Association of Obesity-Related Genetic Variants with Renal Biomarkers: A Case-Control Study

Abstract

Obesity is a heritable and modifiable driver of chronic kidney disease (CKD), acting via glomerular hyperfiltration, ectopic lipid deposition, RAAS activation, and adipokine-driven inflammation, though whether obesity-susceptibility variants track with subclinical renal injury independent of attained body weight remains unclear. This study compared risk-allele frequencies of four validated obesity-susceptibility variants (FTO rs9939609, MC4R rs17782313, TMEM18 rs6548238, FTO rs1421085) between obese and non-obese adults, quantified their association with a five-marker renal panel, and tested whether a composite genetic risk score (GRS) shows a dose–response relationship with renal function, using an age- and sex-matched case–control study of 600 adults (300 obese, BMI ≥30 kg/m²; 300 controls, BMI 18.5–24.9 kg/m²) from 742 screened. Renal status was assessed via serum creatinine, CKD-EPI eGFR, cystatin C, urinary albumin-to-creatinine ratio (UACR), and serum uric acid; SNPs were genotyped by TaqMan (call rate >98%); multivariable linear/logistic regression adjusted for age, sex, systolic blood pressure, and smoking, with the Benjamini–Hochberg procedure controlling false-discovery rate. Cases and controls were matched on age (44.8 vs 44.1 years) and sex (54.0% vs 55.3% female). Cases had higher BMI (34.6 vs 22.3 kg/m²), waist circumference (108.5 vs 82.4 cm), and systolic BP (131 vs 121 mmHg; all P<0.001), with lower eGFR (92.4 vs 101.7 mL/min/1.73 m²) and higher UACR (median 14.8 vs 7.9 mg/g), cystatin C (0.94 vs 0.85 mg/L), and uric acid (6.2 vs 5.3 mg/dL; all P<0.001). Risk-allele frequencies were higher in cases for FTO rs9939609 (0.51 vs 0.39, P<0.001; OR 1.62), MC4R rs17782313 (0.29 vs 0.22, P=0.013; OR 1.44), and FTO rs1421085 (0.49 vs 0.38, P<0.001; OR 1.57), but not TMEM18 rs6548238 (0.86 vs 0.83, P=0.28). Each FTO rs9939609 risk allele was associated with lower eGFR (β=−0.34 SD, P=0.001) and higher UACR (β=0.28 SD, P=0.002), with stepwise eGFR decline across TT→AT→AA genotypes (P-trend=0.004). The GRS showed a graded, per-allele relationship with eGFR (β=−0.29 SD, P<0.001; q=0.002), UACR (β=0.24, P=0.002), uric acid (β=0.21, P=0.004), creatinine (β=0.17, P=0.019), and cystatin C (β=0.15, P=0.038), while TMEM18 was not associated with any biomarker. Obesity-risk alleles, individually and in aggregate, are associated with early renal functional impairment independent of measured adiposity and classical risk factors, supporting shared genetic architecture between adiposity and nephron stress and identifying a genetically defined subgroup for earlier surveillance.