Genetics Research
rs10934753
Population Frequencies12
African
G 0.77376A 0.22624GG 0.599277GA/AG 0.348967AA 0.051756pop=19,360
African American
G 0.77287A 0.22713GG 0.597798GA/AG 0.35015AA 0.052052pop=18,712
African Others
G 0.799A 0.201GG 0.641975GA/AG 0.314815AA 0.04321pop=648
Asian
G 0.7283A 0.2717GG 0.535817GA/AG 0.384909AA 0.079274pop=6,282
East Asian
G 0.7286A 0.2714GG 0.538106GA/AG 0.381062AA 0.080831pop=5,196
European
G 0.564508A 0.435492GG 0.319016GA/AG 0.490984AA 0.19pop=175,916
Latin American 1
G 0.6377A 0.3623GG 0.404255GA/AG 0.466834AA 0.128911pop=1,598
Latin American 2
G 0.7166A 0.2834GG 0.516594GA/AG 0.399933AA 0.083473pop=5,966
Other
G 0.6439A 0.3561GG 0.417996GA/AG 0.451819AA 0.130185pop=3,134
Other Asian
G 0.7265A 0.2735GG 0.524862GA/AG 0.403315AA 0.071823pop=1,086
South Asian
G 0.693A 0.307GG 0.481328GA/AG 0.423237AA 0.095436pop=482
Studies13
Unread Studies13 ▼
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The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step …
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The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step Mendelian randomization (MR) analysis. Methods We analyzed data from genome-wide association studies (GWAS) conducted on European and East Asian populations. To assess the causal effects of circulating glycine levels on the risk of CAD. We used the inverse-variance weighting (IVW), weighted median (WM), MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Furthermore, we conducted mediation analysis to investigate the contribution of blood pressure and other cardiovascular disease-related traits. Results The two-step Mendelian randomization analysis revealed that higher levels of glycine in the blood were associated with a reduced risk of CAD in Europeans [odds ratio ( OR)=0.84, 95% confidence interval ( CI): 0.72, −0.98; P=0.029] and East Asians: ( OR=0.76, 95% CI: 0.66, −0.89; P=3.57×10 −4). Sensitivity analysis confirmed the robustness of these findings. Additionally, our results suggest that about 6.06% of the observed causal effect is mediated through genetically predicted systolic blood pressure (SBP) in the European population. Discussion Our results contribute to the current knowledge regarding the involvement of glycine in the progression of CAD, and provide valuable methodological insights for the prevention and treatment of this condition.
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The aim of this study was to evaluate, in a case‐control design, the association between maternal genotypes for variants in 23 genes involved in folate/one‐carbon metabolism and …
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Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
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The aim of this study was to evaluate, in a case-control design, the association between maternal genotypes for variants in 23 genes involved in folate/one-carbon metabolism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a Chilean population. After applying several filters to an Illumina array, we extracted 175 single nucleotide polymorphisms (SNPs) from 150 mothers of NSCL/P cases and 150 control women. Association was evaluated using computed odds ratio (OR) with a 95% confidence interval (95% CI) in additive, recessive, and dominant models. After multiple comparison correction, only SNP rs4451422 (A>C), located 237 bp downstream of the gene encoding the human folylpolyglutamate synthetase (FPGS), maintained a significant association with NSCL/P in the offspring (OR 3.03; 95% CI 1.69-5.26). The variant rs4451422 is associated with a decrease in FPGS expression according to database annotation. Our results lead to a new hypothesis that a lower activity of FPGS enzyme reduces intracellular folate levels and increases the risk of an offspring having NSCL/P.
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ene–diet interactions in relation to circulating homocysteine concentrations Background: Elevated homocysteine (Hcy) is associated with several disease pathologies and can be manipulated by modifiable factors such as diet, nutritional status, physical activity and smoking, but can also be altered by non-modifiable factors such as age, gender and the genetic susceptibility of an individual. Although both dietary factors and genetic make-up influence plasma Hcy concentrations, very few investigations have examined the interactive effects i.e. gene–diet interactions.
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Now in a revised second edition, Nutrigenomics and Proteomics in Health and Disease brings together the very latest science based upon nutrigenomics and proteomics in food and health. Coverage includes many important nutraceuticals and their impact on gene interaction and health. Authored by an international team of multidisciplinary researchers, this book acquaints food and nutrition professionals with these new fields of nutrition research and conveys the state of the science to date. Thoroughly updated to reflect the most current developments in the field, the second edition includes six new chapters covering gut health and the personal microbiome; gut microbe-derived bioactive metabolites; proteomics and peptidomics in nutrition; gene selection for nutrigenomic studies; gene-nutrient network analysis, and nutrigenomics to nutritional systems biology. An additional five chapters have also been significantly remodelled. The new text includes a rethinking of in vitro and in vivo models with regard to their translatability into human phenotypes, and normative science methods and approaches have been complemented by more comprehensive systems biology-based investigations, deploying a multitude of omic platforms in an integrated fashion. Innovative tools and methods for statistical treatment and biological network analysis are also now included.
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The chapter describes a brief selection of interactions between nutrition, genetics, and epigenetics. Epigenetics can be considered a “fine tuning” mechanism, which may modulate basal genetic and nutrition‐based information. Nutrition and other factors during pregnancy, infancy, and childhood, through epigenetic effects, can result in an increased risk for cancer, metabolic syndrome, diabetes, cardiovascular disease (CVD), and neurodegenerative disease. An excellent example of the impact of nutrition on an intergenerational epigenetic phenomenon is the agouti mouse response to folate and other methyl donors in the diet. The chapter focuses on folate‐related metabolism, with some references to other pathways as appropriate, to illustrate situations or types of interactions between these elements. Although many nutrients can contribute to environmental and genetic factors that lead to disease, folate is particularly relevant to epigenetics since it is the major one‐carbon donor for methylation reactions. The chapter also focuses on genetic changes that are more common, that may contribute to epigenetic disturbances.
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Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10-8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10-17; rs715 at 2q34, P = 9.97 × 10-14; rs477992 at 1p12, P = 2.60 × 10-12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10-6) and serine (P = 2.48 × 10-4) between MacTel cases and controls.
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… It is important to note that the VISP population consists of exclusively ischemic stroke patients examined for recurrent stroke over a 2 year period; rs10934753 was not associated with …
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Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10−63], CBS [p = 3.15×10−26], CPS1 [p = 9.10×10−13], ALDH1L1 [p = 7.3×10−13] and PSPH [p = 1.17×10−16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
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Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p?=?1.60×10-63], CBS [p?=?3.15×10-26], CPS1 [p?=?9.10×10-13], ALDH1L1 [p?=?7.3×10-13] and PSPH [p?=?1.17×10-16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (?POST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ?POST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ?POST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
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Purpose To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. Methods Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. Results We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. Conclusions We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel.
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