Erschienen in:Journal of the American Society of Nephrology
Sprache:
Englisch
DOI:
10.1681/asn.2015111210
ISSN:
1046-6673;
1533-3450
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>An intronic variant at the <jats:italic toggle="yes">complement factor H</jats:italic> (<jats:italic toggle="yes">CFH</jats:italic>) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the <jats:italic toggle="yes">CFH</jats:italic> gene or the neighboring <jats:italic toggle="yes">complement factor H–related 1</jats:italic> (<jats:italic toggle="yes">CFHR1</jats:italic>) gene and <jats:italic toggle="yes">CFHR3</jats:italic>, which harbor an 84-kb combined deletion (<jats:italic toggle="yes">CFHR3,1Δ</jats:italic>) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single–nucleotide variants within the <jats:italic toggle="yes">CFH</jats:italic> cluster. We next performed copy number analysis across the <jats:italic toggle="yes">CFH</jats:italic> locus in two independent Han Chinese case-control cohorts (combined <jats:italic toggle="yes">n</jats:italic>=3581). The <jats:italic toggle="yes">CFHR3,1Δ</jats:italic> and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (<jats:italic toggle="yes">r</jats:italic>
<jats:sup>2</jats:sup>=0.95); of these alleles, <jats:italic toggle="yes">CFHR3,1Δ</jats:italic> associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; <jats:italic toggle="yes">P</jats:italic>=8.5 × 10<jats:sup>−8</jats:sup> versus OR, 0.61; 95% CI, 0.50 to 0.75; <jats:italic toggle="yes">P</jats:italic>=1.6 × 10<jats:sup>−6</jats:sup> for rs6677604-A). Moreover, <jats:italic toggle="yes">CFHR3,1Δ</jats:italic> explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (<jats:italic toggle="yes">P</jats:italic>=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of <jats:italic toggle="yes">CFHR3,1Δ</jats:italic> with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate <jats:italic toggle="yes">CFHR3,1Δ</jats:italic> as the functional allele at this locus.</jats:p>