Synergistical action of the β2 adrenoceptor and fatty acid binding protein 2 polymorphisms on the loss of glomerular filtration rate in Chinese patients with type 2 diabetic nephropathy
- 31 Downloads
Since altered sympathetic nerve activity and insulin resistance are implicated in the pathogenesis of type 2 diabetic nephropathy, we investigated the effect of polymorphic Arg16Gly and Gln27Glu in the β2 adrenoceptor gene and Ala54Thr in the fatty acid binding protein 2 gene on the estimated glomerular filtration rate (eGFR) in Chinese patients with the above disease.
A total of 552 diabetic subjects recruited from annual health examinations were studied. The eGFR was calculated from the Modification of Diet in Renal Disease equation for the Chinese. Plasma norepinephrine level and genotype were determined by high-performance liquid chromatography–tandem mass spectrometry and TaqMan method, respectively. Holter-derived heart rate viability (HRV) and the MRI-generated renal apparent diffusion coefficient (ADC) were evaluated.
The Gly16Gly and Thr54Thr homozygotes had significantly higher microalbuminuria and lower eGFR against other genotypes in their individual polymorphism. Besides, the Gly16Gly variant exhibited markedly elevated norepinephrine level, whereas indicative of insulin resistance was increased in the Thr54Thr one. Multiple linear regression analysis further confirmed the independent genetic effect on the eGFR. Moreover, multifactor dimensionality reduction method detected a gene–gene synergistic action that subjects with the Gly16Gly/Thr54Thr genotype were exposed to higher risk of eGFR loss. Finally, these findings were accompanied by lower HRV and ADC, indicating sympathetically mediated hemodynamic changes.
By uncovering the genetic component of the coherent interplay between the elevated sympathetic nerve activity and metabolic disorders, our observations might promote the development of novel personalized prevention and management strategies against the diabetic nephropathy, especially in the genetically susceptible individuals.
KeywordsType 2 diabetes Diabetic nephropathy Single nucleotide polymorphism β2-Adrenergic receptor Fatty acid binding protein-2
The authors thank Eric J. Gayetsky (Dublin, OH, USA) for English language editing and. Dr. HongYu Geng for the data collection especially the HRV.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 3.Joles JA, Koomans HA (2004) Causes and consequences of increased sympathetic activity in renal disease. Hypertension 43(4):699–706. https://doi.org/10.1161/01.HYP.0000121881.77212.b1 CrossRefPubMedGoogle Scholar
- 8.Chen Y, Lipkowitz MS, Salem RM, Fung MM, Bhatnagar V, Mahata M, Nievergelt CM, Rao F, Mahata SK, Schork NJ, Hicks PJ, Bowden DW, Freedman BI, Brophy VH, O’Connor DT, AASK (2010) Progression of chronic kidney disease: adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis. Am J Nephrol 32(1):23–30. https://doi.org/10.1159/000313927 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Canani LH, Capp C, Ng DP, Choo SG, Maia AL, Nabinger GB, Santos K, Crispim D, Roisemberg I, Krolewski AS, Gross JL (2005) The fatty acid-binding protein-2 A54T polymorphism is associated with renal disease in patients with type 2 diabetes. Diabetes 54(11):3326–3330. https://doi.org/10.2337/diabetes.54.11.3326 CrossRefPubMedGoogle Scholar
- 11.Masuo K, Katsuya T, Sugimoto K, Kawaguchi H, Rakugi H, Ogihara T, Tuck ML (2007) High plasma norepinephrine levels associated with beta2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals. Hypertens Res 30(6):503–511. https://doi.org/10.1291/hypres.30.503 CrossRefPubMedGoogle Scholar
- 12.Weiss EP, Brown MD, Shuldiner AR, Hagberg JM (2002) Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects. Physiol Genomics 10(3):145–157. https://doi.org/10.1152/physiolgenomics.00070.2001 CrossRefPubMedGoogle Scholar
- 13.Yoshida T, Kato K, Yokoi K, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Suzuki T, Nozawa Y, Yamada Y (2009) Association of genetic variants with chronic kidney disease in Japanese individuals with type 2 diabetes mellitus. Int J Mol Med 23(4):529–537. https://doi.org/10.3892/ijmm_00000161 PubMedGoogle Scholar
- 15.Wang T, Karino K, Yamasaki M, Zhang Y, Masuda J, Yamaguchi S, Shiwaku K, Nabika T (2009) Effects of G994T in the Lp-PLA2 gene on the plasma oxidized LDL level and carotid intima-media thickness in Japanese—the Shimane Study. Am J Hypertens 22(7):742–747. https://doi.org/10.1038/ajh.2009.70 CrossRefPubMedGoogle Scholar
- 16.Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML (2003) Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42(4):474–480. https://doi.org/10.1161/01.HYP.0000091371.53502.D3 CrossRefPubMedGoogle Scholar
- 17.Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, Wang M, Xu GB, Wang HY (2006) Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 17:2927–2944. https://doi.org/10.1681/ASN.2006040368 CrossRefGoogle Scholar
- 20.Wang T, Zhang Y, Ma J, Feng Z, Niu K, Liu B (2014) Additive effect of polymorphisms in the β2-adrenoceptor and NADPH oxidase p22phox genes contributes to the loss of estimated glomerular filtration rate in Chinese. Clin Exp Pharmacol Physiol 41(9):657–662. https://doi.org/10.1111/1440-1681.12268 PubMedGoogle Scholar
- 25.Atala MM, Goulart A, Guerra GM, Mostarda C, Rodrigues B, Mello PR, Casarine DE, Irigoyen MC, Pereira AC, Consolim-Colombo FM (2015) Arg16Gly and Gln27Glu β2 adrenergic polymorphisms influence cardiac autonomic modulation and baroreflex sensitivity in healthy young Brazilians. Am J Transl Res 7(1):153–161PubMedPubMedCentralGoogle Scholar
- 28.Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147. https://doi.org/10.1086/321276 CrossRefPubMedPubMedCentralGoogle Scholar