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Fulltext Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease

Zhang X, Seman NA, Falhammar H, Brismar K, Gu HF

J Diabetes Res, 2020;2020:8305460.
PMID: 32626783 DOI: 10.1155/2020/8305460

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the ICAM1 gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of ICAM1 E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the ICAM1 E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.

Matched MeSH terms: Diabetic Nephropathies/genetics*
Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis

Ahmad N, Jamal R, Shah SA, Gafor AHA, Murad NAA

Curr Diabetes Rev, 2019;15(4):263-276.
PMID: 29984662 DOI: 10.2174/1573399814666180709100411

BACKGROUND: The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades.
OBJECTIVE: This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus.
METHODS: The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration.
RESULTS: In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model).
CONCLUSION: In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.

Matched MeSH terms: Diabetic Nephropathies/genetics*
Fulltext Gene expression profiling in ethnic Malays with type 2 diabetes mellitus, with and without diabetic nephropathy

Lokman FE, Seman NA, Ismail AA, Yaacob NA, Mustafa N, Khir AS, et al.

J Nephrol, 2011;24(6):778-89.
PMID: 21360476 DOI: 10.5301/JN.2011.6382

BACKGROUND: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) among type 2 diabetes mellitus patients (DM) in Malaysia. This study used microarray analysis to determine the gene expression profiling in ethnic Malay patients with type 2 DM.
METHODS: A total of 312 patients were recruited; 25 were on dialysis due to ESRD, 128 were classified as normoalbuminuric, 93 as microalbuminuric and 66 as macroalbuminuric, based on urine albumin to creatinine ratio of <3.5, between 3.5 and 35 and =35 mg/mmol, respectively.
RESULTS: Microalbuminuria was associated with up- and down-regulation of 2,694 and 2,538 genes, respectively, while macroalbuminuria was associated with up-regulation of 2,520 genes and down-regulation of 2,920 genes. There was significant up-regulation of 1,135 genes and down-regulation of 908 genes in the ESRD samples. Thirty-seven significantly up-regulated genes and 40 down-regulated genes were commonly expressed in all 3 groups of patients with worsening of renal functions. Up-regulated genes included major histocompatibility complex (HLA-C), complement component 3a receptor 1 (C3AR1), solute carrier family 16, member 3 (SLC16A3) and solute carrier family 9 (sodium/hydrogen exchanger) (SLC9A8). Consistently down-regulated genes included were bone morphogenetic phosphatase kinase (BMP2K), solute carrier family 12, member 1 (SLC12A1), solute carrier family 7 (SLC7A2), paternally expressed 10 (PEG10) and protein phosphatase 1 regulatory (inhibitor unit) (PPP1R1C).
CONCLUSION: This study has identified several genes of interest, such as HLA-C, SLC16A3, SLC9A8, SLC12A1 and SLC7A2, that require verification of their roles as susceptibility genes for diabetic nephropathy in ethnic Malays with type 2 DM.

Matched MeSH terms: Diabetic Nephropathies/genetics*
Gene-environment interaction in chronic kidney disease among people with type 2 diabetes from The Malaysian Cohort project: a case-control study

Ahmad N, Shah SA, Abdul Gafor AH, Abdul Murad NA, Kamaruddin MA, Abd Jalal N, et al.

Diabet Med, 2020 11;37(11):1890-1901.
PMID: 32012348 DOI: 10.1111/dme.14257

AIM: To examine the possible gene-environment interactions between 32 single nucleotide polymorphisms and environmental factors that could modify the probability of chronic kidney disease.
METHODS: A case-control study was conducted involving 600 people with type 2 diabetes (300 chronic kidney disease cases, 300 controls) who participated in The Malaysian Cohort project. Retrospective subanalysis was performed on the chronic kidney disease cases to assess chronic kidney disease progression from the recruitment phase. We genotyped 32 single nucleotide polymorphisms using mass spectrometry. The probability of chronic kidney disease and predicted rate of newly detected chronic kidney disease progression were estimated from the significant gene-environment interaction analyses.
RESULTS: Four single nucleotide polymorphisms (eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228) and five environmental factors (age, sex, smoking, waist circumference and HDL) were significantly associated with chronic kidney disease. Gene-environment interaction analyses revealed significant probabilities of chronic kidney disease for sex (PPARGC1A rs8192678), smoking (eNOS rs2070744, PPARGC1A rs8192678 and KCNQ1 rs2237895), waist circumference (eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228) and HDL (eNOS rs2070744 and PPARGC1A rs8192678). Subanalysis indicated that the rate of newly detected chronic kidney disease progression was 133 cases per 1000 person-years (95% CI: 115, 153), with a mean follow-up period of 4.78 (SD 0.73) years. There was a significant predicted rate of newly detected chronic kidney disease progression in gene-environment interactions between KCNQ1 rs2283228 and two environmental factors (sex and BMI).
CONCLUSIONS: Our findings suggest that the gene-environment interactions of eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228 with specific environmental factors could modify the probability for chronic kidney disease.

Matched MeSH terms: Diabetic Nephropathies/genetics*