Article

Alleles of the alpha1 immunoglobulin gene 3' enhancer control evolution of IgA nephropathy toward renal failure.

Laboratoire d'Immunologie, CNRS EP 118 Faculté de Médecine and Institut Universitaire de France, and Service de Néphrologie, C.H.U. Dupuytren, Limoges; and Service de Néphrologie, C.H.U. Jean Bernard, Poitiers, France.
Kidney International (impact factor: 6.61). 10/2000; 58(3):966-71. DOI:10.1046/j.1523-1755.2000.00253.x pp.966-71
Source: PubMed

ABSTRACT IgA nephropathy is the most common glomerular disease. Mechanisms leading to its occurrence and controlling the evolution of the disease remain largely unknown. Various genetic factors have been found, mostly implicating immunologically relevant genes (IgH, TCR, human lymphocyte antigen, and complement loci). A regulatory region recently identified downstream, the alpha1 gene of the IgH locus, was a likely candidate for the control of IgA1 production in patients. Alleles of this region, differing by size, sequence, and orientation of the alpha1 hs1,2 transcriptional enhancer, were first identified through Southern blot hybridization.
We established a polymerase chain reaction (PCR) method suitable for routine testing that amplifies minisatellites within the alpha1 hs1, 2 enhancer, with variable numbers of tandem repeats (VNTR) defining the two alleles. This assay allowed the typing of 104 patients with IgAN and 83 healthy volunteers. Results from typing of alpha1 hs1,2 alleles were compared with long-term clinical outcome in patients. Enhancer alleles were compared in a luciferase reporter gene assay.
The alpha1 hs1,2 alleles do not constitute a predictive factor for IgA nephropathy, since similar allelic frequencies were observed in healthy individuals and in unrelated European patients. In contrast, among patients, homozygosity for the weakest enhancer allele (AA genotype) was significantly correlated with a milder form of the disease, whereas the allele B was associated with severe evolution. The minisatellite region within the alpha1 hs1,2 enhancer carried potential transcription factor-binding sites, and its duplication increased the transcriptional strength of the alpha1 hs1, 2 allele B over that of allele A.
Altogether, these alleles may constitute a risk factor for the prognosis of IgA nephropathy.

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Keywords

2 enhancer
 
83 healthy volunteers
 
AA genotype
 
allele A
 
alpha1 hs1
 
alpha1 hs1,2 alleles
 
alpha1 hs1,2 enhancer
 
alpha1 hs1,2 transcriptional enhancer
 
common glomerular disease
 
human lymphocyte antigen
 
IgH locus
 
implicating immunologically relevant genes
 
long-term clinical outcome
 
luciferase reporter gene assay
 
potential transcription factor-binding sites
 
similar allelic frequencies
 
Southern blot hybridization
 
unrelated European patients
 
variable numbers
 
weakest enhancer allele