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GWAS Leads to New Lupus Risk Loci in Asian Populations

NEW YORK (GenomeWeb) – An international team reported online today in Nature Genetics that it has linked 10 new loci to systemic lupus erythematosus (SLE) risk in Asian individuals.

Through a multi-stage genome-wide association study that considered nearly 4,500 SLE cases and 12,700 controls from six Korean, Han Chinese, Malaysian Chinese, and Japanese cohorts, the researchers verified previously described SLE associations at 20 loci and uncovered 10 new risk sites in the genome.

In addition to a general over-representation of variants in and around genes related to B cell and T cell immune function, the team tracked down several potential risk variants regulating the expression of other genes. The strongest new association fell at a site near the transcription factor gene GTF2I on chromosome 7, which showed tighter ties to SLE risk in Asian individuals than previously described risk variants in human leukocyte antigen genes.

"GTF2I seems to be one of the key players in lupus susceptibility," senior author Swapan Nath, an arthritis and clinical immunology researcher with the Oklahoma Medical Research Foundation, said in a statement.

Nath and his colleagues began by bringing together 2,485 SLE cases and 3,947 controls from Korean, Han Chinese, and Malaysian Chinese populations, all genotyped on the Immunochip. After uncovering hundreds of suspicious loci, the team added information on another 3,669 Korean control individuals to increase its imputation analysis.

That step led to 16 potential risk loci that the group tested in a Japanese cohort comprised of 891 cases and 3,384 controls; a Han Chinese cohort from Beijing with 601 cases and 1,034 controls; and 501 cases and 622 controls from a Han Chinese cohort from Shanghai.

That left the researchers with 10 genome-wide significant sites and six loci with suggestive associations to SLE containing a set of SNPs that they attempted to functionally annotate through comparisons with existing expression quantitative trait locus and ENCODE data.

The strongest new association the team detected was a chromosome 7 SNP called rs73366469 that fell between the transcription factor-coding genes GTF2I and GTF2IRD1, not far from a GTF2I variant implicated in an autoimmune condition called Sjörgen's syndrome in Asian populations.

They further validated the association by genotyping rs73366469 SNP and a handful of other variants in a subset of the cases and controls, uncovering another, independent association between SLE in Korean individuals and a SNP in GTF2IRD1.

The team's subsequent analyses suggested that at least 10 of the newly detected SLE-variants overlapped with regulatory regions affecting expression of the genes involved in T cell and B cell immune pathways. Moreover, half a dozen of the candidate risk loci shared associations with other immune-related conditions such as type 1 diabetes and rheumatoid arthritis.

"Further analyses in additional populations and experimental validation in cultured and patient-derived cells … will demonstrate which SNPs are causal and elucidate biochemical pathways through which genetic changes contribute to SLE," the authors noted.