The APOL1 Gene is not Associated with Lupus Nephritis in Individuals with Enriched Amerindian Ancestry

Background/Purpose:

The APOL1 gene coding variants G1 and G2 have been described to be associated with chronic renal disease and end-stage Renal Disease (ESRD) in patients of African descent with different nephropaties. The   association of these genes with ESRD but not lupus nephritis (LN) per se has also been recently reported in SLE patients of African descent (1). Amerindian ancestry has been found to be associated with the occurrence of lupus (2) and LN (3) but whether risk variants in the APOL1 gene would be preferentially observed in those who develop LN and have a large Amerindian ancestral component has not been determined.

Methods:

Patients with SLE (ACR criteria) from various sources across North and South America were genotyped for a complete GWAS using the OMNIv1 Illumina array. Data was QC filtered and analyzed using PLINK. Cases were those SLE patients who had LN as per the corresponding ACR criterion and compared to healthy controls. We used PCAdmix to determine local ancestry across the genome and selected the data within the APOL1 locus. We also investigated if we identified proxies for the G1 or G2 variants. The frequency distribution of Amerindian ancestry and APOL1 genes was then compared between cases and controls and a T-test was used to investigate differences between cases and controls within ancestries in the genomic segment.

Results:

There were 400 cases and 1200 healthy controls. Table 1 shows the distribution of European (CEU), West African (YRI) and Amerindian (NAH) ancestry within the segments (windows) of APOL1 variants studied between cases and controls covering 322 SNPs. As the G1 and G2 variants were not genotyped, we attempted to identify proxies using GWAS data for Latin Americans. Two proxies for G1 were observed, but none for G2. The G1 proxies were nearly monomorphic in the Amerindian enriched individuals (maf = <1%). The proportion of African ancestry within the locus was <4%.

Conclusion:

Variants within the nephropathy gene APOL1 were not associated with the occurrence of LN among these SLE patients from the Americas exhibiting a large Amerindian ancestral background. Our results can be ascribed to the low proportion of African ancestry within the locus.

References:

1.     Freedman BL et al. Arthritis Rheum 2014; 66:390-6.

2.     Sanchez E et al. Arthritis Rheum 2012; 64:3687-94.

3.     Alarcon GS et al. Lupus 2006; 15:26-31.