Variants in BANK1 are associated with lupus nephritis of European ancestry

Abstract

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10^-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10^-4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10^-7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.

Fig. 1. Association between 112,815 SNPs and lupus nephritis in the discovery cohort.

Manhattan plot displaying results from the association analysis of 112,815 SNPs in 377 patients with lupus nephritis (LN) and 714 SLE without nephritis in the discovery cohort. The negative logarithm of the p-value is plotted against the chromosomal location of the tested variants. Genes with SNPs associated with LN with p < 1 × 10⁻⁴ are denoted.

Fig. 2. Regional association plot of the BANK1 region.

Regional association plot of the BANK1 region displaying results from the analysis of LN (n = 377) versus SLE without nephritis (n = 714) in the discovery cohort. Top SNP rs4699261 is in strong linkage disequilibrium (r² ≥ 0.8) with a cluster of SNPs located in the first intronic region.

Fig. 3. Genetic regulation of methylation in lupus nephritis at BANK1.

Box plot of the BANK1 meQTL rs6856202−cg01116491. SNP genotypes at rs6856202 are shown on the x-axis, methylation-beta values of CpG site cg01116491 are shown on the y-axis. The major allele (A) of rs6856202 is associated with increased methylation at cg01116491 (p_meQTL = 6.0 × 10⁻⁴) in whole blood from patients with LN. The major allele (A) is the risk allele for LN in the discovery cohort and displayed the highest signal of genetic association to proliferative nephritis in the meta-analysis of discovery and replication cohort 1 (p_meta = 1.3 × 10⁻⁵). Box plot center lines indicate medians, box boundaries indicate first and third quartile, and whiskers extend to data points located within 1.5 times the length of interquartile range from the median.