Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression.
Uteroglobin (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 (95% Cl = 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.
Kim
Y S
YS
Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute Seoul National University Hospital, Chongno-gu, South Korea.
Kang
D
D
Kwon
D Y
DY
Park
W Y
WY
Kim
H
H
Lee
D S
DS
Lim
C S
CS
Han
J S
JS
Kim
S
S
Lee
J S
JS
D020121:5' Untranslated Regions; D000328:Adult; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D005091:Exons; D015870:Gene Expression; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000235:genetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D012307:Risk Factors; D014598:Uteroglobin / Q000235:genetics*
D020121:5' Untranslated Regions; D005819:Genetic Markers; D004247:DNA; D014598:Uteroglobin