Association between PNPLA2 Gene Polymorphisms and the Risk of Diabetic Kidney Disease in a Chinese Han Population with Type 2 Diabetes

Abstract

<jats:p>Diabetic kidney disease (DKD) is one of the most common complications of diabetes and the leading cause of end-stage renal disease. Here, we investigated the association of <jats:italic>PNPLA2</jats:italic> gene variations with DKD susceptibility in a Chinese Han population. A total of 818 participants with type 2 diabetes were recruited in the case-control study, including 379 patients diagnosed with DKD. We observed that 2 tagSNPs, <jats:italic>PNPLA2</jats:italic> rs28633403 (A&gt;G) and rs1138714 (A&gt;G), were associated with DKD (rs28633403: genotype, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.017</mml:mn></mml:math>; allele, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.015</mml:mn></mml:math>; rs1138714: genotype, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.029</mml:mn></mml:math>; allele, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.018</mml:mn></mml:math>). <jats:italic>PNPLA2</jats:italic> rs1138693 (T&gt;C), a missense SNP, showed no association with DKD (genotype, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.966</mml:mn></mml:math>; allele, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.845</mml:mn></mml:math>). Genetic model analysis revealed that minor allele G of <jats:italic>PNPLA2</jats:italic> rs28633403 was a protective factor of DKD in a dominant model adjusted by confounders (AG+GG vs. AA: adjusted odds ratio (aOR), 0.619; 95% CI 0.447-0.857; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.004</mml:mn></mml:math>) and in an additive model (AG vs. AA: aOR, 0.633; 95% CI 0.447-0.895; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.010</mml:mn></mml:math>; GG vs. AA: aOR, 0.588; 95% CI 0.385-0.897; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.014</mml:mn></mml:math>). Minor allele G of <jats:italic>PNPLA2</jats:italic> rs1138714 was associated with a higher risk of DKD in a dominant model adjusted by confounders (AG+GG vs. AA: adjusted odds ratio (aOR), 1.531; 95% CI 1.134-2.067; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.005</mml:mn></mml:math>) and in an additive model (AG vs. AA: aOR, 1.529; 95% CI 1.118-2.091; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.008</mml:mn></mml:math>). The combined effect of <jats:italic>PNPLA2</jats:italic> rs28633403 AA+rs1138714 AG or GG genotype showed an association with DKD, adjusted by confounders (aOR, 2.194; 95% CI 1.378-3.492; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.001</mml:mn></mml:math>), which was considered statistically significant with a markedly increased risk of DKD after a Holm-Bonferroni correction for multiple tests (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.00125</mml:mn></mml:math>). Our results suggest that <jats:italic>PNPLA2</jats:italic> rs28633403 and rs1138714 are significantly associated with the risk of DKD in a Chinese Han population with type 2 diabetes.</jats:p>

Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats

“… 29 Pnpla2 was associated with non-alcoholic fatty liver disease in an obese population and developing renal complications within a diabetic population. 30 , 31 Kim et al 32 demonstrated that ATGL/ Pnpla2 expression is downregulated by insulin and TNF-α in adipocytes at both protein and mRNA levels. This correlates with the findings of our study, with the downregulation of Pnpla2 mRNA likely reflecting the hyperinsulinaemic and hyperinflammatory state of diabetic rodents.…”

Cytosolic lipolysis in non‐adipose tissues: energy provision and beyond

“…In addition, NLSD patients often display several clinical features in non-adipose tissues, such as ichthyosis, myopathy, pancreatitis, cardiac abnormalities, and neurological disorders, including mental retardation and impaired cognition [7][8][9][10]. Genetic polymorphisms of ATGL are associated with increased risk of diabetic kidney disease, and mutation in HSL is associated with increased risk of type II diabetes [11,12]. Since the role of cytosolic lipolysis in adipose tissue, muscle, and liver has been extensively reviewed [4][5][6], this review will focus on the role and potential mechanism of cytosolic lipolysis in non-adipose tissues, including pancreas, heart, kidney, and nervous system.…”