Evidence for genetic factors in the development and progression of IgA nephropathy

Background IgA nephropathy (IgAN) is the most common glomerulonephritis in the world among patients undergoing renal biopsy. Once considered a relativ ely benign condition, longitudinal follow-up studies have revealed that in fact 9 to 50% of patients progress to end-stage renal disease within 20 yea rs of disease onset. In the three decades since its first description by Je an Berger and Nicole Hinglais, clinical, epidemiologic, and immunologic stu dies of the pathogenesis of primary (idiopathic) mesangial glomerulonephrit is with predominant IgA deposits have characterized the features of IgAN as a distinct glomerular disease entity. However, the basic molecular mechani sm(s) underlying abnormal IgA deposition in the mesangium with ensuing extr acellular matrix expansion and mesangial cell proliferation remains poorly understood. The task of elucidating the molecular basis of IgAN is made esp ecially challenging by the fact that both environmental and genetic compone nts likely contribute to the development and progression of IgAN. Methods and Results. We review here the evidence for genetic factors in the development and progression of IgAN, including a reappraisal of earlier co nflicting results from small immunogenetic case-control studies, the eviden ce for racial differences in the prevalence of IgAN, a detailed summary of all reported occurrences of familial IgAN worldwide, and an exhaustive revi ew of new insights gained through the study of two murine models of heredit ary IgAN: the ddY and the uteroglobin-deficient mouse. Conclusions. With the development of powerful molecular genetic approaches to the study of both Mendelian and complex human genetic diseases, and the successful efforts of investigators to identify and clinically characterize large IgAN multiplex families, we propose that genetic analysis of familia l IgAN is the most promising approach to the identification of IgAN disease /susceptibility genes. Alternatively, if the case-control study design is e mployed to identify associations between particular candidate genes or mark ers and the development of IgAN, spurious associations caused by the effect s of population stratification should be ruled out by confirming the findin gs using powerful and sensitive family-based methodologies such as the tran smission/dysequilibrium test (TDT).