Low Levels of HDL in Fragile X Syndrome Patients.
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ABSTRACT:
SUBMITTER: Lisik MZ
PROVIDER: S-EPMC4735238 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
Publications
Low Levels of HDL in Fragile X Syndrome Patients.
Lisik Małgorzata Z MZ Gutmajster Ewa E Sieroń Aleksander L AL
Lipids 20151228 2
Fragile X syndrome (FXS) is the most common form of familial mental retardation and one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the CGG repeats in the promoter region of the FMR1 gene resulting in the transcriptional silencing of the gene in the pathophysiology of Fragile X syndrome was hypothesized. 23 male patients affected by Fragile X syndrome (full mutation in the FMR1 gene) and 24 controls were included in the study. The serum levels ...[more]
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Project description:BackgroundThe protective cardiovascular effect of high-density lipoproteins (HDLs) is considered to chiefly rely on reverse cholesterol transport from peripheral tissues back to the liver. However, HDL particles display pleiotropic properties, including anti-inflammatory, anti-apoptotic or antioxidant functions. Some studies suggest that HDL concentration decreases during sepsis, and an association was reported between low HDL levels and a poor outcome. Like sepsis, trauma is also associated with a systemic inflammatory response syndrome. However, no study has yet explored changes in lipid profiles during trauma. We sought to compare lipid profiles between sepsis and trauma patients in intensive care unit (ICU). In septic patients, we analyzed the association between lipid profile, severity and prognosis.MethodsA prospective, observational, single-centered study was conducted in a surgical ICU. For each patient, total cholesterol, HDL, triglyceride and low-density lipoprotein cholesterol levels were assessed at admission. Short-term prognosis outcome was prospectively assessed.ResultsSeventy-five consecutive patients were admitted (50 sepsis and 25 trauma). There was no difference in SOFA and SAPSII scores between the two groups. Patients with sepsis had lower total cholesterol levels than patients with trauma. Regarding the lipoprotein profile, only HDLs differed significantly between the two groups (median [IQR] = 0.33 mmol/l [0.17-0.78] in sepsis patients versus median [IQR] = 0.99 mmol/l [0.74-1.28] in trauma patients; P < 0.0001). Whereas ICU mortality was not associated with lipid levels in the sepsis group, a significant negative correlation was found between HDL concentration and the length of ICU stay (r = -0.35; P = 0.03) in the group of survivor septic patients at ICU discharge. In addition, poor outcome defined as death or a SOFA score >6 at day 3 was associated with lower HDL levels (median [IQR] = 0.20 mmol/l [0.11-0.41] vs. 0.35 mmol/l [0.19-0.86] in patients with poor outcome versus others; P = 0.03).ConclusionsLipid profile was totally different between sepsis and trauma in ICU patients: HDL levels were low in septic patients, whereas their concentration was not altered in trauma patients. This major difference reinforces the necessity to explore the therapeutic potential of HDL in sepsis.
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| S-EPMC10501784 | biostudies-literature
Project description:BACKGROUND:Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls. METHODS:We have used a sensitive and robust Electro Chemi Luminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n = 25 FXS patients and n = 29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals. RESULTS:While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Using robust regression, we show that six of these biomarkers (CCL2, CCL3, CCL11, CCL22, CCL26 and CXCL10) were negatively associated with FXS diagnosis. Finally, applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories. CONCLUSIONS:Our data show that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.
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Project description:Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.
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| S-EPMC7602182 | biostudies-literature
Project description:Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.
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Project description:Background & aimsDysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis.MethodsA total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0.ResultsSixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (p <0.001). In addition, they presented with increased glycated haemoglobin levels and lower 25-OH vitamin D levels (p <0.05). Intriguingly, patients with higher liver fibrosis scores who subsequently developed HCC had lower HDL-cholesterol (HDL-c) levels at time 0 (p <0.001). Furthermore, in the 484 patients presenting with lower HDL-c at baseline, we found that waist circumference, and then vitamin D and glycated haemoglobin levels, were significantly different in those who developed HCC, regardless of liver fibrosis (p <0.05).ConclusionsThis study identifies HDL-c as a bona fide novel marker to predict HCC in patients with NAFLD. Increased waist circumference and deranged metabolic pathways represent additional predisposing factors among patients with low HDL-c, highlighting the importance of studying cholesterol metabolism and integrating clinical approaches with dietary regimens and a healthy lifestyle to prevent HCC.Impact and implicationsVisceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.
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Project description:Few data has been available on the effect of serum HDL-C levels on the prognosis of lupus nephritis (LN) patients. The present study therefore aimed to explore the effect of serum HDL-C levels on LN patients.We included 775 patients with follow-up information registered in an LN database between 1 January 2006 and 31 December 2011. The patients were divided into groups with low, intermediate and high HDL-C, according to NCEP ATPIII criteria. Cox regression analyses were used to explore the effects of HDL-C levels on end-stage renal disease (ESRD), all-cause mortality and cardiovascular disease (CVD) mortality.During a median follow-up of 56 months (3-206 months), 71 (9.2%) had ESRD. 84 (10.8%) deaths occurred, 17 (20.2%) of which were due to CVD. There was no statistically significant association of HDL-C category or continuous HDL-C levels with ESRD in the total cohort, but in subgroup analyses by eGFR, with each 0.1 mmol/L increase in HDL-C level, adjusted HRs for ESRD were 0.92 (95% CI: 0.83-1.04, P?=?0.173) for eGFR ?60 ml/min/1.73m2 and 1.11 (95% CI: 1.01-1.23, P?=?0.036) for eGFR <60 ml/min/1.73m2. The effect of the interaction between eGFR category and serum HDL-C level on ESRD was statistically significant (??=?-1.738, P?=?0.005). Low HDL-C was associated with all-cause mortality (HR?=?2.16, 95% CI: 1.06-4.40, P?=?0.033) with intermediate HDL-C as reference category after adjusting for several variables.Our results demonstrate that high HDL-C levels were associated with increased risk of ESRD in LN patients with advanced renal dysfunction. While low HDL-C levels were associated with increased risk of all-cause mortality in LN patients.ClinicalTrials.gov Identifier: NCT03001973 , 22 December 2016 retrospectively registered.
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Project description:Background. Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients. Methods. A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8-28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8-38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C. Results. Total cholesterol (TC) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p < 0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP, p = 0.01, OR: 0.74 (CI: 0.6-0.93); DBP, p = 0.023, OR: 1.45 (CI: 1.05-2.0)]. Conclusion. Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP.
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Project description:BackgroundLow levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling.MethodsIn the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses.ResultsIn observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74-0.86, p = 4 × 10-9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74-0.86, p = 2 × 10-4), and critical care admission with sepsis (HR 0.72 95% CI 0.60-0.85, p = 2 × 10-4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89-1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75-1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57-0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count - 0.16, 95% CI - 0.10 to - 0.21 per natural log change in SD-scaled CRP, p = 9 × 10-8).and total HDL particle count (beta - 0.13, 95% CI - 0.09 to - 0.17, p = 7 × 10-10), but that the reverse effect of HDL on IL-6 signalling was largely null.ConclusionsLow number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.
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