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  • 1
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    Familial transmission of parental mood disorders: unipolar and bipolar disorders in offspring
    Wiley ; 2013
    In:  Bipolar Disorders Vol. 15, No. 7 ( 2013-11), p. 764-773
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    In: Bipolar Disorders, Wiley, Vol. 15, No. 7 ( 2013-11), p. 764-773
    Abstract: Offspring of depressed parents are at increased risk for psychiatric disorders. Although bipolar disorder ( BD ) and major depressive disorder ( MDD ) are both found in the same families, it is not clear whether transmission to offspring of BD or MDD tends to occur from parents with the same mood disorder subtype. Our primary hypothesis was that the offspring of parents with BD would be at increased risk for BD and other comorbid disorders common to BD, such as anxiety and substance use, relative to the offspring of parents with MDD . The offspring of parents with BD versus those with MDD were also hypothesized to be at greater risk for externalizing disorders (i.e., conduct disorder, attention‐deficit hyperactivity disorder, or antisocial personality disorder). Methods Parents (n = 320) with mood disorders and their offspring (n = 679) were studied. Adult offspring were administered the Structured Clinical Interview for DSM ‐ IV Axis I Disorders to establish the presence of psychopathology. Offspring aged 10–18 years were assessed using the School Aged Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, and parents of children under the age of ten completed the Child Behavioral Checklist. Data were examined using Cox proportional hazard regression. Results There was no difference in hazard of mood disorders in the offspring of parents with BD as compared to the offspring of parents with MDD . However, a number of other parent and offspring characteristics increased the risk of mood, anxiety, externalizing, and substance use disorders in the offspring, including self‐reported childhood abuse in the parent or offspring, offspring impulsive aggression, and the age at onset of parental mood disorder. Conclusions Mood disorders are highly familial, a finding that appears independent of whether the parent's condition is unipolar or bipolar, suggesting considerable overlap in the heritability of MDD and BD. Although parental characteristics had a limited influence on the risk of offspring psychopathology, reported childhood adversity, be it in the parent or child, is a harbinger of negative outcomes. These risk factors extend previous findings, and are consistent with diathesis–stress conceptualizations.
    Type of Medium: Online Resource
    ISSN: 1398-5647 , 1399-5618
    URL: Issue
    URL: Article
    DOI: 10.1111/bdi.2013.15.issue-7
    DOI: 10.1111/bdi.12107
    Language: English
    Publisher: Wiley
    Publication Date: 2013
    detail.hit.zdb_id: 2001157-X
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  • 2
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    Midlife plasma proteome‐wide analysis identifies peripheral immune networks associated with 25‐year dementia risk
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias. However, there is limited understanding of the biological pathways mechanistically relevant in the earliest phase of disease and a lack of protein biomarkers available to capture the biological systems involved. Method To discover early biomarkers and further understand on a molecular level the systemic factors that may promote neurodegeneration, we used a large‐scale proteomic platform to relate 4,877 plasma proteins measured in middle‐aged adults to dementia risk over a 25‐year period ( n =10,981; 1,874 incident dementia cases) in the Atherosclerosis Risk in Communities (ARIC) study ( Figure 1 ). Dementia‐associated proteins were related to 20‐year cognitive decline in the Whitehall II study, and to AD risk and CSF biomarkers European Medical Information Framework‐AD study. Result Proteome‐wide association study in ARIC discovered 32 midlife dementia‐associated plasma proteins, the majority of which were involved in either immune function, proteostasis/autophagy, or extracellular matrix organization ( Figure 2 ). We replicated the relationship between candidate proteins and neurocognitive outcomes in multiple independent cohorts and demonstrated a relationship between dementia‐associated plasma proteins and cerebrospinal fluid markers of Aß42, p‐tau181, neurodegeneration, and neuroinflammation ( Figure 3 ). Using network analysis, we identified 19 co‐expressed protein modules, 4 of which were strongly associated with either short‐term and long‐term dementia risk ( Figure 4 ). Pathway analyses conducted for the dementia‐associated protein modules suggested dysregulation of specific immune pathways (e.g., JAK‐STAT signaling, Toll‐like receptor activation) and disrupted proteostasis/autophagy and extracellular matrix organization during midlife ∼20 years before dementia onset, and abnormal coagulation/complement signaling ∼10 years before dementia onset ( Figure 5 ). We used two‐sample Mendelian randomization to identify which midlife plasma proteins and protein networks may play a mechanistic role in Alzheimer’s disease, and demonstrated that many of the dementia‐associated proteins may play a causal role in systemic inflammatory and autoimmune diseases associated with heightened AD/dementia risk. Conclusion This work sheds light on the complexity of the systemic immune response in the decades preceding dementia onset and highlights multiple potential biomarkers and therapeutic targets for early AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.060822
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Midlife proteome‐wide analysis identifies plasma biomarkers for 25‐year dementia risk linked to diverse pathophysiology
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD). However, there is limited understanding of the biological pathways mechanistically relevant in the earliest phase of disease and a lack of protein biomarkers available to capture the biological systems involved. Method To discover early biomarkers and further understand on a molecular level the systemic factors that may promote neurodegeneration, we used a large‐scale proteomic platform to relate 4,877 plasma proteins measured in middle‐aged adults to dementia risk over a 25‐year period ( n =10,981; 1,874 incident dementia cases) in the Atherosclerosis Risk in Communities (ARIC) study ( Figure 1 ). Associated proteins were related to 20‐year cognitive decline in the Whitehall II study, and to AD risk and CSF biomarkers in the European Medical Information Framework‐AD (EMIF‐AD) study. Result Proteome‐wide associations in ARIC discovered 32 dementia‐associated plasma proteins involved in proteostasis, immunity, synaptic function, and extracellular matrix organization ( Figure 2 ). We replicated the relationship between 15 candidate proteins and neurocognitive outcomes in Whitehall or EMIF‐AD, and demonstrated that dementia‐associated plasma proteins are associated with cerebrospinal fluid markers of Aß42, p‐tau181, neurodegeneration, and neuroinflammation ( Figure 3 ). We found many of the protein biomarkers were abnormally expressed in AD brain tissue, though some of the strongest midlife dementia‐associated proteins (e.g., GDF‐15) were not detected in brain. Using network analyses, we found an evolving plasma protein signature for dementia risk suggesting a dysregulation of specific immune pathways and disrupted proteostasis/autophagy and extracellular matrix organization in midlife ∼20 years before dementia onset, and abnormal coagulation/complement signaling ∼10 years before dementia onset ( Figure 4 ). We used two‐sample Mendelian randomization to identify which midlife plasma proteins and protein networks may play a causal role in Alzheimer’s disease and demonstrated that many of the dementia‐associated proteins may play a causal role in systemic (e.g., vascular, inflammatory) diseases associated with increased AD/dementia risk. We used the totality of evidence to prioritize midlife plasma proteins as AD/dementia biomarkers linked to discrete pathophysiological processes. Conclusion The current study identified multiple pathway‐specific biomarkers and potential therapeutic targets likely relevant in the earliest phase of the AD and related dementia.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.062935
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 4
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    Whole Exome Sequence Study of Mild Cognitive Impairment in African and European Americans; the Atherosclerosis Risk in Communities‐Neurocognitive Study
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S12 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S12 ( 2021-12)
    Abstract: Mild cognitive impairment (MCI) encompasses cognitive deficits beyond normal aging that minimally impact daily functioning. Uncovering the genetic architecture of MCI, which can progress to Alzheimer’s disease in some individuals, may facilitate the development of lifestyle and pharmacologic interventions to minimize cognitive impairment or prevent dementia. We conducted a whole exome sequence study of MCI in 1,144 African American (AA) and 3,358 European American (EA) participants aged 67‐90 years from the Atherosclerosis Risk in Communities‐Neurocognitive Study. Methods For both single‐variant and gene‐based tests, we employed seqMeta to perform race‐stratified analyses of functional (nonsynonymous, splicing, stopgain, stoploss, or frameshift) variants in each sex alone and both sexes combined. Models were adjusted for age, sex (except sex‐stratified models), field center, and population substructure (the first ten principal components). Logistic regression models were fit on autosomal single‐variants with minor allele frequency (MAF) ≥0.01 while SKAT‐O, T1 burden, and SKAT (beta weights and MAF ≤ 0.05) gene‐based tests were conducted. The significance and suggestive p‐value thresholds were 1.13E‐06 and 2.27E‐05 for single‐variant tests and 2.81E‐06 and 5.63E‐05 for gene‐based tests, respectively, after Bonferroni correction. Results The analysis sample contained 993 MCI cases and 3,509 cognitively normal participants; Table 1 contains the count for each race and sex subgroup. One significant (p‐value=1.06E‐7) single‐variant association (chr6:51712759:T:C in PKHD1 ) was detected in AA males (Figure 1). This variant had MAF=0.025 in AA males but was monomorphic in EA males. Four significant gene‐based associations with minor allele counts (MAC) ≥ 10 were discovered: CDC27 in AA females (SKAT‐O p‐value=6.63E‐07), C19orf18 in AA males (SKAT‐O p‐value=1.26E‐07), SLC16A10 in EA males and females combined (SKAT p‐value=1.90E‐06), and ZNF804A in EA females (T1 p‐value=2.69E‐07). Twenty‐three suggestive single‐variant and gene‐based associations with MAC ≥ 10 were identified (Figure 2). Conclusions MCI‐associated genes have diverse biological functions including cell division, sodium‐independent transportation of amino acids, and zinc finger binding. Our findings imply that the genetic underpinnings of MCI may differ by race and sex. External replication of our findings, as well as investigations using large samples in consortia, will provide insight into the pervasiveness of sex‐specific genetic effects in dementia‐related traits.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S12
    DOI: 10.1002/alz.058619
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 5
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    Pre‐Diagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization
    Wiley ; 2024
    In:  Arthritis Care & Research
    Details
    In: Arthritis Care & Research, Wiley
    Abstract: Our objective was to prospectively investigate pre‐diagnostic population‐based metabolome for risk of hospitalized gout (i.e., most accurate, severe, and costly cases), accounting for serum urate. Methods We conducted pre‐diagnostic metabolome‐wide analyses among 249,677 UK Biobank participants with NMR metabolomic profiling (N=168 metabolites, including eight amino acids) from baseline blood samples (2006‐2010), without a history of gout. We calculated multivariable hazard ratios (HRs) for incident hospitalized gout, before and after adjusting for serum urate levels; we included non‐hospitalised incident gout cases in a sensitivity analysis. Potential causal effects were evaluated with two‐sample Mendelian randomization. Results Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (N=2735) before urate adjustment, including glycine and glutamine (inversely; HR=0.64 [95% CI: 0.54, 0.75], P=8.3x10 ‐8 and HR=0.69 [0.61, 0.78], P=3.3x10 ‐9 between extreme quintiles, respectively), and glycoprotein acetyls (GlycA; HR=2.48 [2.15, 2.87], P=1.96x10 ‐34 ). Associations remained significant and directionally‐consistent following urate adjustment (HR=0.83 [0.70, 0.98], 0.86 [0.76, 0.98] , 1.41 [1.21, 1.63] between extreme quintiles), respectively; corresponding HR per SD were 0.91 (0.86, 0.97), 0.94 (0.91, 0.98), and 1.10 (1.06, 1.14). Findings persisted when including non‐hospitalised incident gout cases. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of ‐0.05 mg/dL (‐0.08, ‐0.01), and ‐0.12 mg/dL (‐0.22, ‐0.03), per SD of glycine and glutamine, respectively, and ORs 0.94 (0.88, 1.00), and 0.81 (0.67, 0.97), for gout. Conclusion These prospective findings with causal implications could lead to biomarker‐based risk prediction and potential supplementation‐based interventions with glycine or glutamine.
    Type of Medium: Online Resource
    ISSN: 2151-464X , 2151-4658
    URL: Article
    DOI: 10.1002/acr.25420
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2016713-1
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  • 6
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    Heritability analysis of nontraditional glycemic biomarkers in the Atherosclerosis Risk in Communities Study
    Wiley ; 2019
    In:  Genetic Epidemiology Vol. 43, No. 7 ( 2019-10), p. 776-785
    Details
    In: Genetic Epidemiology, Wiley, Vol. 43, No. 7 ( 2019-10), p. 776-785
    Abstract: Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5‐anhydroglucitol (1,5‐AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree‐based, SNP‐based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5‐AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study ( N  = 400 first‐degree relatives from sibships, N  = 5,575 unrelated individuals). Pedigree‐based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44–0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP‐based heritabilities (representing heritability from common variants) were lower than pedigree‐based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree‐based, 1.00 SNP‐based) and glycated albumin and 1,5‐AG (0.50 pedigree‐based, 0.47 SNP‐based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5‐AG and a portion of this heritability likely comes from common variants.
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Article
    DOI: 10.1002/gepi.v43.7
    DOI: 10.1002/gepi.22243
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1492643-X
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  • 7
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    Transcription Factor HNF4A Regulates Urate Transporter ABCG2
    Wiley ; 2019
    In:  The FASEB Journal Vol. 33, No. S1 ( 2019-04)
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    In: The FASEB Journal, Wiley, Vol. 33, No. S1 ( 2019-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v33.S1
    DOI: 10.1096/fasebj.2019.33.1_supplement.575.10
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 8
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    Proteomic profiling of cognitive function in middle‐aged and elderly adults
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S11 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S11 ( 2022-12)
    Abstract: Dementia is a pressing public health issue that affects 55 million adults worldwide. Some risk factors for cognitive decline and poor brain health appear to affect the blood brain barrier or cerebrovasculature. Therefore, it is plausible that circulating proteins may reflect causes and consequences of poor brain health. Identifying associated circulating proteins could help uncover important biological pathways in cognitive decline and dementia. Methods We conducted a cross‐sectional study of circulating proteins and cognitive function among participants without prevalent dementia or stroke in three cohorts: Atherosclerosis Risk in Communities (ARIC) study (n = 4,286), Cardiovascular Health Study (CHS, n = 2,297), and Framingham Heart Study (FHS, n = 706). Circulating proteins were quantified using a modified aptamer technology (SomaScan). Cognitive function was assessed by the first principal component (PC1) of measured cognitive scores from three different domains. We used linear regression to evaluate the association between each protein and PC1 controlling for age, sex, race, education level, and APOE Ɛ4 carrier status. We used fixed effect meta‐analysis to combine the cohort results from all age groups and two cohorts aged≥ 65. Statistical significance levels were Bonferroni corrected. Results The mean (SD) age in years was 74 (5) in ARIC, 75 (5) in CHS, and 46 (8) in FHS. Females comprised 58% of ARIC, 62% of CHS, and 55% of FHS. The number of proteins in common was 1,019 for all three cohorts and 4,672 for ≥65 years only. Meta‐analysis identified 76 significant proteins overall (p 〈 4.9E‐5 = 0.05/1,019) and 211 significant proteins among age ≥65 (p 〈 1.1E‐5 = 0.05/4,672). Among the significant associations, heterogeneity was moderate (median I2 of 78% in the overall meta‐analysis and 66% in the older age group). Some significant proteins are known biomarkers of dementia, such as GDF15 and SVEP1. Conclusions Large‐scale proteomic profiling identified plasma proteins significantly associated with cognitive function across 3 cohorts. Further replication and characterization, such as enrichment analysis, are underway to further elucidate the relationship between these associated circulating proteins and brain health.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S11
    DOI: 10.1002/alz.064952
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 9
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    Large‐scale plasma proteomic analysis identifies proteins and biological pathways associated with incident dementia : Biomarkers (non‐neuroimaging): Novel biomarkers
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S5 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: While plasma levels of several etiologically relevant molecules have been associated with Alzheimer’s disease and dementia more broadly, information about the full range of changes in the plasma proteome that precede dementia is lacking. Accordingly, this study used modified aptamer technology (SOMAscan) to examine the relationship between the plasma levels of 4,877 proteins and risk for incident dementia in a large community‐based sample. Methods Plasma levels of 4,877 proteins were measured in non‐demented participants who attended visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (2011‐2013; Figure 1A). We examined the association of log2 protein levels with incident dementia risk over 5 years using Cox proportional hazard models adjusted for demographic and cardiovascular risk factors. Dementia‐associated proteins were then measured from plasma samples collected 18 years earlier (visit 3; 1993‐1995) and related to dementia risk between visits 3 and 5 (Figure 1B). Candidate proteins were related to measures of brain structure (by MRI) and amyloid burden (by PET). Ingenuity Pathway Analyses and Mendelian randomization were used to inform biological pathways and causal relationships. Results Among 4,144 participants seen at visit 5 (age: 75 (SD 5)), there were 444 incident dementia cases over the next 5 years. In a proteome‐wide analysis, 50 proteins were significantly associated with incident dementia at a Bonferroni‐corrected threshold ( P 〈 1.03e‐05; Figure 2A). When these dementia‐associated proteins were measured in plasma collected almost 20 years earlier (n=11,069; 1,131 dementia cases), 21 of the 50 proteins continued to show a significant association with incident dementia ( P 〈 0.001; Figure 2B). We found causal associations with Alzheimer’s disease for two of the top five dementia‐associated proteins using Mendelian randomization, and we demonstrated a relationship between protein levels and neuroimaging measures of atrophy, white matter disease, and cerebral amyloid. A systems‐level analysis of dementia‐associated proteins implicated biological mechanisms involved in metabolic and inflammatory signaling, coagulation and prothrombin activation, and innate immune function, among others (Figure 3). Conclusions These findings provide insight into the plasma proteomic patterns that precede the onset of dementia in old age and middle age and highlight novel molecules and mechanistic pathways for further study.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S5
    DOI: 10.1002/alz.038307
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 10
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    Prediagnostic Glycoprotein Acetyl Levels and Incident and Recurrent Flare Risk Accounting for Serum Urate Levels: A Population‐Based , Prospective Study and Mendelian Randomization Analysis
    Wiley ; 2023
    In:  Arthritis & Rheumatology Vol. 75, No. 9 ( 2023-09), p. 1648-1657
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 75, No. 9 ( 2023-09), p. 1648-1657
    Abstract: To prospectively investigate population‐based metabolomics for incident gout and reproduce the findings for recurrent flares, accounting for serum urate. Methods We conducted a prediagnostic metabolome‐wide analysis among 105,615 UK Biobank participants with nuclear magnetic resonance metabolomic profiling data (168 total metabolites) from baseline blood samples collected 2006–2010 in those without history of gout. We calculated hazard ratios (HRs) for incident gout, adjusted for gout risk factors, excluding and including serum urate levels, overall and according to fasting duration before sample collection. Potential causal effects were tested with 2‐sample Mendelian randomization. Poisson regression was used to calculate rate ratios (RRs) for the association with recurrent flares among incident gout cases. Results Correcting for multiple testing, 88 metabolites were associated with risk of incident gout (N = 1,303 cases) before serum urate adjustment, including glutamine and glycine (inversely), and lipids, branched‐chain amino acids, and most prominently, glycoprotein acetyls (GlycA; P = 9.17 × 10 −32 ). Only GlycA remained associated with incident gout following urate adjustment (HR 1.52 [95% confidence interval (95% CI) 1.22–1.88] between extreme quintiles); the HR increased progressively with fasting duration before sample collection, reaching 4.01 (95% CI 1.36–11.82) for ≥8 hours of fasting. Corresponding HRs per SD change in GlycA levels were 1.10 (95% CI 1.04–1.17) overall and 1.54 (95% CI 1.21–1.96) for ≥8 hours of fasting. GlycA levels were also associated with recurrent gout flares among incident gout cases (RR 1.90 [95% CI 1.27–2.85] between extreme quintiles) with larger associations with fasting. Mendelian randomization corroborated a potential causal role for GlycA on gout risk. Conclusion This prospective, population‐based study implicates GlycA, a stable long‐term biomarker reflecting neutrophil overactivity, in incident and recurrent gout flares (central manifestation from neutrophilic synovitis) beyond serum urate. image
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v75.9
    DOI: 10.1002/art.42523
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2754614-7
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