Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Abstract

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.

Figure 1. Allelic association of SNPs in the CFH-CFHRs region with SLE and their LD patterns.

A) The genomic structure of the CFH-CFHRs region and the location of all SNP and MLPA markers are indicated. The deletion of CFHR3 and CFHR1 detected by MLPA markers is shown as a red box. B) The allelic P value of each SNP with SLE (−log₁₀ P) is plotted as a black circle according to its coordinate. The two SNPs exhibiting the strongest association with SLE in EA (rs6677604) and AA (rs16846039) are highlighted as red triangles. SNPs that failed in the HWE testing or showed low genotyping quality are not shown. SNP-constructed haplotype blocks were defined by Haploview using the confidence intervals model. An arrowhead is used to indicate the position of rs6677604 in the haplotype blocks.

Figure 2. The minor allele of rs6677604 and rs16846039 tag risk haplotypes of SLE.

Haplotypes containing rs6677604 and rs16846039 (frequency>1%) are constructed in both EA and AA subjects, which correspond to the 2^nd and the 4^th block of EA and AA shown in Figure 1, respectively. SNPs not used to construct haplotypes are marked as “-”. The minor alleles of rs6677604 and rs16840639 are highlighted in a yellow box. The minor allele of each SNP is bolded and italicized. The position of CFHR3-1Δ is indicated as “*”.