In this report, we have demonstrated that MTHFR C677T genotype is associated with eGFR in Chinese males, but not in females. The association still holds after adjusting for age, BMI, and blood pressures.
form of MTHFR encoded by the 677T
allele is thermolabile and has reduced enzymatic activity [9
]. The degree of enzyme thermolability (assessed as residual activity after heat inactivation) is much greater in 677TT individuals (18-22%) compared with C677T
(56%) and C677C
(66-67%). The allele frequency of 677T
varies with populations, ranging from less than 10% in African to 50% in Chinese [12
]. Consistent with previous reports, in our study samples 677T
is the major allele with an allele frequency of 0.516 and TT
homozygote frequency of 0.26.
Many cross-sectional studies showed that plasma tHcy and kidney function was negatively correlated. For example, in NHANES III study [1
], the risk for CKD defined as eGFR
in individuals with high tHcy level (>11umol/L) was 40 times higher than those with low tHcy level (<7umol/L). However, it’s still not clear if hyperhomocysteinemia is the true effector that leads to decreased kidney function or it is simply a marker for kidney function. A recent prospective study in the Framingham cohort demonstrated that baseline homocysteine is an independent risk predictor for CKD and urine microalbuminuria [8
]. In animal studies, induced hyperhomocysteinemia could cause podocyte injury and glomerulosclerosis [5
]. Feeding rats with methionine induced hyperhomocysteinemia and resulted in significant decrease of GFR.
In the current study, we explored association between MTHFR C677T
and kidney function indexed by eGFR in a large Chinese sample, and found a significant association in males but not in females. In males, the association model was apparently recessive. While individuals with CC
had similar eGFRs, individuals with TT
were associated with 1.37
lower value in eGFR, and an increased risk for decreased kidney function defined by bottom 20 or 50 percentiles. Of our study subjects, 3.3% had CKD with eGFR
, which is slightly higher than the 2.53% prevalence rate in China adults aged 35–74
years reported from the InterAsia [17
], partly due to the hypertensive nature of our study sample. Our study also suggested TT genotype was associated with an increase risk of CKD (OR
0.22), though it didn’t reach statistical significance probably due to the low percentage of CKD in our sample.
We have also observed a significant interaction between C677T genotype and homocysteine on eGFR in males. In males, the apparent effect size of homocysteine on eGFR was significantly reduced in TT homozygotes compared with subjects with CC genotype. In other words, the TT effect size was bigger in subjects with lower homocysteine level. However, due to collinearity, it is difficult to segregate their effects under current study design. Another limitation of our study is the study population was hypertensive; the findings from this study may not be generalizable to general population. A confirmation in general population would be helpful.