ABSTRACT
The aim of this study was to provide an efficient tool: reliable, able to increase the molecular diagnosis performance, to facilitate the detection of copy number variants (CNV), to assess genetic risk scores (wGRS) and to offer the opportunity to explore candidate genes. Custom SeqCap EZ libraries, NextSeq500 sequencing and a homemade pipeline enable the analysis of 311 dyslipidemia-related genes. In the training group (48 DNA from patients with a well-established molecular diagnosis), this next-generation sequencing (NGS) workflow showed an analytical sensitivity >99% (n = 532 variants) without any false negative including a partial deletion of one exon. In the prospective group, from 25 DNA from patients without prior molecular analyses, 18 rare variants were identified in the first intention panel genes, allowing the diagnosis of monogenic dyslipidemia in 11 patients. In six other patients, the analysis of minor genes and wGRS determination provided a hypothesis to explain the dyslipidemia. Remaining data from the whole NGS workflow identified four patients with potentially deleterious variants. This NGS process gives a major opportunity to accede to an enhanced understanding of the genetic of dyslipidemia by simultaneous assessment of multiple genetic determinants.
Subject(s)
DNA Copy Number Variations/genetics , Dyslipidemias/genetics , Genetic Diseases, Inborn/diagnosis , High-Throughput Nucleotide Sequencing/methods , Dyslipidemias/diagnosis , Dyslipidemias/pathology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Genetic Testing , Humans , Male , Sequence Analysis, DNA/methodsABSTRACT
The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.
Subject(s)
Adaptor Proteins, Signal Transducing , Diabetes Mellitus, Type 2 , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Carrier Proteins/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/therapy , Genetic Predisposition to Disease , Glucokinase/metabolism , Humans , Hypoglycemic Agents/pharmacology , Intracellular Signaling Peptides and Proteins , Metabolomics , MiceABSTRACT
BACKGROUND: The request to lose weight is expanding not only in obese and morbidly obese patients but also in overweight patients affected by co-morbidities as diabetes and hypertension and who do not tolerate diet regimen or lifestyle changes. The aim of this study is a multicenter evaluation of outcomes of intragastric balloon in overweight patients. METHODS: Patients (BMI 27-30 kg/m2) treated with a BioEnterics Intragastric Balloon (BIB) between 1996 and 2010 were extracted from the database of the participating centres in Rome (Italy), Liège (Belgium) and Madrid (Spain). Primary endpoints were the efficacy and safety at 6 and 42 months from balloon positioning. Secondary endpoints included resolution of co-morbidities. RESULTS: A total of 261 patients were included in this study. The most common indication for balloon placement was a psychological disorder (54%). Mean body mass index (BMI) fell from 28.6 ± 0.4 at baseline to 25.4 ± 2.6 kg/m2 at 6 months and to 27.0 ± 3.1 kg/m2 at 3 years from BIB removal. The mean %EWL was 55.6% at 6 months and 29.1% at 3 years. Forty-seven patients (18%) had complications associated with placement of the intragastric balloon (leak = 28, intolerance = 14, duodenal ulcer = 2, gastritis = 1, oesophagitis = 1, duodenal polyps = 1). The rate of patients with hypertension decreased from 29% at baseline to 16% at 3 years. Diabetes decreased from 15 to 10%, dyslipidaemia decreased from 20 to 18%, hypercholesterolaemia decreased from 32 to 21% and osteoarthropathy decreased from 25 to 13%. CONCLUSIONS: The intragastric balloon is safe and effective in overweight patients, helping to reduce progression to obesity and decreasing the prevalence of a number of important co-morbidities.
