Quantile-Dependent Expressivity of Serum Uric Acid Concentrations.
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ABSTRACT: Objective
"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., serum uric acid) is high or low relative to its distribution. Analyses were performed to test whether serum uric acid heritability is quantile-specific and whether this could explain some reported gene-environment interactions.Methods
Serum uric acid concentrations were analyzed from 2151 sibships and 12,068 offspring-parent pairs from the Framingham Heart Study. Quantile-specific heritability from offspring-parent regression slopes (β OP, h 2 = 2β OP/(1 + r spouse)) and full-sib regression slopes (β FS, h 2 = {(1 + 8r spouse β FS)0.5 - 1}/(2r spouse)) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.Results
Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring's sex- and age-adjusted uric acid distribution when estimated from β OP (P trend = 0.001): 0.34 ± 0.03 at the 10th, 0.36 ± 0.03 at the 25th, 0.41 ± 0.03 at the 50th, 0.46 ± 0.04 at the 75th, and 0.49 ± 0.05 at the 90th percentile and when estimated from β FS (P trend = 0.006). This is consistent with the larger genetic effect size of (1) the SLC2A9 rs11722228 polymorphism in gout patients vs. controls, (2) the ABCG2 rs2231142 polymorphism in men vs. women, (3) the SLC2A9 rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the ABCG2 rs6855911 polymorphism in obese vs. nonobese women, and (5) the LRP2 rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an SLC2A9/PKD2/ABCG2 haplotype for high vs. low intakes of alcohol, chicken, or processed meats.Conclusions
Heritability of serum uric acid concentrations is quantile-specific.
SUBMITTER: Williams PT
PROVIDER: S-EPMC8448993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (h 2) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown.MethodsSerum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (βFS, h 2 ={(1 + 8rspouseβFS)0.5 - 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h 2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.ResultsQuantile-specific h 2 (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from βOP (P trend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from βFS (P trend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile.ConclusionHeritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.
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Project description:PURPOSE:"Quantile-dependent expressivity" describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject's triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual's genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs. RESULTS:Consistent with the phenomenon, genetic effect sizes increased (P?0.05) with increasing triglyceride concentrations for polymorphisms associated with ABCA1, ANGPTL4, APOA1, APOA2, APOA4, APOA5, APOB, APOC3, APOE, CETP, FABP2, FATP6, GALNT2, GCKR, HL, IL1b, LEPR, LOX-1, LPL, MC4R, MTTP, NPY, SORT1, SULF2, TNFA, TCF7L2, and TM6SF2. The effect size for these polymorphisms showed a progressively increasing dose-response, with intermediate effect sizes at intermediate triglyceride concentrations. Quantile-dependent expressivity provided an alternative interpretation to their interactions with sex, drugs, disease, diet, and age, which have been traditionally ascribed to gene-environment interactions and genetic predictors of drug efficacy (i.e., personalized medicine). CONCLUSION:Quantile-dependent expressivity applies to the majority of genetic variants affecting postprandial triglycerides, which may arise because the impaired functionalities of these variants increase at higher triglyceride concentrations. Purported gene-drug interactions may be the manifestations of quantile-dependent expressivity, rather than genetic predictors of drug efficacy.
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Project description:BackgroundThe phenotypic expression of a high-density lipoprotein (HDL) genetic risk score has been shown to depend upon whether the phenotype (HDL-cholesterol) is high or low relative to its distribution in the population (quantile-dependent expressivity). This may be due to the effects of genetic mutations on HDL-metabolism being concentration dependent.MethodThe purpose of this article is to assess whether some previously reported HDL gene-lifestyle interactions could potentially be attributable to quantile-dependent expressivity.SummarySeventy-three published examples of HDL gene-lifestyle interactions were interpreted from the perspective of quantile-dependent expressivity. These included interactive effects of diet, alcohol, physical activity, adiposity, and smoking with genetic variants associated with the ABCA1, ADH3, ANGPTL4, APOA1, APOA4, APOA5, APOC3, APOE, CETP, CLASP1, CYP7A1, GALNT2, LDLR, LHX1, LIPC, LIPG, LPL, MVK-MMAB, PLTP, PON1, PPARα, SIRT1, SNTA1,and UCP1genes. The selected examples showed larger genetic effect sizes for lifestyle conditions associated with higher vis-à-vis lower average HDL-cholesterol concentrations. This suggests these reported interactions could be the result of selecting subjects for conditions that differentiate high from low HDL-cholesterol (e.g., lean vs. overweight, active vs. sedentary, high-fat vs. high-carbohydrate diets, alcohol drinkers vs. abstainers, nonsmokers vs. smokers) producing larger versus smaller genetic effect sizes. Key Message: Quantile-dependent expressivity provides a potential explanation for some reported gene-lifestyle interactions for HDL-cholesterol. Although overall genetic heritability appears to be quantile specific, this may vary by genetic variant and environmental exposure.
| S-EPMC8116986 | biostudies-literature
Project description:BACKGROUND:Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. RESULTS:We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid (?2df2=3545, p=3.19×10-23). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women (3.974.935.87 [ 2.55097.5 denoting percentiles], p=4.57×10-23) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes (?2df2=3190,p=7.23×10-08). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude (1.414.707.88, p=5.46×10-03). CONCLUSIONS:This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.
| S-EPMC4118309 | biostudies-literature
Project description:Background:"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability (h2 ) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined. Methods:Plasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (? OP,h2 = 2? OP/(1 + rspouse)) and full-sib regression slopes (? FS, h2 = {(1 + 8rspouse ? FS)0.05-1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. Results:Quantile-specific h2 (± SE) increased with increasing percentiles of the offspring's age- and sex-adjusted adiponectin distribution when estimated from ? OP (P trend = 2.2 × 10-6): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from ? FS (P trend = 7.6 × 10-7): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin's: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations. Conclusion:Adiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.
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Project description:BackgroundAlthough hyperuricemia frequently associates with respiratory diseases, patients with severe coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) can show marked hypouricemia. Previous studies on the association of serum uric acid with risk of adverse outcomes related to COVID-19 have produced contradictory results. The precise relationship between admission serum uric acid and adverse outcomes in hospitalized patients is unknown.MethodsData of patients affected by laboratory-confirmed COVID-19 and admitted to Leishenshan Hospital were retrospectively analyzed. The primary outcome was composite and comprised events, such as intensive care unit (ICU) admission, mechanical ventilation, or mortality. Logistic regression analysis was performed to explore the association between serum concentrations of uric acid and the composite outcome, as well as each of its components. To determine the association between serum uric acid and in-hospital adverse outcomes, serum uric acid was also categorized by restricted cubic spline, and the 95% confidence interval (CI) was used to estimate odds ratios (OR).ResultsThe study cohort included 1854 patients (mean age, 58 years; 52% women). The overall mean ± SD of serum levels of uric acid was 308 ± 96 µmol/L. Among them, 95 patients were admitted to ICU, 75 patients received mechanical ventilation, and 38 died. In total, 114 patients reached composite end-points (have either ICU admission, mechanical ventilation or death) during hospitalization. Compared with a reference group with estimated baseline serum uric acid of 279-422 µmol/L, serum uric acid values ≥ 423 µmol/L were associated with an increased risk of composite outcome (OR, 2.60; 95% CI, 1.07- 6.29) and mechanical ventilation (OR, 3.01; 95% CI, 1.06- 8.51). Serum uric acid ≤ 278 µmol/L was associated with an increased risk of the composite outcome (OR, 2.07; 95% CI, 1.18- 3.65), ICU admission (OR, 2.18; 95% CI, 1.17- 4.05]), and mechanical ventilation (OR, 2.13; 95% CI, 1.06- 4.28), as assessed by multivariate analysis.ConclusionsThis study shows that the association between admission serum uric acid and composite outcome of COVID-19 patients was U-shaped. In particular, we found that compared with baseline serum uric acid levels of 279-422 µmol/L, values ≥ 423 µmol/L were associated with an increased risk of composite outcome and mechanical ventilation, whereas levels ≤ 278 µmol/L associated with increased risk of composite outcome, ICU admission and mechanical ventilation.
| S-EPMC8134697 | biostudies-literature
Project description:Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer's disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N?=?1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (?=?0.006; p?=?0.03) and visuospatial abilities (?=?0.007; p?=?0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p?=?0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women.
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Project description:The aim of the study was to evaluate sleep duration and sleep variability in relation to serum uric acid (SUA) concentrations and SUA to creatinine ratio. This is a cross-sectional analysis of baseline data from 1842 elderly participants with overweight/obesity and metabolic syndromein the (Prevención con Dieta Mediterránea) PREDIMED-Plus trial. Accelerometry-derived sleep duration and sleep variability were measured. Linear regression models were fitted to examine the aforementioned associations. A 1 hour/night increment in sleep duration was inversely associated with SUA concentrations (? = 0.07, p = 0.047). Further adjustment for leukocytes attenuated this association (p = 0.050). Each 1-hour increment in sleep duration was inversely associated with SUA to creatinine ratio (? = 0.15, p = 0.001). The findings of this study suggest that longer sleep duration is associated with lower SUA concentrations and lower SUA to creatinine ratio.
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Project description:Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children.The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study.We conducted a genomewide association study with 1.1 million genetic markers in 815 children.We found serum uric acid to be significantly heritable [h(2) ± SD = 0.45 ± 0.08, P = 5.8 × 10(-11)] and associated with SLC2A9 variants (P values between 10(-16) and 10(-7)). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (?G = 0.45, P = 0.002), percentage of body fat (?G = 0.28, P = 0.04), fat mass (?G = 0.34, P = 0.02), waist circumference (?G = 0.42, P = 0.003), and waist-to-height ratio (?G = 0.46, P = 0.001).Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children.
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Project description:OBJECTIVE:We aimed to investigate the difference in serum uric acid(SUA)levels between subtypes of depression and normal population, and whether SUA can be used to identify bipolar disorder depressive episode and major depressive disorder and predict the length of hospital stay. METHODS:1543 depression patients and 1515 healthy controls were obtained according to the entry and exclusion criteria from one mental health center of a tertiary hospital in southwestern China. The diagnosis and classification of depression was in accordance with ICD-10. The SUA value was derived from fasting plasma samples analysis. The level of SUA of all the participants was quantified using Roche cobas8000-c702-MSB automatic biochemical analyzer. Data were analyzed by SPSS18.0 statistical software package. RESULTS:Overall, the level of SUA in patients with depression was lower than that in normal control. Specifically, males' SUA levels were in the interval of [240, 323.3) and [323.3, 406.6), and women were in the [160, 233.3] levels. The SUA level of bipolar disorder depressive episode was higher compared to major depressive disorder level. Interestingly, male patients who were hospitalized for two weeks had higher SUA than those who were hospitalized for three weeks or four weeks. CONCLUSIONS:Our results suggest that the length of hospital stay may be associated with SUA, and when it is difficult to make a differential diagnosis of bipolar disorder depressive episode and major depressive disorder, the level of SUA may be considered. The adjustment of SUA as a method for treating depression needs to be carefully assessed.
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