HLA Has Strongest Association with IgA Nephropathy in Genome-Wide Analysis

Demographic and family studies support the existence of a genetic contribution to the pathogenesis of IgA nephropathy, but results from genetic association studies of candidate genes are inconsistent. To systematically survey common genetic variation in this disease, we performed a genome-wide analysis in a cohort of patients with IgA nephropathy selected from the UK Glomerulonephritis DNA Bank. We used two groups of controls: parents of affected individuals and previously genotyped, unaffected, ancestry-matched individuals from the 1958 British Birth Cohort and the UK Blood Service. We genotyped 914 affected or family controls for 318,127 single nucleotide polymorphisms (SNPs). Filtering for low genotype call rates and inferred non-European ancestry left 533 genotyped individuals (187 affected children) for the family-based association analysis and 244 cases and 4980 controls for the case-control analysis. A total of 286,200 SNPs with call rates >95% were available for analysis. Genome-wide analysis showed a strong signal of association on chromosome 6p in the region of the MHC (P = 1 × 10⁻⁹). The two most strongly associated SNPs showed consistent association in both family-based and case-control analyses. HLA imputation analysis showed that the strongest association signal arose from a combination of DQ loci with some support for an independent HLA-B signal. These results suggest that the HLA region contains the strongest common susceptibility alleles that predispose to IgA nephropathy in the European population.IgA nephropathy (IgAN) is the most common form of glomerulonephritis and is an important cause of ESRD. Clinical presentation is usually with hematuria with a variable degree of proteinuria; progression to ESRD occurs in ∼25% of those affected in the 20 years after diagnosis.¹ Pathologically, IgAN is characterized by deposition of polymeric IgA1 in the renal mesangium, accompanied by mesangial hypercellularity, mesangial matrix expansion, and varying degrees of glomerulosclerosis and interstitial fibrosis. The pathogenesis is unclear, and diversity in the clinico-pathologic disease spectrum has suggested etiologic heterogeneity.A number of observations suggest that there is a significant genetic contribution to the pathogenesis of IgAN. These include differences in the prevalence of IgAN across ancestry groups, increased disease prevalence in relatives of affected individuals, and reports of large pedigrees containing multiple affected individuals.² To date, the strongest direct evidence for the existence of genetic factors in the development and/or progression of IgAN has been provided by linkage analyses in such families.^3–5 A major disease locus designated IGAN1 on chromosome 6q22–23 was defined in a study of white families.⁶ However, only 60% of the families in the study were linked to this locus, and, to date, no disease-specific genes associated with disease/susceptibility have been identified within the linkage interval. This locus was excluded by linkage analysis in a Japanese family,⁷ whereas in Italian families, linkage has been reported at two different IgAN loci on 4q26–31 and 17q12–22.⁸ A Canadian family study has localized another IgAN susceptibility locus to chromosome 2q36,⁹ whereas analysis of a large Lebanese kindred did not provide evidence for linkage at 6q22–23, 2q36, or 4q22–31.¹⁰These studies therefore suggested that at least part of the genetic basis of IgAN is specified by variants that are confined to specific families or discrete populations (and therefore might not be fundamental to the disease process as a whole), and it is unclear whether there are common IgAN susceptibility haplotypes that operate across large populations. This led to increasing interest in defining the existence and extent of IgAN susceptibility loci in large populations using genetic association. Most studies conducted to date examined small numbers of candidate genes, although some surveyed candidate genes more extensively¹¹ or conducted limited genome-wide analyses.¹² Although a number of potential associations with polymorphisms at candidate gene loci were reported (reviewed in references ^2,13,14), these associations have not all been reproduced, and there is no systematic genome-wide analysis of susceptibility to IgAN.To evaluate evidence for genetic association with IgAN, we undertook a genome-wide analysis in patients with European ancestry using a panel of ∼300,000 tagging single nucleotide polymorphisms (SNPs), designed to maximize coverage of common human haplotypes based on linkage disequilibrium intervals.¹⁵We performed both family-based and case-control association studies, using cases and nuclear families ascertained from the UK MRC/Kidney Research UK National DNA Bank for Glomerulonephritis and controls from the 1958 British Birth Cohort and the UK National Blood Service. Strong signals of association were observed in the MHC on chromosome 6p but not other loci, indicating that, in the UK population, the MHC contains the strongest common susceptibility alleles for IgAN.