Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population

Paré, Guillaume; Chasman, Daniel I.; Parker, Alexander N.; Zee, Robert R.Y.; Mälarstig, Anders; Seedorf, Udo; Collins, Rory; Watkins, Hugh; Hamsten, Anders; Miletich, Joseph P.; Ridker, Paul M.

doi:10.1161/circgenetics.108.829804

Cited by 94 publications

(57 citation statements)

References 56 publications

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“…In a large-scale genome-wide association study from the USA, including subjects aged 54-61 years, the MTHFR C677T polymorphism and environmental factors were described to account for 1 and 9% of the observed variance on blood Hcy concentrations, respectively. 45 All the considerations above could suggest that the difference related to gene-lifestyle interactions between sexes start as early as 22-23 years.…”

Section: Discussionmentioning

confidence: 99%

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

et al. 2016

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BACKGROUND/OBJECTIVES: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (⩾15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction o 0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction o 0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction o 0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future.

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Section: Discussionmentioning

confidence: 99%

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

et al. 2016

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“…There is strong LD between rs715 and rs1047891 (pair-wise r 2 = 0.97). Several studies report a marked sex effect with CPS1 associations, with females showing a stronger association for rs715 with glycine levels 43,44 , and rs1047891 with homocysteine levels 54,55 . We also observe a sex-interaction with MacTel at this locus (Supplementary Table 4 and Online methods).…”

Section: Locus 2q34mentioning

confidence: 99%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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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 genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 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 1134 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 of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

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“…Yet, elevated homocysteine levels occur in many people, including heterozygotes for some CBS alleles, without any clinical symptoms (Motulsky 1996;Guttormsen et al 2001). Additionally, defects in several different genes tangential to cysteine biosynthesis, such as MTHFR, can lead to homocysteinemia and similar symptoms (Frosst et al 1995;Gaughan et al 2001;Pare et al 2009). Hence, elevated homocysteine level is a convenient marker for a metabolic imbalance, but the cause and consequences may be elusive.…”

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confidence: 99%

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

et al. 2012

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Cystathionine-b-synthase (CBS) deficiency is a human genetic disease causing homocystinuria, thrombosis, mental retardation, and a suite of other devastating manifestations. Early detection coupled with dietary modification greatly reduces pathology, but the response to treatment differs with the allele of CBS. A better understanding of the relationship between allelic variants and protein function will improve both diagnosis and treatment. To this end, we tested the function of 84 CBS alleles previously sequenced from patients with homocystinuria by ortholog replacement in Saccharomyces cerevisiae. Within this clinically associated set, 15% of variant alleles were indistinguishable from the predominant CBS allele in function, suggesting enzymatic activity was retained. An additional 37% of the alleles were partially functional or could be rescued by cofactor supplementation in the growth medium. This large class included alleles rescued by elevated levels of the cofactor vitamin B6, but also alleles rescued by elevated heme, a second CBS cofactor. Measurement of the metabolite levels in CBS-substituted yeast grown with different B6 levels using LC-MS revealed changes in metabolism that propagated beyond the substrate and product of CBS. Production of the critical antioxidant glutathione through the CBS pathway was greatly decreased when CBS function was restricted through genetic, cofactor, or substrate restriction, a metabolic consequence with implications for treatment.T HE first complete human genome sequence seeded the defining challenge of human genetics for the foreseeable future: interpreting the impact of variations in the sequences of individual human genomes. Comparative genome sequencing reveals an average of one single-nucleotide change per 1200 bp between any two individuals. In the absence of strong Mendelian inheritance and linkage, confirming that any human genotype actually caused a phenotype is a significant challenge given the approximately 3 million genetic variants per person. Indeed, 4000 traits of medical interest show evidence for inheritance but lack a clear determinant (Online Mendelian Inheritance in Man 2012). Next-generation sequencing within small pedigrees (Ng et al. 2010a,b;Fan et al. 2011), or a more narrowly defined clinical phenotype (Schubert et al. 1997), can sometimes disentangle the underlying contribution of a gene to disease. In this work we have taken an approach that complements both increased sequencing capacity and expanded phenotypic description. We used surrogate genetics to assay directly the function of allelic variants and then evaluate their potential contribution to phenotypes of clinical importance.Homocystinuria, elevated levels of the sulfur-containing metabolite homocystine in the urine, illustrates several Reference numbers for publicly available data; GenBank: L14577.1 (CBS); dbSNP: rs17849313 (A69P), rs2229413 (P70L), rs11700812 (R369P); SGD: YGR155W (CYS4) and YDR232W (HEM1 challenges inherent to elucidating the molecular bases of human geneti...

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Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population

Abstract: Background-Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies.

Cited by 94 publications

References 56 publications

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

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