Table 6

Nine genetic studies in African-Americans with lupus

Author, yearNObjectiveResultsConclusionsLevel of evidence
Larsen et al, 201363546To investigate whether APOL1 risk alleles associate with SLE-associated CGEvaluation of biopsies from 188 cases with zero risk alleles, 264 cases with one risk allele and 94 cases with two risk alleles revealed 26 cases with CG, and APOL1 was strongly associated with SLE-associated CG (p<0.001).APOL1 genotyping of African-American patients with SLE might help identify patients at risk for CG, a phenomenon with a poor prognosis often resistant to treatmentIII
Freedman et al, 2014641389To investigate whether the APOL1 nephropathy risk alleles G1/G2, common in African-Americans and rare in European Americans, contribute to the ethnic disparity in riskTwo risk alleles, G1/G2, were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having two nephropathy alleles (OR 2.57, recessive model p=1.49×10−9). The population-attributable risk (adjusted for age, sex and admixture) for ESRD among patients with G1/G2 polymorphisms was 0.26 compared with 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was about 2 years earlier among individuals with APOL1 risk genotypes (p=0.01).The high frequency of APOL1 G1/G2 alleles in African-Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African-AmericansIII
Namjou et al, 2012655To assess and characterise C1q deficiency in an African-American lupus pedigreeA novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1 (Met1Arg) was identified in an African-American patient with lupus and C1q deficiency and her family members, along with absence of total complement activity consistent with a recessive pattern of inheritance.The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) expands the knowledge and importance of the C1q gene in the pathogenesis of lupus in the high-risk African-American populationIII
Ramos et al, 2013663364To analyse variation in reactive intermediate genes for association with SLE in two populations with African ancestryThe glutathione reductase gene GSR (rs2253409; p=0.0014, OR 1.26, 95% CI 1.09 to 1.44) was the most significant single SNP association in African-Americans. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p=0.0065, OR 2.10, 95% CI 1.23 to 3.59) and NO synthase gene NOS1 (rs561712; p=0.0072, OR 0.62, 95% CI 0.44 to 0.88) were most strongly associated with SLE. When both populations were analysed together, GSR remained the most significant effect (rs2253409; p=0.00072, OR 1.26, 95% CI 1.10 to 1.44).Results suggest distinct patterns of association with SLE in African-derived populationsIII
Ruiz-Narvaez et al, 2011671148To conduct a screening of the MHC region for SNPs and the deletion of the C4A gene in a SLE case–control studyThe rs9271366 SNP was most strongly associated with SLE (OR, OR=1.70, p=5.6×10−5). Conditional haplotype analysis revealed three other SNPs, rs204890 (OR=1.86, p=1.2×10−4), rs2071349 (OR=1.53, p=1.0×10−3), and rs2844580 (OR=1.43, p=1.3×10−3) to be associated with SLE independent of the rs9271366 SNP. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR=1.67 per high-risk allele, p<0.0001).There are four independent signals in the MHC region associated with risk of SLE in African-American womenIII
Sánchez et al, 2011683748To examine whether some of the same susceptibility loci increase lupus risk in African-American individualsAuthors found the first evidence of genetic association between lupus in African-American patients and five susceptibility loci (C8orf13-BLK, BANK1, TNFSF4, KIAA1542 and CTLA4; p=8.0×10−6, p=1.9×10−5, p=5.7×10−5, p=0.00099, and p=0.0045, respectively). Authors also confirmed the genetic association between lupus and five additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4 and FCGR2A; p=7.5×10−11, p=5.2×10−8, p=8.7×10−7, p=0.0058, and p=0.0070, respectively), and provided evidence of genome-wide significance for the association between lupus in African-American patients and ITGAM and MSH5 (HLA region).Novel genetic susceptibility loci for lupus were identified in African-Americans and authors demonstrated that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicitiesIII
Dozmorov et al, 20137040To study the higher rates of lupus-related ESRD in African-AmericansA strong link was detected between APOL1 G1 and G2 variants and LN-ESRD in African-Americans.Findings further support the role of G1 and G2 variants of APOL1 gene in higher rates of lupus-related ESRD in African-AmericansIII
Wu et al, 200372361To explore the −844C genotype in African-Americans with SLEThere was enrichment of the –844C homozygous genotype in the patients with SLE compared with ethnically matched controls.Findings further support the potential importance of SNPs in regulatory regionsIII
Freedman et al, 201369N/ATo review the current status of APOL1-associated nephropathyThere is a genetic association between the APOL1 gene and several severe non-diabetic forms of kidney disease in African-Americans that nears Mendelian inheritance patterns. This associated accounts for and account for a large percentage of glomerulosclerosis in populations of African ancestry.Emerging data support an important role for APOL1 in the progression of kidney diseaseV
  • APOL1, apolipoprotein L1; CG, collapsing glomerulopathy; ESRD, end-stage renal disease; HLA, human leukocyte antigen; LN, lupus nephritis; MHC, major histocompatibility complex; N/A, not available; SLE, systemic lupus erythematosus; SNP, single-nucleotide polymorphism.