A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset

Affinity selection and sequence-activity relationships of HIV-1 membrane fusion inhibitors directed at the drug-resistant variants

Enfuvirtide is the first approved membrane fusion inhibitor against HIV-1. Although this drug is effective against multi-drug resistant strains, the emergence of enfuvirtide-resistant strains has been reported in patients who have received an enfuvirtide-containing regimen. Based on the high affinity of synthetic HIV-1 gp41 C-terminal heptad repeat (C-HR) peptides to the counterpart trimeric N-terminal heptad repeat (N-HR) coiled-coil structure, a novel screening approach has been established to facilitate the identification of potent fusion inhibitors against wild-type and enfuvirtide-resistant HIV-1. In this process, affinity selection using histidine-tagged N-HR peptides with the sequences derived from wild-type and resistant strains efficiently captured potent inhibitory peptides from a pool of highly water-soluble C-HR peptides with α-helix-inducible motifs. A highly potent peptide was found from a single amino acid substitution observed in an enfuvirtide-resistant variant as well as peptides with unprecedented modifications at the mutated site

Results of a genome-wide association study for Japanese patients with SLE.

a<p>SNPs that satisfied the threshold of <i>P</i><5.0×10⁻⁸ were indicated.</p>b<p>Based on forward strand of NCBI Build 36.3.</p><p>SLE, systemic lupus erythematosus; OR, odds ratio.</p

Design of the GWAS and multi-stage replication studies for SLE in Japanese subjects.

<p>A total of 2,278 SLE cases and 31,948 controls were enrolled. The clinical characteristics of the subjects are summarized in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455.s003" target="_blank">Table S1</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455.s004" target="_blank">S2</a>. Details of the genome-wide scan data for SLE referenced in the <i>in silico</i> SNP selection 2 are described elsewhere (Tahira T et al. Presented at the 59th Annual Meeting of the American Society of Human Genetics, October 21, 2009).</p

Associations among previously reported SLE-related loci.

a<p>Based on forward strand of NCBI Build 36.3.</p>b<p>Defined using gene expression data measured in lymphoblastoid B cell lines <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455-Stranger1" target="_blank">[28]</a>.</p>c<p>Based on the previously reported studies for SLE susceptibility loci <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455-Sigurdsson1" target="_blank">[3]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455-Yang2" target="_blank">[18]</a>.</p><p>SLE, systemic lupus erythematosus; OR, odds ratio; eQTL, expression quantitative trait locus; GWAS, genome-wide association study.</p

Results of combined study for Japanese patients with SLE.

a<p>Defined using gene expression data measured in lymphoblastoid B cell lines <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002455#pgen.1002455-Stranger1" target="_blank">[28]</a>.</p