Download β cell glucotoxic-associated SNPs in impaired glucose tolerance

2099
β cell glucotoxic-associated SNPs in impaired glucose tolerance and NODAT
Chand S1, Shabir S1, Chan W1, McCaughan J2, McKnight AJ2, Maxwell AP2, Borrows R1
1
Renal Department, Queen Elizabeth Hospital Birmingham, 2Regional Genetics Unit, Belfast City
BACKGROUND: Despite successes in first year survival in renal transplantation, impaired glucose
tolerance (IGT) and new onset diabetes after transplantation (NODAT) remain significant risk factors
for morbidity and mortality in this population. Recently, 8 potential risk associated single nucleotide
polymorphisms (SNPs) have been identified suggestive of a pancreatic β cell glucotoxic pathway to
NODAT development following a GWAS and de novo genotyping of a Belfast renal transplant
population from 1986 to 2005 (McCaughan et al, JASN 2014). The purpose of this study was to seek
replication in a contemporary renal transplant population, using biochemical diagnoses of IGT and
NODAT.
METHODS: From 2009 to 2012, 113 patients were prospectively followed-up for 12months after
renal transplantation in a single centre adult tertiary centre with oral glucose tolerance tests (OGTT)
performed at baseline, 7 days, 3 months and 12 months, if initial fasting glucose or HbA1c tests did
not identify those with IGT or NODAT. IGT was diagnosed if the 2hour OGTT glucose was 7.811mmol/l and NODAT if either HbA1c ≥6.5%, fasting glucose ≥7mmol/l or 2hour OGTT
≥11.1mmol/l. Exclusion criteria of pre-transplant diabetes and non-white ethnicity resulted in 68
patients being tested for 8 SNPs (spanning several potential candidate genes): rs10484821,
rs11580170, rs1836882, rs198372, rs2020902, rs2861484, rs4394754, rs7533125; genotyping was
performed using Sequenom iPLEX and Taqman technologies. Event analyses using binary logistic
regression was used adjusting for age, gender, baseline BMI and change in BMI over 12 months.
RESULTS: IGT or NODAT occurred in over half the study population, with median time of onset 7
days and 18 days respectively post transplantation (IQR 7-90). There were no significant differences
in diagnoses or transplant immunosuppression regimens between those with or without IGT and
NODAT. Significant differences were seen in the BMI change over 12 months for those who
developed IGT (p=0.007) and NODAT (p=0.002) compared to those who did not. The NODAT group
were also significantly older compared to those without NODAT (54years vs 41 years of age;
p=0.002).
Rs198372 genotype GG (vs nonGG) was protective for IGT onset (OR 0.21(0.05-0.88)); p=0.033).
No other SNPs were significant for NODAT or IGT.
CONCLUSIONS: These results do not replicate those found in the Belfast cohort as expected with
this sized cohort. The cohorts differ in nature and definition of NODAT. The Birmingham cohort all
received CNI therapy over 12 months, whilst 25% Belfast had CNI-free regimens, with 9.6% of their
population developing NODAT over a median follow-up of 12 years (57 patients with a median onset
of 100 months). In Birmingham, at 12 months, over 25% (18 patients) developed IGT in 12 months,
whilst the same number had NODAT diagnosed over a median period of 18days. One candidate SNP
that was found to be associated with post-transplant hyperglycaemia in both cohorts was rs198372 for
gene NPPA. This encodes natriuretic peptides that have been shown to inhibit cytokine and leptin
production that are linked to inflammation and insulin resistance in human adipose tissue. Elevated
leptin levels increase IL-1β promoting βcell apoptosis in pancreatic islets and free fatty acids inducing
apoptosis by caspase activation. This study supports further replication of the initial Belfast findings
and investigation in rs198372 as an important SNP for identifying those at risk for developing IGT
and a biochemical pathway for manipulation.