Association of mTOR genetic variants and kidney function decline in Chinese with type 2 diabetes: The Hong Kong Diabetes Registry (HKDR)
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Gene-environment interaction mediates sexual dimorphism in chronic kidney disease (CKD). As mTOR pathway regulates energy metabolism and drives kidney injury, its genetic polymorphisms potentially accelerate CKD progression with gender difference in type 2 diabetes (T2D).

We estimated annual estimated glomerular filtration rate (eGFR) change (slope) from a least-square regression model using ≥3 eGFR follow-up measurements from HKDR participants (1994-2007) with data censored on 31 May 2015. We included participants with CKD (eGFRcreat <60ml/min/1.73m2 [CKD-EPI-equation]) diagnosed at baseline or during follow-up. In a linear regression analysis, we examined associations of 35 genotyped single nucleotide polymorphisms (SNPs) within mTOR locus (minor allele frequency ≥0.01) with slope in an additive model, stratified by gender and adjusting for age, duration of diabetes, baseline eGFR and principal components of global ancestry.

We included 5017 participants (3139 CKD, 1878 non-CKD) after a mean 12-year follow-up. At baseline, mean age was 57.6±12.9 years, median (interquartile range, IQR) duration of diabetes was 6 (2-11) years with 1483 (64.7%) men and 1656 (60.8%) women having CKD. During follow up, the median (IQR) slope was -1.04 (-2.75 to -0.17) in men and -1.11 (-2.48 to -0.23) ml/min/1.73m2/year in women (P=0.911). The respective values were -3.08 (-3.70 to -0.75) in CKD and -0.41 (-0.90 to 0.13) ml/min/1.73m2/year in non-CKD cohorts (P=0.000). In the CKD cohort, rs12133922, rs6685950, rs2275525, rs6701524 and rs1074078 showed greater eGFR decline in women than men (betawomen -0.120 to -0.019, betamen 0.010-0.058, Psex-interaction=0.003-0.019). The effect sizes of rs2275525, rs6701524 and rs1074078 were aggravated in women (betawomen -0.145 to -0.039, betamen 0.010-0.096, Psex-interaction=0.000-0.017) after further adjusting for baseline cardiovascular risk-factors, albuminuria, smoking status and drug use. In this model, the effect sizes in both genders for rs6685950 were attenuated whilst rs12133922 lost its significance for gender difference.

Besides conventional risk-factors, accelerated kidney function decline was associated with 5 mTOR variants in Chinese with T2D and CKD with gender difference.
Acceptance Date05/10/2017
All Author(s) ListLee-Ling Lim, Katie K.H. Chan, Ronald C.W. Ma, Eric S.H. Lau, Claudia H.T. Tam, Guozhi Jiang, Heung-Man Lee, Cadmon K.P. Lim, Alex C.W. Ng, Risa Ozaki, Andrea O.Y. Luk, Juliana C.N. Chan, Alice P.S. Kong
Name of Conference15th Symposium of the International Diabetes Epidemiology Group
Start Date of Conference08/12/2017
End Date of Conference10/12/2017
Place of ConferenceAbu Dhabi
Country/Region of ConferenceUnited Arab Emirates
LanguagesEnglish-United Kingdom
Keywordsgenetic, diabetic kidney disease

Last updated on 2018-13-06 at 09:51