Does the esv3587290 Copy Number Variation in the VANGL1 Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients?

TL;DR

This study explores whether a specific genetic variation in the VANGL1 gene protects Mexican children with lupus from developing kidney inflammation.

Contribution

The study identifies a protective genetic variant against lupus nephritis in Mexican childhood-onset SLE patients.

Findings

The esv3587290 CNV allele and heterozygous genotype show a significant protective effect against LN development.

The precise breakpoint of the esv3587290 CNV was characterized in the studied population.

The study supports the idea of genetic heterogeneity in LN susceptibility.

Abstract

A ~3-kb deletion-type DNA copy number variation (CNV, esv3587290) located at intron 7 of the VANGL1 gene (1p13.1, MIM*610132) has been proposed as a genetic factor in lupus nephritis (LN) development in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: cSLE patients with (N = 39) or without (N = 27) LN, as diagnosed by renal biopsy (N = 17), proteinuria (N = 33), urinary protein–creatinine ratio > 0.2 (N = 34), and erythrocyturia and/or granular casts in urinary sediment (N = 16). For esv3587290 CNV genotyping, we performed an end-point PCR assay with breakpoint confirmation using Sanger sequencing. We also determined the allelic frequencies of the esv3587290 CNV in 181 deidentified ethnically matched individuals (reference group). The obtained genotypes were tested for Hardy–Weinberg equilibrium using the χ2 test. Associations between LN and esv3587290 CNV were tested by calculating the odds ratio (OR) and using Pearson’s χ2 tests, with a 95% confidence interval and p ≤ 0.05. The esv3587290 CNV allele (OR 0.108, 95% CI 0.034–0.33, p = 0.0003) and the heterozygous genotype (OR 0.04, 95% CI 0.119–0.9811, p = 0.002) showed a significant protective effect against LN development. Finally, we characterized the precise breakpoint of the esv3587290 CNV to be NG_016548.1(NM_138959.3):c.1314+1339_1315-897del in our population. This report supports the notion that a broad genetic heterogeneity underlies the susceptibility for developing LN.

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