The association of cell cycle checkpoint 2 variants and kidney function: findings of the Family Blood Pressure Program and the Atherosclerosis Risk In Communities study

Abstract

Background: Recent experimental evidence suggests that DNA damage and cell cycle regulatory proteins are involved in kidney injury and apoptosis. The checkpoint 2 gene (CHEK2) is an important transducer in DNA damage signaling pathways in response to injury, and therefore, CHEK2 variants may affect susceptibility to kidney disease.

Methods: We used tag-single-nucleotide polymorphisms (tag-SNPs) to evaluate the association of the CHEK2 with kidney function (estimated glomerular filtration rate, eGFR) in 1,549 African-American and 1,423 white Hypertension Genetic Epidemiology Network (HyperGEN) participants. We performed replication analyses in the Genetic Epidemiology Network of Arteriopathy (GENOA) participants (1,746 African Americans and 1,418 whites), GenNet participants (706 whites), and Atherosclerosis Risk in Communities (ARIC) study participants (3,783 African Americans and 10,936 whites). All analyses were race-stratified and used additive genetic models with adjustments for covariates and for family structure, if needed.

Results: One tag-SNP, rs5762764, was associated with eGFR in HyperGEN (P = 0.003) and GENOA white participants (P = 0.009), and it was significantly associated with eGFR in meta-analyses (P = 0.002). The associations were independent of type 2 diabetes.

Conclusions: These results suggest that CHEK2 variants may influence eGFR in the context of hypertension.

Figure 1

Meta-analyses of the effect of rs5762764 (CHEK2) on estimated glomerular filtration rate (N = 19,847 individuals). ARIC, Atherosclerosis Risk in Communities; CI, confidence interval; ES, estimate; GENOA, Genetic Epidemiology Network of Arteriopathy.