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1.
Adv Clin Chem ; 101: 95-120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706891

RESUMO

Osteoarthritis (OA) is a multifactorial disease with huge phenotypic heterogeneity. The disease affects all tissues in the joint, and the loss of articular cartilage is its hallmark. The main biochemical components of the articular cartilage are type II collagen, aggrecan, and water. Transforming growth factor-beta (TGF-ß) signaling is one of the signaling pathways that maintains the healthy cartilage. However, the two subpathways of the TGF-ß signaling-TGF-ß and bone morphogenetic proteins (BMP) subpathways, lose their balance in OA, resulting an increased expression of cartilage degradation enzymes including matrix metallopeptidase 13 (MMP13), cathepsin B (CTSB), and cathepsin K (CTSK) and a decreased expression of aggrecan (ACAN). Thus, restoring the balance of two subpathways might provide a new avenue for treating OA patients. Further, metabolic changes are seen in OA and can be used to distinguish different subtypes of OA patients. Metabolomics studies showed that at least three endotypes of OA can be distinguished: 11% of OA patients are characterized by an elevated blood butyryl carnitine, 33% of OA patients have significant reduced arginine concentration, and 56% with metabolic alteration in phospholipid metabolism. While these findings need to be confirmed, they are promising personalized medicine tools for OA management.

2.
Arthritis Rheumatol ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760399

RESUMO

OBJECTIVES: Systemic inflammatory factors have been implicated in symptomatic hand osteoarthritis (SHOA). Gut microbiome dysbiosis promotes systematic inflammation. The aim of the study was to examine the association between gut microbiome with the presence of SHOA in a population-based study. METHODS: Study participants were derived from the Xiangya Osteoarthritis (XO) Study, a community-based observational study. SHOA was defined as the presence of both symptoms and radiographic osteoarthritis in the same hand. The gut microbiome was analyzed using 16S ribosomal RNA sequencing from stool samples. We examined the relation of α diversity, ß diversity, relative abundance of gut microbiome and potential bacterial functional pathways based on predictive metagenome profiling to SHOA. RESULTS: A total of 1,388 participants (women: 57.4%; mean age: 61.3 years; SHOA prevalence: 5.2%) were included. ß diversity, but not α diversity, was significantly associated with SHOA (P=0.003). Higher relative abundance of genus Bilophila and Desulfovibrio as well as lower relative abundance of genus Roseburia were associated with SHOA. Most Kyoto Encyclopedia of Genes and Genomes pathways altered in participants with SHOA belonged to amino acid, carbohydrate and lipid metabolic pathways. CONCLUSIONS: This large population-based study provides the first evidence that alteration of gut microbiome composition was observed among participants with SHOA, and low relative abundance of Roseburia but high relative abundance of Bilophila and Desulfovibrio at genus level were associated with prevalent SHOA. Our findings may help understand the role of microbiome in the development of SHOA and contribute to potential translational opportunities.

3.
Arthritis Res Ther ; 23(1): 59, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33610191

RESUMO

BACKGROUND: Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. METHODS: One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) were measured by enzyme-linked immunosorbent assay. RESULTS: rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10-10), while the levels of TNF-α, IL-6 and IL-1ß in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1ß protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04-0.19 and 4.42-16.82, respectively), but TNF-α and IL-6 became non-significant. CONCLUSIONS: Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

4.
J Arthroplasty ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33288389

RESUMO

BACKGROUND: While total joint replacement (TJR) is the most effective treatment for end-stage osteoarthritis (OA), one-third of patients do not experience clinically important improvement in pain or function following the surgery. Thus, it is important to identify factors for nonresponders and develop strategies to improve TJR outcomes. METHODS: Study participants were patients who underwent TJR (hip/knee) due to OA and completed the WOMAC before and on average 4 years after surgery. Nonresponders (pain nonresponders, function nonresponders, pain and function nonresponders) were determined using the WOMAC change score from baseline to follow-up under two previously reported criteria. Eighty-eight self-reported factors collected by a general health questionnaire were examined for associations with nonresponders. RESULTS: A total of 601 patients (30.8% hip and 69.2% knee replacement) were included; 18% of them were found to be either pain or function nonresponders. Nine factors were identified in the univariable analyses to be associated with nonresponders, and 5 of them (clinical depression, multisite musculoskeletal pain [MSMP], younger age, golfer's elbow, and driving more than 4 hours on average per working day) remained significant in the multivariable analyses in at least one of six categories. Clinical depression, having MSMP, and younger age were the major factors to be independently associated with nonresponders across five categories. In addition, two factors (age at menopause and age at hysterectomy) were significantly associated with female nonresponders. CONCLUSION: Our data suggested potential roles of pain perception, widespread pain sensitization, patient expectations, and early menopause in females in TJR outcomes, warranting further investigation.

5.
Pain ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33273416

RESUMO

Metabolic dysfunction has been suggested to be involved in musculoskeletal pain; however, few studies have identified metabolic markers associated with multisite musculoskeletal pain (MSMP). This study sought to identify metabolic marker(s) for MSMP by metabolomic analysis. The Tasmanian Older Adult Cohort Study (TASOAC) provided the discovery cohort with the Newfoundland Osteoarthritis Study (NFOAS) providing the replication cohort. MSMP was assessed by a self-reported pain questionnaire and defined as painful sites ≥4 in both TASOAC and NFOAS. Further, MSMP was also defined as painful sites ≥7, while non-MSMP was defined as either painful sites <7 or ≤1 in NFOAS. Serum samples of TASOAC received metabolic profiling using The Metabolomics Innovation Centre (TMIC) Prime Metabolomics Profiling Assay. The data on the identified metabolites were retrieved from NFOAS metabolomic database for the purpose of replication. A total of 409 participants were included in TASOAC, 38% of them had MSMP. Among the 143 metabolites assessed, 129 passed quality control and were included in the analysis. Sphingomyelin (SM) C18:1 was significantly associated with MSMP (OR per log µM increase=3.96, 95%CI, 1.95-8.22; p=0.0002). The significance remained in multivariable analysis (OR per log µM increase=2.70, 95%CI, 1.25-5.95). A total of 610 participants were included in NFOAS and the association with SM C18:1 was successfully replicated with three MSMP definitions (OR ranging from 1.89 to 2.82; all p<0.03). Our findings suggest that sphingomyelin metabolism is involved in the pathogenesis of MSMP and circulating level of SM C18:1 could serve as a potential marker in the management of MSMP.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33159799

RESUMO

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

7.
Pain ; 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32833795

RESUMO

Musculoskeletal pain often occurs simultaneously at multiple anatomical sites. The aim of the study was to identify metabolic biomarkers for multisite musculoskeletal pain (MSMP) by metabolomics with an extreme phenotype sampling strategy. The study participants (n = 610) were derived from the Newfoundland Osteoarthritis Study. Musculoskeletal pain was assessed using a self-reported pain questionnaire where painful sites were circled on a manikin by participants and the total number of painful sites were calculated. Targeted metabolomic profiling on fasting plasma samples was performed using the Biocrates AbsoluteIDQ p180 kit. Plasma cytokine concentrations including tumor necrosis factor-α, interleukin-6, interleukin-1ß, and macrophage migration inhibitory factor were assessed by enzyme-linked immunosorbent assay. Data on blood cholesterol profiles were retrieved from participants' medical records. Demographic, anthropological, and clinical information was self-reported. The number of reported painful sites ranged between 0 and 21. Two hundred and five participants were included in the analysis comprising 83 who had ≥7 painful sites and 122 who had ≤1 painful site. Women and younger people were more likely to have MSMP (P ≤ 0.02). Multisite musculoskeletal pain was associated with a higher risk of having incontinence, worse functional status and longer period of pain, and higher levels of low-density lipoprotein and non-high-density lipoprotein cholesterol (all P ≤ 0.03). Among the 186 metabolites measured, 2 lysophosphatidylcholines, 1 with 26 carbons with no double bond and 1 with 28 carbons with 1 double bond, were significantly and positively associated with MSMP after adjusting for multiple testing with the Bonferroni method (P ≤ 0.0001) and could be considered as novel metabolic markers for MSMP.

8.
J Rheumatol ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358162

RESUMO

OBJECTIVE: To identify plasma markers associated with an increased risk of radiographic knee osteoarthritis (OA) progression using a metabolomics approach. METHODS: Study participants were from the Multicenter Osteoarthritis Study (MOST) and were categorized into 2 groups based on the presence of baseline radiographic OA. Subjects in group 1 had unilateral knee OA and subjects in group 2 had bilateral knee OA. Progression was defined as a half-grade or greater worsening in joint space width at 30-month follow-up. For group 1, a participant progressed when their OA knee showed radiographic progression and the contralateral knee developed OA; for group 2, a participant progressed when both knees with OA showed radiographic progression. Metabolomic profiling was performed on plasma samples collected at baseline and logistic regression was performed to test the association between each metabolite and knee OA progression after adjustment for age, sex, BMI, and clinic site. Significance was defined as P ≤ 0.0003 in the combined analysis. RESULTS: There were 234 progressors (57 in group 1 and 177 in group 2) and 322 nonprogressors (206 in group 1 and 116 in group 2) included in the analyses. Among 157 metabolites studied, we found that odds of progression were 1.46 times higher per SD increase of phenylalanine level (95% CI 1.20-1.77, P = 0.0001) in the combined analysis. Sex-specific analysis showed that an association was seen in women (P = 0.0002) but not in men. CONCLUSION: Our data suggest that phenylalanine might be a novel plasma marker for higher risk of bilateral radiographic knee OA progression in women.

9.
Metabolomics ; 16(5): 61, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32335722

RESUMO

INTRODUCTION: Up to one third of total joint replacement patients (TJR) experience poor surgical outcome. OBJECTIVES: To identify metabolomic signatures for non-responders to TJR in primary osteoarthritis (OA) patients. METHODS: A newly developed differential correlation network analysis method was applied to our previously published metabolomic dataset to identify metabolomic network signatures for non-responders to TJR. RESULTS: Differential correlation networks involving 12 metabolites and 23 metabolites were identified for pain non-responders and function non-responders, respectively. CONCLUSION: The differential networks suggest that inflammation, muscle breakdown, wound healing, and metabolic syndrome may all play roles in TJR response, warranting further investigation.

10.
J Orthop Res ; 38(4): 793-802, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31743460

RESUMO

Although total joint replacement (TJR) surgery is considered as the most effective treatment for advanced osteoarthritis (OA) patients, up to one-third of patients reported unfavorable long-term post-operative pain outcomes. We aimed to identify metabolic biomarkers to predict non-responders to TJR using a metabolomics approach. TJR patients were recruited and followed-up at least 1-year post-surgery; TJR outcomes were assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Targeted metabolomic profiling was performed on plasma samples collected pre-surgery and pairwise metabolite ratios, as proxies for enzymatic reactions, were calculated. Association tests were performed between each metabolite ratio and non-responders. The metabolome-wide significance was defined as p < 2 × 10-5 . A total of 461 TJR patients due to primary OA were included in the analysis. Fifteen percent of patients were classified as pain non-responders; 16% were classified as function non-responders. Lower baseline WOMAC pain and function scores were significantly associated with pain and function non-responders, respectively (both p < 0.03). Two metabolite ratios were significantly associated with pain non-responders; acetylcarnitine (C2) to phosphatidylcholine acyl-alkyl C40:1 (PC ae C40:1) was five times higher in pain non-responders whereas phosphatidylcholine diacyl C36:4 (PC aa C36:4) to isoleucine was twenty one times lower in pain non-responders than responders (all p ≤ 1.93 × 10-5 ). One metabolite ratio, glutamine to isoleucine, was significantly lower in function non-responders than responders (eight times lower; p = 1.08 × 10-5 ). Three metabolite ratios (C2 to PC ae C40:1, PC aa C36:4, and glutamine to isoleucine) related to inflammation and muscle breakdown could be considered as novel plasma markers for predicting non-responders to TJR and warrant further investigation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:793-802, 2020.


Assuntos
Artroplastia de Substituição/efeitos adversos , Osteoartrite/cirurgia , Dor Pós-Operatória/sangue , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Osteoartrite/sangue , Dor Pós-Operatória/etiologia
11.
Arthritis Res Ther ; 21(1): 224, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694709

RESUMO

BACKGROUND: Identification of the optimal treatment for a given patient is of paramount importance. This is of particular relevance in osteoarthritis (OA) because of the high prevalence of the disease, extensive heterogeneity of the disease, and need for long-term treatment. The aim of the study was to examine whether serum lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio can predict clinical response to licofelone and naproxen treatments in symptomatic knee OA patients. METHODS: One hundred fifty-eight OA patients who completed the study according to protocol (ATP) of a previous 24-month clinical trial cohort comparing the effect of licofelone vs. naproxen in symptomatic knee OA patients were included. Symptomatic responses to either treatments were classified according to the OARSI-OMERACT criteria based on the WOMAC scores at 24 months. Total concentrations of PCs and lysoPCs were measured in the serum samples collected before the initiation of the treatments, and the lysoPCs to PCs ratio was calculated. Student's t test was utilized to compare the difference in the ratio of lysoPCs to PCs between the symptomatic responders and non-responders. Logistic regression was utilized to adjust for the potential confounders. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff of the ratio for prediction. RESULTS: Data showed that 61.4% of the patients symptomatically responded to licofelone and naproxen and 38.6% were deemed as therapeutic failures (non-responders). There was no difference in responders between licofelone and naproxen (p = 0.87). Responders had a significantly higher lysoPCs to PCs ratio than non-responders (0.097 ± 0.003 vs. 0.085 ± 0.003; p = 0.006). Patients with a ratio greater than the optimal cutoff of 0.088 had 2.93 times more likely to respond to licofelone and naproxen (p = 0.002). CONCLUSIONS: Serum lysoPCs to PCs ratio is a marker for response to licofelone and naproxen and may aid in the personalized treatment to knee OA.


Assuntos
Lisofosfatidilcolinas/sangue , Naproxeno/uso terapêutico , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/tratamento farmacológico , Fosfatidilcolinas/sangue , Pirróis/uso terapêutico , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Sci Rep ; 9(1): 9648, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273319

RESUMO

To identify serum biomarker(s) for predicting knee cartilage volume loss over time, we studied 139 knee osteoarthritis (OA) patients from a previous 24-month clinical trial cohort. Targeted metabolomic profiling was performed on serum collected at baseline. The pairwise metabolite ratios as proxies for enzymatic reaction were calculated and used in the analysis. Cartilage volume loss between baseline and 24 months was assessed quantitatively by magnetic resonance imaging (MRI). Data revealed an association between the serum ratio of lysophosphatidylcholine 18:2 (lysoPC 18:2) to phosphatidylcholine 44:3 (PC44:3) and the cartilage volume loss in the lateral compartment (ß = -0.21 ± 0.04, p = 8.53*10-7) and with joint degradation markers, COMP (r = 0.32, p = 0.0002) and MMP1 (r = 0.26, p = 0.002). The significance remained after adjustment for age, sex, BMI, diabetes, hypertension, dyslipidemia, and the treatment taken in the original study. As the ratio indicated the over activation of the conversion pathway of PC to lysoPC catalyzed by phospholipase A2 (PLA2), we assessed and found that a specific PLA2, PLA2G5, was significantly increased in human OA cartilage and synovial membrane (85% and 19% respectively, both p < 0.04) compared to controls, and its overexpression correlated with IL-6 (r = 0.63, p = 0.0008). Our data suggest that the serum lysoPC 18:2 to PC44:3 ratio is highly associated with a greater risk of cartilage volume loss of the knee and warrants further investigation in an independent cohort.


Assuntos
Cartilagem Articular/patologia , Articulação do Joelho/patologia , Lisofosfatidilcolinas/metabolismo , Osteoartrite do Joelho/patologia , Fosfatidilcolinas/metabolismo , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Articulação do Joelho/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Membrana Sinovial/metabolismo
13.
Metabolites ; 9(1)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634493

RESUMO

Sir Archibald Edward Garrod, who pioneered the field of inborn errors of metabolism and first elucidated the biochemical basis of alkaptonuria over 100 years ago, suggested that inborn errors of metabolism were "merely extreme examples of variations of chemical behavior which are probably everywhere present in minor degrees, just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carried out on exactly the same lines", and that this "chemical individuality [confers] predisposition to and immunities from various mishaps which are spoken of as diseases". Indeed, with advances in analytical biochemistry, especially the development of metabolomics in the post-genomic era, emerging data have been demonstrating that the levels of many metabolites do show substantial interindividual variation, and some of which are likely to be associated with common diseases, such as osteoarthritis (OA). Much work has been reported in the literature on the metabolomics of OA in recent years. In this narrative review, we provided an overview of the identified alteration of metabolic pathways in OA and discussed the role of those identified metabolites and related pathways in OA diagnosis, prognosis, and treatment.

14.
PLoS One ; 13(11): e0207775, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30500833

RESUMO

Females and males are known to have different abilities to cope with stress and disease. This study was designed to investigate the effect of sex on properties of a complex interlinked network constructed of central biochemical metabolites. The study involved the blood collection and analysis of a large set of blood metabolic markers from a total of 236 healthy participants, which included 140 females and 96 males. Metabolic profiling yielded concentrations of 168 metabolites for each subject. A differential correlation network analysis approach was developed for this study that allowed detection and characterization of interconnection differences in metabolites in males and females. Through topological analysis of the differential network that depicted metabolite differences in the sexes, we identified metabolites with high centralities in this network. These key metabolites were identified as 10 phosphatidylcholines (PCaaC34:4, PCaaC36:6, PCaaC34:3, PCaaC42:2, PCaeC38:1, PCaeC38:2, PCaaC40:1, PCaeC34:1, PC aa C32:1 and PC aa C40:6) and 4 acylcarnitines (C3-OH, C7-DC, C3 and C0). Identification of these metabolites may help further studies of sex-specific differences in the metabolome that may underlie different responses to stress and disease in males and females.


Assuntos
Redes e Vias Metabólicas , Metabolômica , Caracteres Sexuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Artigo em Inglês | MEDLINE | ID: mdl-30473679

RESUMO

Background: Our previous study of 29 obese food addiction (FA) patients found that FA is associated with lipid profiles and hormones which may be a factor in cardiovascular disease (CVD) and insulin resistance (IR). However, there is currently no data available regarding the relationship between FA symptoms and metabolic characteristics of CVD and IR in the general population. We designed this study to investigate the correlation between FA symptoms with lipid profiles and IR in men and women of the general Newfoundland population. Methods: 710 individuals (435 women and 275 men) recruited from the general Newfoundland population were used in analysis. FA symptoms were evaluated using the Yale Food Addiction Scale (YFAS). Glucose, insulin, HDL, LDL, total cholesterol and triglycerides levels were measured. IR was evaluated using the homeostatic model of assessment (HOMA). Participants were grouped by sex and menopausal status. Age, physical activity, calories and total % body fat were controlled. Results: Partial correlation analysis revealed that in men, YFAS symptom counts were significantly correlated with HOMA-ß (r = 0.196, p = 0.021), triglycerides (r = 0.140, p = 0.025) and inversely correlated with HDL (r = -0.133, p = 0.033). After separating by menopausal status, pre-menopausal women exhibited no correlations and post-menopausal women had a significantcorrelation with triglycerides (r = 0.198, p = 0.016). Conclusion: FA is significantly correlated with several markers of metabolic disturbance in men and to a lesser extent, post-menopausal women, in the general population. Further research is required to explain sex specific associations and elucidate any potentially causal mechanisms behind this correlation.

16.
PeerJ ; 6: e5854, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30397551

RESUMO

Colorectal cancer (CRC) has a high incident rate in both men and women and is affecting millions of people every year. Genome-wide association studies (GWAS) on CRC have successfully revealed common single-nucleotide polymorphisms (SNPs) associated with CRC risk. However, they can only explain a very limited fraction of the disease heritability. One reason may be the common uni-variable analyses in GWAS where genetic variants are examined one at a time. Given the complexity of cancers, the non-additive interaction effects among multiple genetic variants have a potential of explaining the missing heritability. In this study, we employed two powerful ensemble learning algorithms, random forests and gradient boosting machine (GBM), to search for SNPs that contribute to the disease risk through non-additive gene-gene interactions. We were able to find 44 possible susceptibility SNPs that were ranked most significant by both algorithms. Out of those 44 SNPs, 29 are in coding regions. The 29 genes include ARRDC5, DCC, ALK, and ITGA1, which have been found previously associated with CRC, and E2F3 and NID2, which are potentially related to CRC since they have known associations with other types of cancer. We performed pairwise and three-way interaction analysis on the 44 SNPs using information theoretical techniques and found 17 pairwise (p < 0.02) and 16 three-way (p ≤ 0.001) interactions among them. Moreover, functional enrichment analysis suggested 16 functional terms or biological pathways that may help us better understand the etiology of the disease.

17.
PLoS One ; 13(6): e0199618, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29958292

RESUMO

Multiple factors can help predict knee osteoarthritis (OA) patients from healthy individuals, including age, sex, and BMI, and possibly metabolite levels. Using plasma from individuals with primary OA undergoing total knee replacement and healthy volunteers, we measured lysophosphatidylcholine (lysoPC) and phosphatidylcholine (PC) analogues by metabolomics. Populations were stratified on demographic factors and lysoPC and PC analogue signatures were determined by univariate receiver-operator curve (AUC) analysis. Using signatures, multivariate classification modeling was performed using various algorithms to select the most consistent method as measured by AUC differences between resampled training and test sets. Lists of metabolites indicative of OA [AUC > 0.5] were identified for each stratum. The signature from males age > 50 years old encompassed the majority of identified metabolites, suggesting lysoPCs and PCs are dominant indicators of OA in older males. Principal component regression with logistic regression was the most consistent multivariate classification algorithm tested. Using this algorithm, classification of older males had fair power to classify OA patients from healthy individuals. Thus, individual levels of lysoPC and PC analogues may be indicative of individuals with OA in older populations, particularly males. Our metabolite signature modeling method is likely to increase classification power in validation cohorts.


Assuntos
Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/classificação , Artroplastia do Joelho , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Modelos Biológicos , Osteoartrite do Joelho/cirurgia
18.
Curr Rheumatol Rep ; 20(8): 51, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29951774

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to highlight recent evidence with respect to expression and metabolomic profiling in axial spondyloarthritis (axSpA) that included ankylosing spondylitis (AS). RECENT FINDINGS: AxSpA is not only characterized by the strongest genetic contribution for any complex rheumatic disease but is also influenced by environmental and immunological factors. Large-scale association-based studies have identified over 100 genetic variants contributing to 30% of the genetic risk of ankylosing spondylitis. Recent studies in global expression and metabolomic profiling appear to highlight common themes despite differences in tissues, populations, techniques, and relative paucity of patients in many of these studies. Expression studies support a role for immunomodulation and bone remodeling in the pathogenesis and progression of axSpA/AS, while metabolomic studies implicate the importance of the intestinal microbial metabolism as well as fat and choline metabolic pathways in AS.


Assuntos
Metaboloma , MicroRNAs/metabolismo , Espondilartrite/metabolismo , Progressão da Doença , Humanos , Metabolômica
19.
PLoS Comput Biol ; 14(3): e1005986, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29494586

RESUMO

Metabolomics studies use quantitative analyses of metabolites from body fluids or tissues in order to investigate a sequence of cellular processes and biological systems in response to genetic and environmental influences. This promises an immense potential for a better understanding of the pathogenesis of complex diseases. Most conventional metabolomics analysis methods exam one metabolite at a time and may overlook the synergistic effect of combining multiple metabolites. In this article, we proposed a new bioinformatics framework that infers the non-linear synergy among multiple metabolites using a symbolic model and subsequently, identify key metabolites using network analysis. Such a symbolic model is able to represent a complex non-linear relationship among a set of metabolites associated with osteoarthritis (OA) and is automatically learned using an evolutionary algorithm. Applied to the Newfoundland Osteoarthritis Study (NFOAS) dataset, our methodology was able to identify nine key metabolites including some known osteoarthritis-associated metabolites and some novel metabolic markers that have never been reported before. The results demonstrate the effectiveness of our methodology and more importantly, with further investigations, propose new hypotheses that can help better understand the OA disease.


Assuntos
Metaboloma , Metabolômica/métodos , Osteoartrite/metabolismo , Algoritmos , Bases de Dados Factuais , Humanos , Aprendizado de Máquina , Metaboloma/genética , Metaboloma/fisiologia , Curva ROC , Biologia de Sistemas
20.
BMC Cancer ; 18(1): 155, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409465

RESUMO

BACKGROUND: The rs2282679 A>C polymorphism in the vitamin D binding protein gene is associated with lower circulating levels of vitamin D. We investigated associations of this SNP with colorectal cancer (CRC) risk and survival and whether the associations vary by dietary vitamin D intake and tumor molecular phenotype. METHODS: A population-based case-control study identified 637 incident CRC cases (including 489 participants with follow-up data on mortality end-points) and 489 matched controls. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. Logistic regression examined the association between the rs2282679 polymorphism and CRC risk with inclusion of potential confounders. Kaplan-Meier curves and multivariable Cox models assessed the polymorphism relative to overall survival (OS) and disease-free survival (DFS). RESULTS: The rs2282679 polymorphism was not associated with overall CRC risk; there was evidence, however, of effect modification by total vitamin D intake (Pinteraction = 0.019). Survival analyses showed that the C allele was correlated with poor DFS (per-allele HR, 1.36; 95%CI, 1.05-1.77). The association of rs2282679 on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95%CI, 1.12-2.23). For OS, the C allele was associated with higher all-cause mortality among patients with higher levels of dietary vitamin D (HR, 2.11; 95%CI, 1.29-3.74), calcium (HR, 1.93; 95%CI, 1.08-3.46), milk (HR, 2.36; 95%CI, 1.26-4.44), and total dairy product intakes (HR, 2.03; 95%CI, 1.11-3.72). CONCLUSION: The rs2282679 SNP was not associated with overall CRC risk, but may be associated with survival after cancer diagnosis. The association of this SNP on survival among CRC patients may differ according to dietary vitamin D and calcium intakes and according to tumor BRAF mutation status.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Vitamina D/genética , Idoso , Estudos de Casos e Controles , Dieta , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem
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