Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.
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ABSTRACT:
SUBMITTER: Van Driest SL
PROVIDER: S-EPMC4452656 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Project description:IntroductionSerum cystatin C can improve glomerular filtration rate (GFR) estimation over creatinine alone, but whether this translates into clinically relevant improvements in drug dosing is unclear.MethodsThis prospective cohort study enrolled adults receiving scheduled intravenous vancomycin while hospitalized at the Mayo Clinic in 2012. Vancomycin dosing was based on weight, serum creatinine with the Cockcroft-Gault equation, and clinical judgment. Cystatin C was later assayed from the stored serum used for the creatinine-based dosing. Vancomycin trough prediction models were developed by using factors available at therapy initiation. Residuals from each model were used to predict the proportion of patients who would have achieved the target trough with the model compared with that observed with usual care.ResultsOf 173 patients enrolled, only 35 (20%) had a trough vancomycin level within their target range (10 to 15 mg/L or 15 to 20 mg/L). Cystatin C-inclusive models better predicted vancomycin troughs than models based upon serum creatinine alone, although both were an improvement over usual care. The optimal model used estimated GFR by the Chronic Kidney Disease Epidemiology Collaborative (CKD-EPI) creatinine-cystatin C equation (R(2) = 0.580). This model is expected to yield 54% (95% confidence interval 45% to 61%) target trough attainment (P <0.001 compared with the 20% with usual care).ConclusionsVancomycin dosing based on standard care with Cockcroft-Gault creatinine clearance yielded poor trough achievement. The developed dosing model with estimated GFR from CKD-EPIcreatinine-cystatin C could yield a 2.5-fold increase in target trough achievement compared with current clinical practice. Although this study is promising, prospective validation of this or similar cystatin C-inclusive dosing models is warranted.
| S-EPMC4075252 | biostudies-literature
Project description:Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
| S-EPMC3605033 | biostudies-literature
Project description:BACKGROUND: Serum alkaline phosphatase (ALP) is a complex phenotype influenced by both genetic and environmental factors. Recent Genome-Wide Association Studies (GWAS) have identified several loci affecting ALP levels; however, such studies in Chinese populations are limited. We performed a GWAS analyzing the association between 658,288 autosomal SNPs and serum ALP in 1,461 subjects, and replicated the top SNPs in an additional 8,830 healthy Chinese Han individuals. The interactions between significant locus and environmental factors on serum ALP levels were further investigated. RESULTS: The association between ABO locus and serum ALP levels was replicated (P = 2.50 × 10?²¹, 1.12 × 10??? and 2.82 × 10?²? for SNP rs8176720, rs651007 and rs7025162 on ABO locus, respectively). SNP rs651007 accounted for 2.15% of the total variance of serum ALP levels independently of the other 2 SNPs. When comparing our findings with previously published studies, ethnic differences were observed across populations. A significant interaction between ABO rs651007 and overweight and obesity was observed (FDR for interaction was 0.036); for individuals with GG genotype, those with normal weight and those who were overweight or obese have similar serum ALP concentrations; minor allele A of rs651007 remarkably reduced serum ALP levels, but this effect was attenuated in overweight and obese individuals. CONCLUSIONS: Our findings indicate that ABO locus is a major determinant for serum ALP levels in Chinese Han population. Overweight and obesity modifies the effect of ABO locus on serum ALP concentrations.
| S-EPMC3851471 | biostudies-literature
Project description:Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10(-13)), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain approximately 18.0 and approximately 1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10(-13)), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.
| S-EPMC2701336 | biostudies-literature
Project description:A large-scale, genome-wide association study was performed to identify genetic variations influencing serum bilirubin levels using 8841 Korean individuals. Significant associations were observed at UGT1A1 (rs11891311, P = 4.78 x 10(-148)) and SLCO1B3 (rs2417940, P = 1.03 x 10(-17)), which are two previously identified loci. The two single-nucleotide polymorphisms (SNPs) were replicated (rs11891311, P = 3.18 x 10(-15)) or marginally significant (rs2417940, P = 8.56 x 10(-4)) in an independent cohort of 1096 individuals. In a conditional analysis adjusted for the top UGT1A1 variant (rs11891311), another variant in UGT1A1 (rs4148323, P = 1.22 x 10(-121)) remained significant; this suggests that in UGT1A1 at least two independent genetic variations influence the bilirubin levels in the Korean population. The protein coding variant rs4148323, which is monomorphic in European-derived populations, may be specifically associated with serum bilirubin levels in Asians (P = 2.56 x 10(-70)). The SLCO1B3 variant (rs2417940, P = 1.67 x 10(-18)) remained significant in a conditional analysis for the top UGT1A1 variant. Interestingly, there were significant differences in the associated variations of SLCO1B3 between Koreans and European-derived populations. While the variant rs2417940 at intron 7 of SLCO1B3 was more significantly associated in Koreans, variants rs17680137 (P = 0.584) and rs2117032 (P = 2.76 x 10(-5)), two of the top-ranked SNPs in European-derived populations, did not reach the genome-wide significance level. Also, variants in SLCO1B1 did not reach genome-wide significance in Koreans. Our result supports the idea that there are considerable ethnic differences in genetic association of bilirubin levels between Koreans and European-derived populations.
| S-EPMC2928134 | biostudies-literature
Project description:We carried out a genome-wide association study of serum aspartate aminotransferase (AST) activity in 866 Amish participants of the Heredity and Phenotype Intervention Heart Study and identified significant association of AST activity with a cluster of single nucleotide polymorphisms located on chromosome 10q24.1 (peak association was rs17109512; P=2.80E-14), in the vicinity of GOT1, the gene encoding cytosolic AST (cAST). Sequencing of GOT1 revealed an in-frame deletion of three nucleic acids encoding asparagine at position 389 c.1165_1167delAAC (p.Asn389del) in the gene. Deletion carriers had significantly lower AST activity levels compared with homozygotes for the common allele (mean±s.d.: 10.0±2.8 versus 18.8±5.2?U?l(-1); P=2.80E-14). Further genotyping of the deletion in other Amish samples (n=1932) identified an additional 20 carriers (minor allele frequency (MAF)=0.0052). The deletion was not detected in 647 outbred Caucasians. Asn at codon 389 is conserved among known mammalian cASTs. In vitro transient transfection of wild-type and mutant cAST indicated that mutant cAST protein was barely detectable in the cells. Furthermore, even after correction for cAST expression, mutant cAST had markedly diminished enzymatic activity. Remarkably, we did not find any association between the deletion and metabolic traits including serum fasting glucose or insulin, fasting and post-meal lipids, inflammatory markers, or sub-clinical markers of cardiovascular disease. In conclusion, we discovered a rare in-frame deletion in GOT1 gene, which inactivates cAST enzyme in the Old Order Amish. This finding will help us to understand structure and function of the enzyme and would be useful for predicting serum AST levels.
| S-EPMC3608855 | biostudies-literature
Project description:Calcium, magnesium, potassium, sodium, chloride and phosphorus are the major dietary minerals involved in various biological functions and are commonly measured in the blood serum. Sufficient mineral intake is especially important for children due to their rapid growth. Currently, the genetic mechanisms influencing serum mineral levels are poorly understood, especially for children. We carried out a genome-wide association (GWA) study on 5,602 European-American children and 4,706 African-American children who had mineral measures available in their electronic medical records (EMR). While no locus met the criteria for genome-wide significant association, our results demonstrated a nominal association of total serum calcium levels with a missense variant in the calcium -sensing receptor (CASR) gene on 3q13 (rs1801725, P = 1.96 × 10(-3)) in the African-American pediatric cohort, a locus previously reported in Caucasians. We also confirmed the association result in our pediatric European-American cohort (P = 1.38 × 10(-4)). We further replicated two other loci associated with serum calcium levels in the European-American cohort (rs780094, GCKR, P = 4.26 × 10(-3); rs10491003, GATA3, P = 0.02). In addition, we replicated a previously reported locus on 1q21, demonstrating association of serum magnesium levels with MUC1 (rs4072037, P = 2.04 × 10(-6)). Moreover, in an extended gene-based association analysis we uncovered evidence for association of calcium levels with the previously reported gene locus DGKD in both European-American children and African-American children. Taken together, our results support a role for CASR and DGKD mediated calcium regulation in both African-American and European-American children, and corroborate the association of calcium levels with GCKR and GATA3, and the association of magnesium levels with MUC1 in the European-American children.
| S-EPMC4401557 | biostudies-literature
Project description:Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33 × 10(-11) and P = 1.83 × 10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19 × 10(-22) to 5.62 × 10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.
| S-EPMC3441730 | biostudies-literature
Project description:Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.
| S-EPMC4309561 | biostudies-literature
Project description:Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women's Health Initiative (WHI). We tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p < 1 × 10(-5). None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003) in the second stage (WHI). Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11) and had p between 2.62 × 10(-7) and 4.04 × 10(-7) in the combined analysis (PLCO + WHI). Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.
| S-EPMC3708345 | biostudies-literature