RGD Reference Report - Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC). - Rat Genome Database

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Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC).

Authors: Fung, MM  Salem, RM  Lipkowitz, MS  Bhatnagar, V  Pandey, B  Schork, NJ  O'Connor, DT  O'Connor, Daniel T 
Citation: Fung MM, etal., Nephrol Dial Transplant. 2012 Jan;27(1):197-205. Epub 2011 May 25.
RGD ID: 6893469
Pubmed: PMID:21613384   (View Abstract at PubMed)
PMCID: PMC3350339   (View Article at PubMed Central)
DOI: DOI:10.1093/ndt/gfr257   (Journal Full-text)

BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over approximately 4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over approximately 4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MTHFRHumannephrosclerosis  IAGP DNA:transition more ...RGD 
MthfrRatnephrosclerosis  ISOMTHFR (Homo sapiens)DNA:transition more ...RGD 
MthfrMousenephrosclerosis  ISOMTHFR (Homo sapiens)DNA:transition more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MTHFRHumanDecreased glomerular filtration rate  IAGP DNA:transition more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Mus musculus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Homo sapiens)
MTHFR  (methylenetetrahydrofolate reductase)


Additional Information