Date of Award
Doctor of Philosophy (PhD)
Donna Hathaway, Ph.D., R.N., F.A.A.N.
Yvette Conley, Ph.D. Patricia Cowan, Ph.D., R.N. Ramin Homayouni, Ph.D. Carol Thompson, Ph.D., D.N.P., A.C.N.P., F.N.P., C.C.R.N., F.C.C.M., F.A.A.N.P., F.A.A.N.
Background: Kidney transplant recipients are a population who experience a high likelihood of gaining a significant amount of weight (between 6 and 13 kilograms) during the first year after transplantation. However, not all kidney transplant recipients gain weight. Studies have found little difference in physical activity and nutritional intake among those who do and do not gain weight. Immunosuppressant medications have also not been shown to play a substantive role in post-transplant weight gain. Additionally, although some studies have shown that age, gender, and race can influence weight gain, this information does not fully capture the observed variance. These observations suggest that genetic factors may have a role in the differential weight gain experienced by kidney transplant recipients. Dopamine is a neurotransmitter that has previously been implicated in substance addiction. Recently, neuroimaging and neurogenetic data have shown that dopamine may also play a role in obesity. Both dopamine receptor genes and genes related to overall dopamine activity have been associated with obesity, weight gain, and food addiction. Gene expression studies in subcutaneous adipose tissue of kidney transplant recipients showed that expression of some dopaminergic pathway genes was negatively correlated with weight gain. Polymorphisms in some of these genes have been linked to weight gain by others. Taken together, these results suggest that genetic variation in some dopaminergic genes may underlie changes in their expression or function and may contribute to the risk for gaining weight. The purpose of the proposed study was to determine if polymorphisms associated with these previously found dopaminergic genes have predictive value when combined with demographic characteristics to identify kidney transplant recipients who are at risk of gaining weight.
Methods: The subjects for this study represent a subsample of participants in a previous observational study. As a part of this study, age, race, and gender information were collected, as well as baseline and twelve month weight and height. Additionally, white blood cells were collected at baseline. Quantitative real time polymerase chain reaction (qPCR) and restriction fragment length polymorphism (RFLP) techniques were used to determine the genotype of these dopaminergic polymorphisms noted in previous work and in the literature as being related to weight gain. This included a total of 10 variants in 7 genes: dopamine receptor type 2 gene (DRD2) single nucleotide polymorphisms (SNPs) rs1800497, rs6277, and rs12364283, dopamine receptor type 3 gene (DRD3) SNP rs6280, dopamine receptor type 4 gene (DRD4) variable number tandem repeat (VNTR), catechol-o-methyltransferase gene (COMT) SNPs rs4680 and rs4818, monoamine oxidase A gene (MAOA) VNTR, monoamine oxidase B gene (MAOB) SNP rs1799836, and dopamine active transporter gene (SLC6A3/DAT1) VNTR. Genotypes were analyzed using dose dependent and risk allele approaches, and those variants with p≤0.20 were included in regression modeling. Regression models were built in a stepwise manner, first by building a model with only demographic characteristics, then by building a model with only genetic variants. Next, models were built with demographic and just individual genetic variants, and finally a model was built with demographic and all genetic variants included.
Results: Seventy subjects were included in this study (43% female, 57% African American, mean age 50.7 ±13.2 years). Age was found to be weakly correlated with percent weight change (r=-0.32), but race and gender showed no appreciable relationship to percent weight change at 12 months. A simple regression of age on percent weight change was significant (p=0.006) and explained 11.2% of the variance. Multiple regression models of genetic and demographic factors explained between 11.4 and 25% of the variance, but no model reached statistical significance overall. However, age was consistently significant as a regressor. The SLC6A3/DAT1 9/10 genotype and the DRD2 rs1800497 TC genotype both approached significance in the modeling with p values of 0.08 and 0.07 respectively. The DRD2 rs1800497 genotype was also significantly correlated with percent weight gain in a dose dependent fashion (r=-0.28, p=0.05).
Conclusions: Increasing age is associated with less weight gain in the first year after kidney transplantation. Although the regression modeling failed to find significant association between weight gain and specific genotypes in the set of dopaminergic genes, this study was conducted as a pilot study to test the feasibility of the methodology. Even with the current sample size and effect size limitations, these results suggest that the DRD2 SNP rs1800497 and the SLC6A3/DAT1 VNTR have value in prediction of weight gain in kidney transplant recipients. To test the predictive value of these polymorphisms, further studies using a larger cohort of patients is required.
Stanfill, Ashley Grimes , "Dopaminergic Genetic Contributions to Obesity in Kidney Transplant Recipients" (2014). Theses and Dissertations (ETD). Paper 254. http://dx.doi.org/10.21007/etd.cghs.2014.0297.