The Genetics of IgA Nephropathy: An Overview from Western Countries

Abstract

Background: IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide and a significant cause of chronic kidney disease and end-stage renal disease. It is widely accepted that genetic factors play a role in the pathogenesis of IgAN. However, the identity of these genetic factors remains uncertain. Summary: Critical to all genetic studies is a precise phenotypic definition of the disease. It is well recognised that IgAN displays striking phenotypic variation, raising the possibility that it may not be a single disease and it may not be the same disease in different parts of the world. In this review, we discuss the challenges that this phenotypic variation poses to interpreting genetic data and the current evidence for specific gene involvement in IgAN, focusing particularly on data from European IgAN cohorts. Key Messages: With advances in genetic techniques, in particular next-generation sequencing, and an increased understanding of the importance of copy number variations, epigenetics and transcriptomics, it is likely that we will gain a greater understanding of the genetic basis for IgAN. However, due to the lack of consistency in epidemiological clinicopathological studies both within and between continents, this will only be achieved if we are able to more precisely phenotype IgAN populations. Facts from East and West: The reported prevalence of IgAN is higher in Asia than in Europe and North America. However, differences in use of biopsy for the diagnosis of IgAN should be taken into account in analysing data from both East and West. In Europe, IgAN affects men more frequently than women; this is not the case in Asia. Familial IgAN has been more frequently reported in Europe than in Asia. Within Europe, familial IgAN is more evident in southern than in northern populations. Changes in the pattern of serum IgA1 O-glycosylation is a common finding in IgAN patients in the East and West. SNPs within the gene coding for the enzyme C1GALT1 have been reported in Chinese and European patients. However, there is no evidence for a role of gene polymorphism of the C1GALT1 chaperone cosmc in Europeans. Genetic variants in the HLA gene family have been observed in populations from the East and West. Associations between IgAN and variants of the TAP1/PSMB and DEFA genes were observed in Asian but not in Western patients. Association with the angiotensin-converting enzyme gene was seen only in Asian patients.

Multiple rare genetic variants co‐segregating with familial IgA nephropathy all act within a single immune‐related network

“…Then, we sought to evaluate whether the variants identified in our WES cohort were also present in other well‐characterized IgAN patients and unrelated HBDs, but none carried the tested variants. The failure to identify a single rare segregating variant in more than one family or any of the rare variants in the other tested familial or sporadic IgAN cases supports the hypothesis that this complex and fairly common disease may be ascribed not to a single gene or variant but to a cumulative effect of rare variants .…”

Is immunoglobulin A nephropathy different in different ethnic populations?

“…The study of genetics in IgAN is challenging in that the phenotype of the disease can only be confirmed by a renal biopsy. Familial clustering of IgAN supports a genetic basis of pathogenesis in IgAN and studies of familial IgAN have been reported in four kindreds in which a Mendelian inheritance of autosomal dominance and incomplete penetrance has been described . However, the genetic linkage was unique to each kindred and cannot be generalized to the sporadic form of IgAN.…”

“…Familial clustering of IgAN supports a genetic basis of pathogenesis in IgAN and studies of familial IgAN have been reported in four kindreds in which a Mendelian inheritance of autosomal dominance and incomplete penetrance has been described. 24 However, the genetic linkage was unique to each kindred and cannot be generalized to the sporadic form of IgAN. In the last decade, genome-wide association studies (GWAS) have revolutionized the identification of genetic susceptibility loci in many conditions, including IgAN, and to date, several large GWAS have been performed in European populations (France, Italy, UK, USA) and Chinese populations with IgAN.…”

Genetic Variations rs859, rs4646, and rs372883 in the 3′-Untranslated Regions of Genes Are Associated with a Risk of IgA Nephropathy

“…IgAN also is the main cause of chronic kidney disease, and approximately 40% of IgAN patients progress to end-stage renal disease (ESRD) following diagnosis [2]. The prevalence of IgAN is particularly high in individuals of Asian ancestry, but is rare among Africans and is of intermediate prevalence among Europeans [3, 4]. The disease is characterized by the presence of IgA-dominant or co-dominant immune deposits in the glomeruli, accompanied by the proliferation of mesangial cells and expansion of matrix [5].…”