Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation

S Chand; A J McKnight; S Shabir; W Chan; J A McCaughan; A P Maxwell; L Harper; R Borrows

doi:10.1016/j.bbacli.2015.12.004

Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation

S Chand, A J McKnight, S Shabir, W Chan, J A McCaughan, A P Maxwell, L Harper, R Borrows

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

INTRODUCTION: Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.

METHODS: One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.

RESULTS: Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05.

CONCLUSION: This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.

GENERAL SIGNIFICANCE: 1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.

Original language	English
Pages (from-to)	41-45
Number of pages	5
Journal	Biochimica et Biophysica Acta. Clinical
Volume	5
Early online date	8 Jan 2016
DOIs	https://doi.org/10.1016/j.bbacli.2015.12.004 https://doi.org/10.1016/j.bbacli.2015.12.004
Publication status	Published - Jun 2016

Keywords

New-onset diabetes after transplantation
single nucleotide polymorphisms
mTOR

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

Cite this

Chand, S., McKnight, A. J., Shabir, S., Chan, W., McCaughan, J. A., Maxwell, A. P., Harper, L., & Borrows, R. (2016). Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation. Biochimica et Biophysica Acta. Clinical, 5, 41-45. Advance online publication. https://doi.org/10.1016/j.bbacli.2015.12.004, https://doi.org/10.1016/j.bbacli.2015.12.004

@article{52e0fb66844f4d7bb91e7f000def3f3c,

title = "Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation",

abstract = "INTRODUCTION: Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.METHODS: One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.RESULTS: Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05.CONCLUSION: This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.GENERAL SIGNIFICANCE: 1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.",

keywords = "New-onset diabetes after transplantation , single nucleotide polymorphisms , mTOR",

author = "S Chand and McKnight, {A J} and S Shabir and W Chan and McCaughan, {J A} and Maxwell, {A P} and L Harper and R Borrows",

year = "2016",

month = jun,

doi = "10.1016/j.bbacli.2015.12.004",

language = "English",

volume = "5",

pages = "41--45",

journal = "Biochimica et Biophysica Acta. Clinical",

issn = "2214-6474",

publisher = "Elsevier",

}

Chand, S, McKnight, AJ, Shabir, S, Chan, W, McCaughan, JA, Maxwell, AP, Harper, L & Borrows, R 2016, 'Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation', Biochimica et Biophysica Acta. Clinical, vol. 5, pp. 41-45. https://doi.org/10.1016/j.bbacli.2015.12.004, https://doi.org/10.1016/j.bbacli.2015.12.004

TY - JOUR

T1 - Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation

AU - Chand, S

AU - McKnight, A J

AU - Shabir, S

AU - Chan, W

AU - McCaughan, J A

AU - Maxwell, A P

AU - Harper, L

AU - Borrows, R

PY - 2016/6

Y1 - 2016/6

N2 - INTRODUCTION: Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.METHODS: One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.RESULTS: Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05.CONCLUSION: This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.GENERAL SIGNIFICANCE: 1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.

AB - INTRODUCTION: Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.METHODS: One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.RESULTS: Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05.CONCLUSION: This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.GENERAL SIGNIFICANCE: 1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.

KW - New-onset diabetes after transplantation

KW - single nucleotide polymorphisms

KW - mTOR

U2 - 10.1016/j.bbacli.2015.12.004

DO - 10.1016/j.bbacli.2015.12.004

M3 - Article

C2 - 27051588

SN - 2214-6474

VL - 5

SP - 41

EP - 45

JO - Biochimica et Biophysica Acta. Clinical

JF - Biochimica et Biophysica Acta. Clinical

ER -

Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this