scholarly journals Genomic Study of Cardiovascular Continuum Comorbidity

Acta Naturae ◽  
2015 ◽  
Vol 7 (3) ◽  
pp. 89-99 ◽  
Author(s):  
O. A. Makeeva ◽  
A. A. Sleptsov ◽  
E. V. Kulish ◽  
O. L. Barbarash ◽  
A. M. Mazur ◽  
...  
Keyword(s):  
Genetic Markers ◽  
Genetic Variants ◽  
Association Studies ◽  
Control Group ◽  
Genetic Profile ◽  
Genomic Study ◽  
Disease Predisposition ◽  
Cardiovascular Continuum ◽  
Modern Technologies

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the My Gene genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype IHD only, including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the IHD and AH phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the IHD only and IHD and AH phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the IHD and AH phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the syntropy and IHD only phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the IHD only phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated single forms of a disease.

scholarly journals Rare Variant in the SLC6A2 Encoding a Norepinephrine Transporter Is Associated with Elite Athletic Performance in the Polish Population

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 919
Author(s):  
Jakub P. Fichna ◽  
Kinga Humińska-Lisowska ◽  
Krzysztof Safranow ◽  
Jakub G. Adamczyk ◽  
Paweł Cięszczyk ◽  
...  
Keyword(s):  
Athletic Performance ◽  
Genetic Variants ◽  
Pain Perception ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Norepinephrine Transporter ◽  
Control Group ◽  
Brain Functioning ◽  
Mental Abilities ◽  
Functional Analyses

Numerous genetic factors have been shown to influence athletic performance, but the list is far from comprehensive. In this study, we analyzed genetic variants in two genes related to mental abilities, SLC6A2 (rs1805065) and SYNE1 (rs2635438) in a group of 890 athletes (320 endurance, 265 power, and 305 combat athletes) vs. 1009 sedentary controls. Genotyping of selected SNPs was performed using TaqMan SNP genotyping assays. SLC6A2 codes for norepinephrine transporter, a protein involved in modulating mood, arousal, memory, learning, and pain perception, while SYNE1 encodes protein important for the maintenance of the cerebellum—the part of the brain that coordinates complex body movements. Both SNPs (rs2635438 and rs1805065) showed no statistically significant differences between the frequencies of variants in the athletes and the sedentary controls (athletes vs. control group) or in the athlete subgroups (martial vs. control, endurance vs. control, and power vs. control). The rs1805065 T variant of SLC6A2 was found to be overrepresented in male high-elite martial sports athletes when compared to sedentary controls (OR = 6.56, 95%CI = 1.82–23.59, p = 0.010). This supports the hypothesis that genetic variants potentially affecting brain functioning can influence elite athletic performance and indicate the need for further genetic association studies, as well as functional analyses.

scholarly journals Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Tae-Joon Park ◽  
Heun-Sik Lee ◽  
Young Jin Kim ◽  
Bong-Jo Kim
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Genetic Regulation ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

Shared Genomics of Type 2 and Gestational Diabetes Mellitus

2011 ◽  
Vol 29 (1) ◽  
pp. 227-260 ◽  
Author(s):  
Shu-Fen Wung ◽  
Pei-Chao Lin
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Genetic Variants ◽  
Association Studies ◽  
Regulatory Subunit ◽  
Significant Heterogeneity ◽  
Replication Studies ◽  
Genetic Risks

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and the prevalence of GDM is increasing worldwide. Short- and longterm complications of GDM on mothers and fetuses are well-recognized. These include more than seven-fold higher risk for type 2 diabetes mellitus (T2DM) later in life in women with GDM than those without. Evidence supports that GDM shares several risk factors with T2DM, including genetic risks. This chapter reviewed studies on candidate genes shared by T2DM and GDM published from 1990 to 2011. At least 20 susceptible genes of T2DM have been studied in women with GDM in various races. Results from current association studies on T2DM susceptible genes in GDM have shown significant heterogeneity. There may be primary evidence that polymorphisms of susceptible genes of T2DM such as transcription factor 7-like 2 (TCF7L2) gene, potassium channel voltagegate KQT-like subfamily member 1 (KCNQ1) gene, and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene, may increase risk of GDM. Associations between GDM and many genetic variants have led to different findings across populations. Many genetic polymorphisms related to GDM were investigated in a single study or a single population. Replication studies to verify contributions of both common and rare genetic variants for GDM and T2DM in specific racial/ethnic groups are needed.

scholarly journals A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes

2015 ◽  
Vol 47 (6) ◽  
pp. 215-224 ◽  
Author(s):  
L. Maria Belalcazar ◽  
George D. Papandonatos ◽  
Jeanne M. McCaffery ◽  
Inga Peter ◽  
Nicholas M. Pajewski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lifestyle Intervention ◽  
Genetic Variants ◽  
Association Studies ◽  
Lifestyle Changes ◽  
Genome Wide Association Studies ◽  
Look Ahead ◽  
Genome Wide

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent ( n = 1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 ( ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: β ± SE = 0.05 ± 0.02, P = 0.008; in non-Hispanic whites: 0.06 ± 0.02, P = 0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

scholarly journals Mendelian randomization studies of biomarkers and type 2 diabetes

2015 ◽  
Vol 4 (4) ◽  
pp. 249-260 ◽  
Author(s):  
Ali Abbasi
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Current Evidence ◽  
Genome Wide Association Studies ◽  
Glycaemic Traits

Many biomarkers are associated with type 2 diabetes (T2D) risk in epidemiological observations. The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D. A systematic literature search in PubMed and EMBASE (until April 2015) was done to identify Mendelian randomization studies that examined potential causal effects of biomarkers on T2D. To replicate the findings of identified studies, data from two large-scale, genome-wide association studies (GWAS) were used: DIAbetes Genetics Replication And Meta-analysis (DIAGRAMv3) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for glycaemic traits. GWAS summary statistics were extracted for the same genetic variants (or proxy variants), which were used in the original Mendelian randomization studies. Of the 21 biomarkers (from 28 studies), ten have been reported to be causally associated with T2D in Mendelian randomization. Most biomarkers were investigated in a single cohort study or population. Of the ten biomarkers that were identified, nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin, pro-B-type natriuretic peptide, delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC. Several Mendelian randomization studies investigated the nature of associations of biomarkers with T2D. However, there were only a few biomarkers that may have causal effects on T2D. Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants.

Genetic effects, gene-lifestyle interactions, and type 2 diabetes

Open Medicine ◽  
2008 ◽  
Vol 3 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Lu Qi
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Positional Cloning ◽  
Association Studies ◽  
Dietary Habit ◽  
Genetic Components ◽  
Genome Wide ◽  
Prediction And Prevention ◽  
Intervention Trials

AbstractType 2 diabetes has become a major public health challenge worldwide. It is now widely accepted that genetic components affect the development of type 2 diabetes, in concert with environmental factors such as lifestyle and diet. Traditional linkage mapping, positional cloning, and candidate gene-based association studies have identified a few genetic variants in genes such as TCF7L2, PPARG, and KCNJ11 that are reproducibly related to the risk of type 2 diabetes. To date, about ten genome-wide association (GWA) studies have been published. These studies discovered new susceptibility genes for type 2 diabetes and provide novel insight into the diabetes etiology. In addition, data especially from lifestyle intervention trials display promising evidence that the genetic variants may interact with changes of dietary habit and physical activity in predisposing to type 2 diabetes. The gene-lifestyle interactions merit extensive exploration in large, prospective studies. The findings from these areas will substantially improve the prediction and prevention of type 2 diabetes.

P4470Identification of four genes as novel susceptibility loci for early-onset type 2 diabetes mellitus, metabolic syndrome, or hyperuricemia in Japanese

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Yamase ◽  
H Horibe ◽  
K Kato ◽  
M Oguri ◽  
T Fujimaki ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Syndrome ◽  
Genetic Variants ◽  
Early Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Genome Wide

Abstract Background Given that early-onset type 2 diabetes mellitus (T2DM), metabolic syndrome, and hyperuricemia have been shown to have strong genetic components, statistical power of a genetic association study may be increased by focusing on early-onset subjects with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with T2DM, metabolic syndrome, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to early-onset T2DM, metabolic syndrome, or hyperuricemia in Japanese. We have now performed exome-wide association studies (EWASs) for early-onset subjects with T2DM, metabolic syndrome, or hyperuricemia and corresponding controls. Methods A total of 8102 individuals aged ≤65 years was enrolled in the study. The EWAS for T2DM was performed with 7407 subjects (1696 cases, 5711 controls), that for metabolic syndrome with 4215 subjects (2296 cases, 1919 controls), and that for hyperuricemia with 7919 subjects (1365 cases, 6554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control to T2DM, metabolic syndrome, or hyperuricemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with T2DM, metabolic syndrome, or hyperuricemia, we applied Bonferroni's correction for statistical significance of association. Results The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P<1.60 × 10–6), metabolic syndrome (P<1.59 × 10–6), or hyperuricemia (P<1.61 × 10–6), respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that three, six, or nine SNPs were significantly related to T2DM (P<0.0031), metabolic syndrome (P<0.0021), or hyperuricemia (P<0.0014). After examination of the association of identified SNPs to T2DM-, metabolic syndrome-, or hyperuricemia-related traits, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, we have newly identified ZNF860 and OR4F6 as susceptibility loci for T2DM, OR52E4 and OR4F6 for metabolic syndrome, and HERPUD2 for hyperuricemia. Conclusion Given that OR4F6 was significantly associated with both T2DM and metabolic syndrome, we thus newly identified four genes (ZNF860, OR4F6, OR52E4, HERPUD2) that confer susceptibility to early-onset T2DM, metabolic syndrome, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, metabolic syndrome, or hyperuricemia in Japanese.

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