Association of Haptoglobin Genotype with Cardiovascular Disease and Left Ventricular Ejection Fraction in Kidney Transplant Recipients

Background: Cardiovascular disease remains a major determinant of long-term outcomes after kidney transplantation. Haptoglobin (HP) is a genetically polymorphic hemoglobin-binding protein involved in hemoglobin scavenging, oxidative stress, and inflammation. Although the HP 2–2 genotype has been associated with cardiometabolic risk in non-transplant populations, its clinical relevance after kidney transplantation remains uncertain. Methods: We conducted a single-center retrospective cohort study of 229 adult kidney transplant recipients who underwent recipient HP genotyping by polymerase chain reaction. Recipients were categorized a priori as HP 2–2 (n = 119) or non–HP 2–2 (HP 2–1/HP 1–1; n = 110). Documented cardiovascular disease burden, cardiometabolic characteristics, laboratory parameters, echocardiographic measures, overall biopsy-proven rejection, graft failure, death-censored graft survival, and all-cause mortality were analyzed. Multivariable logistic, linear, and Cox regression models were used as appropriate, with covariates selected according to clinical relevance and event number. Results: Compared with non–HP 2–2 recipients, HP 2–2 recipients had a higher prevalence of diabetes mellitus (23.5% vs. 12.7%; p = 0.03) and documented cardiovascular disease burden (24.4% vs. 10.9%; p = 0.008). Median left ventricular ejection fraction (LVEF) was lower in HP 2–2 recipients (65% [interquartile range (IQR), 60–67] vs. 68% [IQR, 62–70]; p < 0.001), with higher unadjusted frequencies of sex-defined left atrial enlargement and left ventricular hypertrophy. In multivariable analyses, HP 2–2 showed nominal associations with documented cardiovascular disease burden (adjusted odds ratio (aOR), 2.32; 95% confidence interval (CI), 1.07–5.03; p = 0.033; false discovery rate (FDR) q = 0.163) and lower continuous LVEF (β, −2.00 percentage points; 95% CI, −3.61 to −0.38; p = 0.015; FDR q = 0.154); neither association remained significant after FDR correction. In complementary allele-dosage analyses, increasing HP2 allele dosage remained associated with lower LVEF after FDR correction (β, −1.93 percentage points per additional HP2 allele; 95% CI, −3.20 to −0.65; p = 0.0033; FDR q = 0.036). Overall biopsy-proven rejection, graft failure, death-censored graft survival, and all-cause mortality were not associated with HP 2–2. Conclusions: Recipient HP 2–2 genotype showed nominal associations with greater documented cardiovascular disease burden and lower LVEF, whereas the graded inverse association between HP2 allele dosage and LVEF remained after FDR correction. These findings are exploratory and require prospective validation before clinical risk-stratification implications can be considered.