Abstract
KEY POINTS: Genetic factors are key players in CKD, with two linked single-nucleotide polymorphisms in the GTF2I gene, associated with CKD susceptibility in the Taiwanese population. Individuals with specific GTF2I genotypes (CT/TT for rs117026326 and CT/CC for rs73366469) show higher CKD prevalence and earlier onset. Men with the specific genotypes of rs117026326 and rs73366469 face a heightened CKD risk compared with women, particularly at lower eGFR. BACKGROUND: CKD poses a global health challenge, but its molecular mechanisms are poorly understood. Genetic factors play a critical role, and phenome-wide association studies and genome-wide association studies shed light on CKD's genetic architecture, shared variants, and biological pathways. METHODS: Using data from the multicenter collaborative precision medicine cohort, we conducted a retrospective prospectively maintained cross-sectional study. Participants with comprehensive information and genotyping data were selected, and genome-wide association study and phenome-wide association study analyses were performed using the curated Taiwan Biobank version 2 array to identify CKD-associated genetic variants and explore their phenotypic associations. RESULTS: Among 58,091 volunteers, 8420 participants were enrolled. Individuals with CKD exhibited higher prevalence of metabolic, cardiovascular, autoimmune, and nephritic disorders. Genetic analysis unveiled two closely linked single-nucleotide polymorphisms, rs117026326 and rs73366469, both associated with GTF2I and CKD (r(2) = 0.64). Further examination revealed significant associations between these single-nucleotide polymorphisms and various kidney-related diseases. The CKD group showed a higher proportion of individuals with specific genotypes (CT/TT for rs117026326 and CT/CC for rs73366469), suggesting potential associations with CKD susceptibility (P < 0.001). Furthermore, individuals with these genotypes developed CKD at an earlier age. Multiple logistic regression confirmed the independent association of these genetic variants with CKD. Subgroup analysis based on eGFR demonstrated an increased risk of CKD among carriers of the rs117026326 CT/TT genotypes (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.07 to 1.24; P < 0.001; OR, 1.32, 95% CI, 1.04 to 1.66; P = 0.02, respectively) and carriers of the rs73366469 CT/CC genotypes (OR, 1.13; 95% CI, 1.05 to 1.21; P < 0.001; OR, 1.31; 95% CI, 1.08 to 1.58; P = 0.0049, respectively). In addition, men had a higher CKD risk than women at lower eGFR levels (OR, 1.35; 95% CI, 1.13 to 1.61; P < 0.001). CONCLUSIONS: Our study reveals important links between genetic variants GTF2I and susceptibility to CKD, advancing our understanding of CKD development in the Taiwanese population and suggesting potential for personalized prevention and management strategies. More research is needed to validate and explore these variants in diverse populations.