Functional Follow-up of Genetic Variants Using FTO as the Prime Example

2013 ◽  
pp. 113-125
Author(s):  
Stefanie Seehaus ◽  
Ulrich Rüther
Keyword(s):  
Genetic Variants

scholarly journals Dietary patterns modify the association between fat mass and obesity-associated genetic variants and changes in obesity phenotypes

2019 ◽  
Vol 121 (11) ◽  
pp. 1247-1254
Author(s):  
Firoozeh Hosseini-Esfahani ◽  
Glareh Koochakpoor ◽  
Parvin Mirmiran ◽  
Maryam S. Daneshpour ◽  
Fereidoun Azizi
Keyword(s):  
Fat Mass ◽  
Dietary Patterns ◽  
Genetic Variants ◽  
Genetic Risk Score ◽  
Fast Foods ◽  
Risk Alleles ◽  
Vegetables And Fruits ◽  
Harmful Effects ◽  
Dietary Data

AbstractThe present study investigated whether dietary patterns could interact with fat mass and obesity-associated (FTO) polymorphisms in relation to changes in BMI and waist circumference (WC) over 3⋅6 years of follow-up. Subjects were selected from participants of the Tehran Lipid and Glucose Study (n 4292, 43⋅2 % male). Dietary data were collected using a valid and reliable FFQ. Dietary patterns were determined using factor analysis. The genotypes of polymorphisms (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973 and rs3751812) were determined. Genetic risk score (GRS) was calculated using the weighted method. Mean ages of men and women were 42·6 (sd 14) and 40⋅4 (sd 13) years, respectively. The healthy (e.g. vegetables and fruits) and the Western dietary patterns (WDP; e.g. soft drinks and fast foods) were extracted. In carriers of the risk alleles rs1121980, rs1421085, rs8050136, rs1781799 and rs3751812, BMI was approximately 2-fold higher in individuals in the higher quartile of WDP score, compared with the first quartile (P < 0⋅05). WC increased with increasing WDP score in carriers of the risk alleles rs1121980 and rs3751812, but not in individuals who did not carry any risk alleles. BMI and WC increased to a greater extent in the high GRS group while increasing quartiles of the WDP score, compared with the low GRS group (BMI change; Q1: 1⋅04 (se 0⋅34) v. Q4: 2⋅26 (se 0⋅36)) (WC change; Q1: 0⋅47 (se 0⋅32) v. Q4: 0⋅95 (se 0⋅34)) (P interaction < 0⋅05). These results suggest that adults with higher genetic predisposition to obesity are more susceptible to the harmful effects of adherence to the WDP, which emphasised the need to reduce the consumption of unhealthy foods for the prevention of obesity.

A Genetic Risk Score for Insulin Resistance Identify Patients with Chronic Myeloid Leukemia, Treated with Nilotinib, Developing Diabetes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3098-3098
Author(s):  
Bruno Martino ◽  
Claudia Labate ◽  
Caterina Alati ◽  
Domenica Ielo ◽  
Carmelo Laganà ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Risk Score ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Risk Allele ◽  
Genetic Risk Score ◽  
First Line ◽  
Predictive Values ◽  
Overt Diabetes

Abstract BACKGROUD: Nilotinib, a potent 2nd generation tyrosin kinase inhibitor, is efficacious in the treatment of chronic myelogenous leukemia (CML). Impaired glucose metabolism represents one of the most frequently observed adverse events and several clinical trials, reported a high diabetes incidence during treatment with this drug. The mechanism of this side effect is poorly understood, but recently has been hypothesized an increased postreceptorial insulin resistence. Moreover, "in vitro"results indicated that c-ABL is involved in the insulin receptor signaling pathway. A large number of genetic variants associated with Type 2 diabetes (T2D) are implicated in beta-cell function but the role of common genetic variants associated with insulin resistance in the etiology of T2D, remains poorly documented. Scott R. and al. (Diabetes 2014) recently identified 10 multiple single nucleotide polymorphisms (SNPs) associated with insulin resistance and created a genetic risk scores (uGRS) as complementary tool to for insulin resistance. AIM of the study was to identify whether this uGRS could be a valid prognostic tool in identifying patients developing diabetes during Nilotinib therapy PATIENTS AND METHODS:45 patients (19 males) were included in the study. Twenty-four were treated with Nilotinib in first-line and 21 as second line (10 for resistance, 8 intolerance and 3 for other reasons). None of the subjects studied had abnormal blood glucose or took any antidiabetic drug before Nilotinib treatment. We genotyped all patients with the GRS created by Scott R. including those in, or near, the IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes that have primary effects on subcutaneous adipocyte function. Also we added 2 new variants, one for TCF7L2 gene, associated with insulin secretion and another in FTO gene, whose effect on insulin levels is mediated by BMI. The uGRS was calculated, as previously reported, by summing the number of risk alleles across the 12 variants (0 for risk allele absent, 1 for heterozygosity and 2 for homozygosity for risk allele). A cut-off point for uGRS, maximizing predictivity and sensitivity of the score was calculated using Youden's index. Diabetes and impaired fasting Glycaemia were defined using the American Diabetes association (ADA) criteria. Data were reported as median and range, RESULTS:Age at diagnosis was 45(18-82) years, the Sokal was low in 16 (42%), intermediate in 12 (26%) and high in 17 (32%) patients. During treatment and subsequent follow up of 45(7-127) months, 28 patients remained euglycemic, 5 (2 treated in the first line) developed diabetes after 14(1-32) months and 12 (6 treated as first line) developed IFG in 6 (1-12) months. No IFG patients developed an overt diabetes in the subsequent follow-up of 60.3 (33-102) months. We calculated a cut-off point of 12 for uGRS. When the 28 euglycemic patient were compared with 5 patients becoming diabetics after Nilotinib, uGRS showed a sensibility of 100% and a specificity of 46% in predicting diabetes. Consequently, the positive predictive valuewas 25% where the negative predictive values 100%. When the 28 euglycemic patients were compared with the 12 patients developing IFG after Nilotinib, the sensibility and specificity of uGRS was low: 50% and 46% respectively. CONCLUSIONS: A Genetic risk score for insulin resistance showed high specificity and a strong negative predictive values when used to identify CML patients treated with Nilotinib developing an overt diabetes. Further studies in lager populations are needed to confirm this predictivity that can be used in clinical practice to tailor the best anti TKI therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals A follow-up association study of two genetic variants for bone mineral density variation in Caucasians

2011 ◽  
Vol 23 (7) ◽  
pp. 1867-1875 ◽  
Author(s):  
L.-S. Zhang ◽  
H.-G. Hu ◽  
Y.-J. Liu ◽  
J. Li ◽  
P. Yu ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Association Study ◽  
Bone Mineral ◽  
Genetic Variants ◽  
Density Variation ◽  
Mineral Density

scholarly journals Hepatic Lipase, Genetically Elevated High-Density Lipoprotein, and Risk of Ischemic Cardiovascular Disease

2009 ◽  
Vol 94 (4) ◽  
pp. 1264-1273 ◽  
Author(s):  
Trine Holm Johannsen ◽  
Pia R. Kamstrup ◽  
Rolf V. Andersen ◽  
Gorm B. Jensen ◽  
Henrik Sillesen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
High Density Lipoprotein ◽  
Genetic Variants ◽  
Hepatic Lipase ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Ischemic Cerebrovascular Disease

Abstract Context: Hepatic lipase influences metabolism of high-density lipoprotein (HDL), a risk factor for ischemic cardiovascular disease (ICD: ischemic heart disease and ischemic cerebrovascular disease). Objective: We tested the hypothesis that genetic variation in the hepatic lipase genetic variants V73M, N193S, S267F, L334F, T383M, and −480c>t influence levels of lipids, lipoproteins, and apolipoproteins and risk of ICD. Design: For the cross-sectional study, we genotyped 9003 individuals from the Copenhagen City Heart Study; hereof were 8971 individuals included in the prospective study, 1747 of whom had incident ICD during 28 yr of follow-up. For the case-control studies, 2110 ischemic heart disease patients vs. 4899 controls and 769 ischemic cerebrovascular disease patients vs. 2836 controls, respectively, were genotyped. Follow-up was 100% complete. Results: HDL cholesterol was higher by 0.21 mmol/liter in S267F heterozygotes, by 0.06 mmol/liter in −480c>t heterozygotes, and by 0.13 mmol/liter in −480c>t homozygotes, as compared with noncarriers. These HDL increases theoretically predicted hazard ratios for ICD of 0.87 [95% confidence interval (CI) 0.84–0.90], 0.96 (95% CI 0.95–0.97), and 0.91 (95% CI 0.89–0.94), respectively; this calculation assumes that genetically elevated HDL levels confer decreased risk similar to common HDL elevations. In contrast, when all cases and controls were combined, the observed odds ratios for ICD for these three genetic variants vs. noncarriers were 1.19 (0.76–1.88), 1.04 (0.96–1.13), and 1.08 (0.89–1.30), respectively. Hazard/odds ratios for ICD in carriers vs. noncarriers of the four remaining hepatic lipase genetic variants did not differ consistently from 1.0. Conclusion: Hepatic lipase genetic variants with elevated levels of HDL cholesterol did not associate with risk of ICD.

scholarly journals Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

2020 ◽  
Vol 9 (8) ◽  
pp. 793-803
Author(s):  
Ailsa Maria Main ◽  
Maria Rossing ◽  
Line Borgwardt ◽  
Birgitte Grønkær Toft ◽  
Åse Krogh Rasmussen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Prognostic Markers ◽  
Clinical Phenotype ◽  
Study Cohort ◽  
Clinical Genetic ◽  
Systematic Screening ◽  
Tertiary Centre ◽  
Pathogenic Variants ◽  
Combined Algorithm

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype–phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.

scholarly journals Increased Risk of Early Hematologic Toxicity during Maintenance Therapy in Acute Lymphoblastic Leukemia Patients of South Indian Origin Carrying NUDT15*3 Allele

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5059-5059
Author(s):  
Sunitha Kodidela ◽  
Dorababu Patchva ◽  
Dimpal Thakkar: ◽  
Biswajit Dubashi ◽  
Rajan Sundaram ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Candidate Genes ◽  
Genetic Variants ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
South Indian ◽  
Grade 3 ◽  
Methotrexate Polyglutamate

Background and Objectives: Globally the survival of ALL has increased tremendously with the five-year overall survival (OS) reaching 90% in high-income countries (HICs) (1, 2). However, in India, the five-year OS has been reported to be 30-70 %( 3) and deaths due to treatment related toxicity (TRT) in ALL were ranged from 2-24 % (4), which is ten times higher compared to HICs suggesting increased susceptibility to the toxicity of the chemotherapeutic drugs. This could be due to frequent variants in candidate genes determining the pharmacodynamic response or pharmacokinetics of the chemotherapeutic drugs used during maintenance therapy of ALL. Variations in the patient management, supportive care therapy are the other possible reasons of this increased incidence of TRT. Many patients are lost to follow-up due to the TRT, and eventually will die of the disease progression. The present study aimed to explore the association of common genetic variants in the candidate genes with early treatment related hematological toxicities (grade 3-4) in patients with Acute Lymphoblastic Leukemia (ALL) receiving low-dose MTX (LDMTX) and 6-Mercaptopurine (6-MP) based maintenance therapy. Materials and Methods: This prospective study was conducted between August 2011 and May 2016 and approved by institutional scientific and ethics committees. A total of 71 patients (43 males and 28 females aged between 1-51 years) with ALL were enrolled in the study after obtaining written informed consent and in the case of children, from legally accepted guardians. Patients below 25 years of age were treated using protocol-841 (MCP) I2A and those older than 25 years were treated with modified GMALL-84 protocols. MTX and 6-MP doses did not differ across both the protocols during maintenance therapy. Germline DNA samples collected at the time of remission from peripheral mononuclear cells was used to genotype15 selected variants frequent in the following candidate genes : ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15 using allele discrimination assay by real-time PCR. LC-MS/MS method was used to measure methotrexate polyglutamate (MTXPG3-5) levels in RBC's.Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE-version 4.03). Early grade 3-4 hematological toxicities occurring within first 100 days of the maintenance therapy was studied for its association with the genetic variants and other risk factors. Cumulative incidence curves were plotted and a risk factor analysis was performed using multivariate Cox regression. Co-linearity between variables was assessed. We used a back-ward selection method, retaining those variables with P-values<0.05 in the final model. Data analysis was done using statistical software « R ». Results: The cumulative incidences of early hematological TRT (grade 3-4) and relapse were 54.9 %, and 38.0 %, respectively. The relapse free survival was 59.2 %. The median follow-up of all patients from the start of maintenance was 1018 days. In multivariate analysis including all genetic variants, age, and WBC counts at diagnosis, we observed a significant increase in the risk of TRT in carriers of NUDT15*3 allele(rs116855232 ; p=0.002 ; univariate Hazards ratio : 2.81 (95% CI : 1.41-5.59). 3435C>T variant in ABCB1 gene showed a trend of association with that of relapse free survival. Neither the genetic variants studied were associated with the methotrexate polyglutamate levels, nor were the levels associated with the clinical outcomes. Conclusion: The NUDT15*3 allele carriers status could be used as one of the stratifying markers in South Indian ALL patients at the time of diagnosis to distinguish high and low-risk patients to develop early hematological toxicity, especially related to 6-mercaptopurine based ALL maintenance therapy protocols. Disclosures No relevant conflicts of interest to declare.

scholarly journals Association of maternal weight with FADS and ELOVL genetic variants and fatty acid levels- The PREOBE follow-up

PLoS ONE ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. e0179135 ◽  
Author(s):  
Andrea de la Garza Puentes ◽  
Rosa Montes Goyanes ◽  
Aida Maribel Chisaguano Tonato ◽  
Francisco José Torres-Espínola ◽  
Miriam Arias García ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Genetic Variants ◽  
Maternal Weight

scholarly journals Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis

Blood ◽  
2019 ◽  
Vol 134 (5) ◽  
pp. 456-468 ◽  
Author(s):  
Javier I. Muñoz-González ◽  
Iván Álvarez-Twose ◽  
María Jara-Acevedo ◽  
Ana Henriques ◽  
Esther Viñas ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Systemic Mastocytosis ◽  
Progression Free Survival ◽  
Scoring Systems ◽  
Prognostic Impact ◽  
Limited Information ◽  
Free Survival ◽  
Pathogenic Variants ◽  
Indolent Systemic Mastocytosis

Abstract Indolent systemic mastocytosis (ISM) patients have a normal life expectancy, except in the 5% to 10% of cases that progress to more advanced SM (advSM), which has a significantly poorer outcome. Mutations in genes other than KIT frequently found in myeloid neoplasms have been associated with a poorer outcome among advSM, whereas limited information exists about their frequency and prognostic impact in ISM. We investigated the frequency and prognostic impact of variants in 18 genes, found to be altered in advSM, in 322 ISM patients (median follow-up, 5.7 years) divided into discovery (n = 200) and validation (n = 122) cohorts. Overall, 71 genetic variants were detected in 55 of 322 (17%) patients. Mutated ISM cases, particularly those carrying ASXL1, RUNX1, and/or DNMT3A (A/R/D) pathogenic variant allele frequencies (VAFs) ≥ 30%, exhibited significantly shortened (P &lt; .001) progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that serum β2-microglobulin (sβ2M) levels &gt; 2.5 µg/mL (hazard ratio [HR], 9.8; P = .001), together with a KIT D816V VAF ≥ 1% in bone marrow (BM) (HR, 10.1; P = .02) and pathogenic variants of A/R/D VAFs ≥ 30% (HR, 4.2; P = .02), were the best combination of independent predictors for PFS. In turn, A/R/D gene pathogenic VAF ≥ 30% was the only independent predictor for OS (HR, 51.8; P &lt; .001). Based on these variables, 2 scoring systems were constructed for risk stratification of ISM at diagnosis with significantly different 10-year PFS (100%, 91%, 0% for scores of 0, 1, ≥2, respectively) and OS (100% and 50% for scores of 0 and 1) rates.

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