Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation: Insight into mechanisms of disease

K. D. Watt, R. Dierkhising, C. Fan, J. K. Heimbach, H. Tillman, D. Goldstein, A. Thompson, A. Krishnan, M. R. Charlton

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Abstract

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients. Analysis of donor and recipient genetic risk factors for obesity and diabetes after transplant finds that recipient, but not donor, PNPLA-3 G allele is independently associated with obesity after liver transplantation, pointing to a peripheral rather than central mechanism of action and explaining some of the risk for posttransplant obesity.

Original languageEnglish (US)
Pages (from-to)2450-2457
Number of pages8
JournalAmerican Journal of Transplantation
Volume13
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Liver Transplantation
Obesity
Genotype
Fasting
Tissue Donors
Glucose
Alleles
Insulin Resistance
Transplantation
Odds Ratio
Liver

Keywords

  • Diabetes
  • genetic risk
  • insulin resistance
  • liver transplant
  • obesity

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

Cite this

Watt, K. D., Dierkhising, R., Fan, C., Heimbach, J. K., Tillman, H., Goldstein, D., ... Charlton, M. R. (2013). Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation: Insight into mechanisms of disease. American Journal of Transplantation, 13(9), 2450-2457. https://doi.org/10.1111/ajt.12355

Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation : Insight into mechanisms of disease. / Watt, K. D.; Dierkhising, R.; Fan, C.; Heimbach, J. K.; Tillman, H.; Goldstein, D.; Thompson, A.; Krishnan, A.; Charlton, M. R.

In: American Journal of Transplantation, Vol. 13, No. 9, 09.2013, p. 2450-2457.

Research output: Contribution to journalArticle

Watt, KD, Dierkhising, R, Fan, C, Heimbach, JK, Tillman, H, Goldstein, D, Thompson, A, Krishnan, A & Charlton, MR 2013, 'Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation: Insight into mechanisms of disease', American Journal of Transplantation, vol. 13, no. 9, pp. 2450-2457. https://doi.org/10.1111/ajt.12355
Watt, K. D. ; Dierkhising, R. ; Fan, C. ; Heimbach, J. K. ; Tillman, H. ; Goldstein, D. ; Thompson, A. ; Krishnan, A. ; Charlton, M. R. / Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation : Insight into mechanisms of disease. In: American Journal of Transplantation. 2013 ; Vol. 13, No. 9. pp. 2450-2457.
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abstract = "To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7{\%}, CG 48.3{\%} and GG 82.4{\%}, p = 0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients. Analysis of donor and recipient genetic risk factors for obesity and diabetes after transplant finds that recipient, but not donor, PNPLA-3 G allele is independently associated with obesity after liver transplantation, pointing to a peripheral rather than central mechanism of action and explaining some of the risk for posttransplant obesity.",
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AU - Heimbach, J. K.

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