Association between COL4A3 variant rs55703767 and susceptibility to diabetic kidney disease in patients with type 2 diabetes mellitus: results from the INDEED cohort study
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. The etiology of DKD is complex and remains largely unknown. A genome-wide association study previously identified a common missense variant in COL4A3, rs55703767, which was found to play a protective role in DKD in type 1 diabetes mellitus (T1DM) among Europeans. This protective effect was observed to depend on blood glucose levels. However, data on the association of this variant with DKD in type 2 diabetes mellitus (T2DM) are insufficient.
This case-control study aimed to investigate the association between the COL4A3 variant rs55703767 and susceptibility to DKD in patients with T2DM. The study was conducted as part of the INDEED (Incidence, Development, and Prognosis of Diabetic Kidney Disease) cohort study. The research complied with the Declaration of Helsinki and was approved by the Ethics Committee of Peking University First Hospital. Informed consent was obtained from each participant.
Patients were diagnosed with T2DM according to the American Diabetes Association criteria. Among these T2DM patients, those who developed kidney damage, defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m² or a urinary albumin-to-creatinine ratio (uACR) greater than 3.0 mg/mmol for more than three months, were classified as having DKD. Patients with coexisting non-diabetic-related renal diseases were excluded. All patients were required to have a minimum diabetes duration of 10 years. The study enrolled a total of 1311 T2DM patients, including 580 with DKD and 731 without DKD.
Demographic data were collected using standardized questionnaires. Laboratory tests included measurements of triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, fasting blood glucose (FBG), urinary creatinine, uACR, and urinary α1-microglobulin. These tests were conducted in the central laboratory at Peking University First Hospital.
DNA was extracted from peripheral blood samples, and the genotyping of rs55703767 was performed using the TaqMan SNP Genotyping Assay on the ViiA™ 7 Real-Time PCR System. Categorical variables, allele frequencies, and genotype distributions were compared using the chi-square test. Continuous variables were compared using the Student’s t-test. The Hardy-Weinberg equilibrium (HWE) was tested using the chi-square test with one degree of freedom. All P values were calculated based on two-tailed tests of statistical significance, with a P value less than 0.05 considered statistically significant. Statistical power was calculated using QUANTO, and data analysis was performed using SPSS version 23.0.
The general characteristics of the two groups were presented in a supplementary table. Patients with DKD had significantly higher levels of systolic and diastolic blood pressure, abdominal circumference, body mass index, triglycerides, total cholesterol, FBG, and serum creatinine, and a lower level of eGFR compared to those without DKD. Both groups were in accordance with the HWE, indicating the suitability of the population for genetic analysis.
The frequency distributions of the COL4A3 variant rs55703767 (G/T) genotypes in the T2DM without DKD group were as follows: GG, 589 (80.6%); GT, 135 (18.5%); and TT, 7 (0.9%). In the T2DM with DKD group, the distributions were: GG, 451 (77.8%); GT, 124 (21.4%); and TT, 5 (0.9%). There was no significant difference in the genotypic distribution between the two groups. The minor allele frequencies (MAFs) for the “T” allele of rs55703767 were 0.116 in the T2DM without DKD group and 0.102 in the T2DM with DKD group, consistent with the frequency in the Asian population (MAF = 0.11) provided by the ALFA project.
Dominant, recessive, overdominant, and additive model analyses were performed for the COL4A3 variant rs55703767. No significant difference in the genotypic distribution between the two groups was identified in any model. The association analysis of rs55703767 genotypes with clinical parameters showed that in the T2DM with DKD group, individuals with the TT genotype had a significantly higher level of HbA1c compared to those with GT/GG genotypes (P = 0.025).
The association analysis between rs55703767 and the risk of DKD was conducted by stratifying HbA1c levels below or above 7.5%, and no significant difference was observed. Further analysis using different cut-off levels of HbA1c from 6.0% to 9.0% also showed no significant difference. The differing results between this study and the study by Salem et al. regarding hyperglycemia specificity might be explained by several factors. First, the renal protective effect of rs55703767 may vary among different races. Second, this study focused on T2DM, whereas the study by Salem et al. focused on T1DM, which have different etiologies and pathogenesis. Third, the association between glucose levels and rs55703767 could be influenced by confounding factors such as hypoglycemic drugs.
This study has several limitations. First, although patients with regular follow-up visits from 2006 to 2016 were enrolled to ensure a minimum diabetes duration of 10 years, the exact duration of diabetes was not available. Second, the statistical power of the study, calculated using QUANTO, was only 25.59%, indicating that a larger sample size is warranted in future studies. Third, this was a single SNP study, and false-negative results could occur due to population structure.
In conclusion, the findings of this study suggest that there is no detectable association between the COL4A3 variant rs55703767 and susceptibility to DKD in the Chinese T2DM population.
doi.org/10.1097/CM9.0000000000001955
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