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism. The minor allele of RGS14 was also associated with lower gene expression in the kidney. Further studies are needed to elucidate the effect of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.
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    Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths
    (American Society of Hematology, 2019-08-27) Karaesmen, Ezgi; Hahn, Theresa; Dile, Alexander James; Rizvi, Abbas A.; Wang, Junke; Wang, Tao; Haagenson, Michael D.; Preus, Leah; Zhu, Qianqian; Liu, Qian; Yan, Li; Liu, Song; Haiman, Christopher A.; Stram, Daniel; Pooler, Loreall; Sheng, Xin; Van Den Berg, David; Brock, Guy; Webb, Amy; McCarthy, Philip L.; Pasquini, Marcelo C.; Spellman, Stephen R.; Lee, Stephanie J.; Paczesny, Sophie; Sucheston-Campbell, Lara E.; Pediatrics, School of Medicine
    Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of IL1RL1 in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in IL1RL1 correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and P values were corrected for multiple comparisons. Donor risk alleles in rs22441131 (P meta = .00026) and rs2310241 (P meta = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 (P meta = 9.7 × 10-7), rs13019803 (P meta = 8.9 × 10-6), and rs13015714 (P meta = 5.3 × 10-4) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.
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    Validation of genetic associations with acute GVHD and nonrelapse mortality in DISCOVeRY-BMT
    (American Society of Hematology, 2019-08-13) Tang, Hancong; Hahn, Theresa; Karaesmen, Ezgi; Rizvi, Abbas A.; Wang, Junke; Paczesny, Sophie; Wang, Tao; Preus, Leah; Zhu, Qianqian; Wang, Yiwen; Haiman, Christopher A.; Stram, Daniel; Pooler, Loreall; Sheng, Xin; Van Den Berg, David; Brock, Guy; Webb, Amy; Pasquini, Marcelo C.; McCarthy, Philip L.; Spellman, Stephen R.; Sucheston-Campbell, Lara E.; Pediatrics, School of Medicine