Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese

Abstract

Background and objectivesIgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy.Design, setting, participants, & measurementsWe performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored.ResultsWe identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta<5×10−5) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy.ConclusionsFive novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.

Complement catalyzing glomerular diseases

“…IgA nephropathy (IgAN) as a leading cause of chronic kidney diseases is likely made up of several subgroups with different pathogenetic factors (Zhou et al 2021 ). Glomerular deposition of galactose-deficient IgA1 immune complexes may trigger complement activation via the alternative pathway, resulting in deposition of complement components.…”

“…Glomerular deposition of galactose-deficient IgA1 immune complexes may trigger complement activation via the alternative pathway, resulting in deposition of complement components. Genome-wide association studies linked the FHR -gene cluster with IgA Nephropathy (Gharavi et al 2011 ; Zhu et al 2018 ; Zhou et al 2021 ). Homozygous deletion of FHR1-FHR3 has a strong protective role.…”

Assessing Genetic Risk for IgA Nephropathy

“…The top signal was in CFB, encoding a regulator of the alternative complement pathway, thus a biologically plausible signal. Altogether, Zhou et al (8) pave the way for additional studies that can replicate their suggestive signals in larger cohorts. Given that this study was performed in the Han Chinese population, the transferability of findings to other populations will also need to be determined.…”

“…In this issue of CJASN, Zhou et al (8) performed an exome chip association study for IgA nephropathy in a Han Chinese population. They analyzed both common and low-frequency variants in 601 patients and 4076 ancestry-matched controls and replicated their findings in a separate cohort of 2762 patients and 5803 controls.…”

“…In the meantime, the summary statistics reported by Zhou et al (8) may also be useful for genome-wide assessment of genetic risk. A recent conceptual advance involves computation of polygenic risk score involving the genome-wide summation of the effects of all common variants simultaneously.…”