K121Q allele has been associated with increased risk for type 2 diabetes in several populations,14
including the Framingham cohort.15
Although induced impairment in the insulin signaling pathway seems to be the main mediator of systemic insulin resistance and susceptibility to type 2 diabetes conferred by this allele (gain of function),16
the mechanistic details whereby ENPP1
K121Q increases diabetes risk is still under active investigation. There are no data regarding the contribution of this allele in diabetes development for special populations. Our study evaluated the role of polymorphic ENNP1
in predicting development of diabetes in patients who undergo kidney transplant for reasons other than diabetic nephropathy. Previous studies have indicated that approximately 16% of the transplanted patients develop diabetes within 1 year.4
We found about 30% of the transplant patients in our cohort developed diabetes. This higher frequency could be related to the high percentage of blacks participating in our study. Genetic susceptibility could interact with other known contributing variables such as age, increased BMI, and antirejection therapy to increase risk for PTDM.
We found that the frequency of ENPP1 121Q allele is higher in the PTDM group than in the group of transplant patients who did not develop diabetes within 1 year. We also found that the ENPP1 K121Q variant has a strong association with PTDM in the logistic regression and ROC analysis (). However, because our population included three major different ethnicity/race groups, and because the risk for diabetes is related to ethnicity/race, the overall results do not allow a firm conclusion on the allele effects on PTDM risk. With the limitations derived by the relatively small number of study subjects, our study confirms several previous observations reported in regard to predictors of PTDM risk. We confirmed that age, ethnicity, BMI, and therapy with tacrolimus are significant predictors.
Larger studies on the effects of genetics in predicting onset of PTDM have been performed in a Korean population and suggested that genetic variants, such as SLC30A8, TCF7L2, HHEX, CDKLA1, CDKN2A/B, and KCNQ1 are associated with increased risk for PTDM.7–9
K121Q-adjusted OR in our population was 1.4 for the risk of developing diabetes after transplant, which is consistent an expected clinical effect size. The width of the 95% CI from 0.5 to 4.2 (adjusted for race, age, BMI, and tacrolimus) indicates that our study was not powered to detect this size of OR. The analysis is further complicated by the much higher prevalence of the polymorphism in blacks, a well-represented population among the transplant patients in the United States. Hence, the lack of an independent genetic effect on the risk for development of diabetes in our transplant population could be due to a type 2 statistical error. On the other hand, because the ENPP1
121Q allele is thought to increase diabetes risk through worsening insulin resistance, the apparent lack of a significant independent effect of this allele in our study could be related to a predominantly β-cell-dependent mechanism of hyperglycemia on PTDM.
Future studies in much larger sample size will allow discriminating the role of genetics of insulin resistance versus β-cell dysfunction and race/ethnicity in PTDM risk. Of interest in our study, the gene allele frequency within Hispanics and blacks was similar in the study subjects as compared to the general population (). However, the frequency of ENPP1
K121Q was significantly higher in the white study group as compared to the Dallas Heart Study whites (). We do not have an explanation for this finding. However, two previous studies performed in both type 117
and type 2 diabetes patients18
have suggested a role of the polymorphic ENPP1
K121Q in early development of nephropathy. Eller et al.19
have also reported that in patients with end-stage renal disease receiving dialysis, ENPP1
K121Q variant associates with higher vascular calcifications. The mechanisms involved in these findings are unclear, but they clearly suggest accelerated progression of renal disease in the presence of other initiating etiologic factors (diabetes or end-stage renal disease from other causes) in carriers of K121Q allele and could explain the increased frequency of ENPP1
K121Q in the white group of our study cohort. Clearly, the possibility of an effect of ENPP1
121Q allele on kidney dysfunction leading to transplant in nondiabetic patients deserves further investigation in a much larger cohort.
A previous analysis of U.S. Renal Data System in Medicare beneficiaries who had received kidney transplants identified a PTDM relative risk increase of 68% for African Americans and 35% increase for Hispanics, when compared to the white patients.4
That study also identified age, BMI, HCV, and use of tacrolimus as predictors of PTDM. In our study, black race was the strongest predictor of PTDM risk. Over 90% of blacks developed PTDM within 1 year of observation. The ROC analysis depicted in shows that adding the information of age to the black race provided the most robust information (ROC-AUC 0.78). Adding BMI and tacrolimus treatment did not improve prediction of risk.
In conclusion, this study conducted in a series of consecutive, unrelated patients who underwent kidney transplantation revealed black race and age to be the major determinants of risk for development of diabetes mellitus within 1 year from transplant. BMI and use of tacrolimus also contributed to increasing relative risk but the incremental effect was small. The role of ENPP1 K121Q genetic variant remains uncertain and is not independently associated with PTDM in this study. Larger studies are needed to assess the independent contribution of genetics to development of PTDM, a major cause of morbidity, transplant failure, and overall mortality for the transplanted patient population.