Genetic disorders – Development
Kidney International (2003) 63, 1211–1219; doi:10.1046/j.1523-1755.2003.00856.x
Association of an IL-1A 3'UTR polymorphism with end-stage renal disease and IL-1
expression
Jeannette T Bensen, Carl D Langefeld, Liwu Li, Charles E Mccall, Susan L Cousart, Bonnie N Dryman, Barry I Freedman and Donald W Bowden
The Center for Human Genomics and Department of Public Health Sciences, Department of Internal Medicine, and Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Correspondence: Jeannette Bensen, Ph.D., The Center of Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. E-mail: jbensen@wfubmc.edu
Received 3 July 2002; Revised 3 October 2002; Accepted 11 November 2002.
Abstract
Association of anIL-1A 3'UTR polymorphism with end-stage renal disease and IL-1
expression.
Background
We evaluated polymorphisms in the interleukin-1 alpha 3'-untranslated region (IL-1A 3'[UTR]) for association with type 2 diabetes–associated (DM) and nondiabetic-associated (non-DM) end-stage renal disease (ESRD) in two ethnic groups.
Methods
3'UTR polymorphisms were identified by alignment of overlapping human expressed sequence tags (ESTs). Sequence ambiguities were experimentally confirmed and variants genotyped to test for association with ESRD in 75 unrelated Caucasians with DM ESRD, 95 unrelated Caucasian controls and, in a parallel study, 92 unrelated African Americans with type 2 DM ESRD, 95 unrelated African Americans with non-DM ESRD, and 86 unrelated African American controls. IL-1A 3' UTR genotype and lipopolysaccharide (LPS)-stimulated IL-1
protein levels were measured in healthy Caucasians (N = 112) and African Americans (N = 101) to evaluate association between genotype and protein level.
Results
A polymorphism in the 3' UTR of the human IL-1A gene was associated with ESRD and IL-1 protein expression. The polymorphism consists of two single nucleotide polymorphisms (SNPs) and an insertion/deletion generating four different haplotypes: TN7TTCAA, AN7TTCAA, TN7TTCAG and an allele deleted for four internal bases, TN7(delTTCA)A. The 4 bp deletion allele, TN7(delTTCA)A, was significantly less common among Caucasian DM ESRD and African American non-DM ESRD patients (recessive model; P = 0.0364 and P = 0.0293, respectively). In vitro, this polymorphism is associated with the amount of IL-1 protein synthesized in LPS-stimulated lymphocytes from healthy subjects (P = 0.0013, additive model), with the TN7(delTTCA)A haplotype associated with higher levels of stimulated IL-1.
Conclusion
The association of the TN7(delTTCA)A haplotype with higher levels of IL-1 expression and reduced risk for ESRD is consistent with involvement of cytokines in risk for developing nephropathy.
Keywords:
interleukin-1 alpha, 3'-untranslated region, end-stage renal disease, association, interleukin-1 alpha protein level
