IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22–23

Abstract

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

“…Many LGWS and GWAS in both familial and sporadic IgAN suggest that there is a strong genetic component in the disease. [7][8][9][10][11][12] However, most studies have not evaluated the contribution to this complex disorder of other forms of genetic variation, such as structural variations, mainly in the form of CNVs. 15 Indeed, CNVs have recently been shown to have an important role in complex disease phenotypes as psoriasis, 30 rheumatoid arthritis 31 and systemic lupus erythematosus.…”

“…)del overlapped with the region named IGAN1 identified in a GWLS. 7 The aberrations chr17. ?)dup, containing ankyrinrepeat and fibronectin type III domain gene, overlapped with the region found in linkage in our previous GWLS.…”

“…Three GWLS of familial IgAN have reported linkages at 2q36, 4q26-31, 6q22-23 and 17q12-22, but no disease genes were identified within these areas. [7][8][9] Three GWAS that allows hypothesis-free examination have been performed for IgAN, leading to the identification of susceptibility alleles in the major histocompatibility complex (MHC) region on chromosome 6p [10][11][12] and additional loci on chromosomes 1q32, 22q12, 17p13 and 8p23. So far, no genetic variants or genes underlying these loci have been identified as causative or affecting the pathology, plausibly because of the presence of genetic/environmental and locus heterogeneity and to contribution from noncoding susceptibility alleles such as point mutations or structural genomic variants within intronic or promoter regions.…”

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

“…Association studies identified distinct loci on chromosomes 6p21, 8p23, 17p13, 22q12, 1q32. 6,7 On the other hand, classical linkage studies performed on AD families identified additional loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22, [8][9][10] lending further support to the complex etiology and broad genetic heterogeneity of the disease.…”

Association of genetic variants with chronic kidney disease in Japanese individuals with or without hypertension or diabetes mellitus

“…although genetic linkage analyses (5) and association studies (6)(7)(8) have implicated several loci and candidate genes in the predisposition to cKd, the genes that confer susceptibility to this condition remain to be identified definitively. In addition, given ethnic differences in lifestyle and environmental factors as well as in genetic background and renal function, it is necessary to examine genetic variants related to cKd in each ethnic group.…”