P-selectin gene haplotype associations with albuminuria in the Diabetes Heart Study

Abstract

Background. Adhesion molecules, such as P-selectin, play a pivotal role in leukocyte adhesion to the endothelium during inflammation. We investigated the relationship between P-selectin gene polymorphisms and albuminuria in 565 European American siblings (84% with type 2 diabetes) from 227 families participating in the Diabetes Heart Study (DHS). Methods. Three common missense P-selectin polymorphisms (S290N, N562D, and T715P) were genotyped. Albuminuria was defined as an albumin:creatinine ratio (ACR) ≥ 17 mg/g in males, and ≥ 25 mg/g in females. Tests of association were based on generalized estimating equations (GEE1) and tests of linkage disequilibrium were based on the quantitative pedigree disequilibrium test (QPDT). Results. Each copy of the 290Asn (S290N) allele was associated with a 45% absolute increase in ACR (P = 0.007), and a higher risk for the presence of albuminuria [odds ratio (OR), 1.71 for each 290A sn allele] (P = 0.002). Adjustment for other determinants of ACR, including stratification by age, gender, and presence of diabetes, did not alter these results. Haploytpe analyses using both GEE1 and QPDT methods revealed that the N-N-T haplotype, containing asparagine codons at sites S290N and N562D, was associated with an increased risk of albuminuria (OR 1.77) (P = 0.005, for each additional copy of the N-N-T haplotype). Conclusion. The 290Asn (S290N) variant of P-selectin was associated with a higher prevalence and greater degree of albuminuria in European American siblings of type 2 diabetic families. © 2005 by the International Society of Nephrology.