Research Article: Interactions between Serum Vitamin D Levels and Vitamin D Receptor Gene FokI Polymorphisms for Renal Function in Patients with Type 2 Diabetes

Date Published: December 4, 2012

Publisher: Public Library of Science

Author(s): Keitaro Yokoyama, Akio Nakashima, Mitsuyoshi Urashima, Hiroaki Suga, Takeshi Mimura, Yasuo Kimura, Yasushi Kanazawa, Tamotsu Yokota, Masaya Sakamoto, Sho Ishizawa, Rimei Nishimura, Hideaki Kurata, Yudo Tanno, Katsuyoshi Tojo, Shigeru Kageyama, Ichiro Ohkido, Kazunori Utsunomiya, Tatsuo Hosoya, Hideharu Abe.


We aimed to examine associations among serum 25-hydroxyvitamin D (25OHD) levels, 1,25-dihyroxyvitamin D (1,25OHD) levels, vitamin D receptor (VDR) polymorphisms, and renal function based on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.

In a cross-sectional study of 410 patients, chronic kidney disease (CKD) stage assessed by eGFR was compared with 25OHD, 1,25OHD, and VDR FokI (rs10735810) polymorphisms by an ordered logistic regression model adjusted for the following confounders: disease duration, calendar month, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers or statins, and serum calcium, phosphate, and intact parathyroid hormone levels.

1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations; peak levels were seen from May to October and the lowest levels were seen from December to February. These findings were evident in patients with CKD stage 3∼5 but not stage 1∼2. eGFR was in direct proportion to both 25OHD and 1,25OHD levels (P<0.0001), but it had stronger linearity with 1,25OHD (r = 0.73) than 25OHD (r = 0.22) levels. Using multivariate analysis, 1,25OHD levels (P<0.001), but not 25OHD levels, were negatively associated with CKD stage. Although FokI polymorphisms by themselves showed no significant associations with CKD stage, a significant interaction between 1,25OHD and FokITT was observed (P = 0.008). The positive association between 1,25OHD and eGFR was steeper in FokICT and CC polymorphisms (r = 0.74) than FokITT polymorphisms (r = 0.65). These results suggest that higher 1,25OHD levels may be associated with better CKD stages in patients with type 2 diabetes and that this association was modified by FokI polymorphisms.

Partial Text

Worldwide, the number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030 [1]. Chronic kidney disease (CKD) is one of the major complications of type 2 diabetes. CKD in patients with diabetes has become one of the major causes of end-stage renal disease (ESRD) requiring dialysis and transplantation. Therefore, avoiding the development of ESRD in patients with diabetes is important.

In this study, we found that 1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations in our study population. Peak values were seen from May to October and the lowest values were seen from December to February. Of interest, this oscillation of 1,25OHD levels was observed only in diabetic patients with advanced CKD (stage 3∼5), but not in patients with early CKD (stage 1∼2). Seasonal oscillations have been well documented in 25OHD levels [17], but to our knowledge, have not been reported in 1,25OHD levels, which is consistent with our previous study targeting patients with Parkinson’s disease [14]. eGFR values were in direct proportion to both 25OHD and 1,25OHD levels, but they showed stronger linearity with 1,25OHD levels compared with 25OHD levels. A vicious cycle of 1,25OHD and renal dysfunction may make this association stronger than that of 25OHD levels. We hypothesized that 1OHase in the kidney was impaired by renal dysfunction, and when 25OHD levels decreased during winter, 1,25OHD levels also decreased in parallel to the levels of 25OHD.