OLF1/EBF-associated zinc finger protein gene: a novel lupus susceptibility locus on chromosome 16q identified in a Chinese cohort

Objective

Three independent genome scans have established the presence of a significant systemic lupus erythematosus (SLE)-linked locus on chromosome 16q12, which overlaps with the intervals identified in several other autoimmune diseases. To identify the putative SLE susceptibility gene within this interval, we fine-mapped a 10 cM interval of 16q12 containing nine densely spaced microsatellite markers (D16S419, D16S3044, D16S409, D16S540, D16S517, D16S3136, D16S416, D16S3034, and D16S415) using a cohort of 240 Chinese SLE patients and their parents.

Methods

Evidence for linkage disequilibrium was assessed using the ETDT and GeneHunter programs. TaqMan real-time quantitative PCR was used for detecting mRNA expression of a positional candidate gene. Five single nucleotide polymorphisms (SNPs) located within the candidate gene were genotyped by allelic discrimination-PCR using a 5'-nuclease assay.

Results

Our data showed overall skewing of the transmission (t) of alleles of maker D16S517 (P = 0.000008, Pc = 0.00001) from heterozygous parents to affected offspring, and showed preferential transmission of one of the alleles of D16S517 to affected offspring (transmission:nontransmission = 68:21, P = 0.000001, Pc = 0.00001). The marker D16S517 is located within an intron of a positional candidate gene, OLF1/EBF-associated zinc finger protein (OAZ), which may be involved in lymphocyte early development and regulation. Elevated levels of the OAZ gene expression were found in SLE patients (mean ΔC_T ± SEM = 5.21 ± 0.85, n = 42) compared with in normal controls (mean ΔC_T ± SEM = 6.22 ± 0.95, n = 36; P < 0.001). The gene expression level of OAZ was not correlated with SLE disease activity index scores and the treatment status. Genotyping of five SNPs within OAZ gene introns in an extended Chinese cohort of 325 families also indicated preferential transmission of a certain four SNP haplotypes (haplotype T-A-G-G, transmission:nontransmission = 43:26, P = 0.04). Haplotypes combining SNPs and the SLE-associated D16S517 allele showed significant association with SLE susceptibility (transmission:nontransmission = 58:15, P = 0.000001; transmission:nontransmission = 54:15, P = 0.000003; transmission:nontransmission = 41:13, P= 0.000139, respectively).

Conclusion

These data suggest the presence of a SLE susceptibility gene physically close to marker D16S517 in a Chinese cohort. The high expression of OAZ and the significant association of OAZ haplotypes with SLE susceptibility suggested OAZ might be a novel candidate susceptibility gene within the 16q interval.