Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression

Utero globin (UG) is an anti-inflammatory/immunomodulatory protein, Targeted disruption of UG rendered mouse glomerulonephritis resembling immunoglobulin (Ig)A nephropathy (IgAN), Sequence analysis on exon 1 of UG showed several putative binding sites for transcription factors, and polymorphisms in this site might influence the expression level of UG as a competitive protein, We speculated that the single nucleotide polymorphism at the 38th nucleotide (A to G) from the transcription initiation site of UG exon 1 would impact the progression of IgA nephropathy (IgAN), Polymerase chain reaction-restriction fragment length polymorphism and single-strand conformation polymorphism were instituted to determine the genetic polymorphism, Luciferase assay was performed using the gene constructs containing a region 404-bp long located upstream of UG exon 1 initiation site to analyse whether this polymorphism would affect the expression level. UG polymorphism was distributed no differently in patients with IgAN (n = 111) compared to 60 healthy control subjects, An excess of A genotype was found in one patient having progressive disease (P = 0.03) and the risk for the disease progression increased as the number of A alleles increased (P for trend = 0.03) after follow-up for 116 months. The odds ratio for progression with the AA genotype was 4.9 (95U% CI=1.0-23.9) compared to patients having the GG genotype, Significant interactive effects of hypertension and genetic polymorphisms of UG on the disease progression were observed (P for interaction = 0.001), In the luciferase assay, the gene construct with A at the 38th site showed a decreased activity of 74 +/- 8.4% compared to that showed by G gene construct, Our results suggest that polymorphism at the 5' UTR region of UG exon 1 is an important marker for the progression of IgAN and may modulate the level of protein expression, Pharmacogenetics 11:199-305 (C) 2001 Lippincott Williams & Wilkins.