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Studies ID Lupus Risk Variants in Individuals of Chinese and European Ancestry

NEW YORK (GenomeWeb News) – In a pair of studies appearing online yesterday in Nature Genetics, one group of researchers identified the first systemic lupus erythematosus, or SLE, risk variants in a Chinese population while another group added to the growing list of lupus-associated genes in individuals of European descent.

SLE is an autoimmune disease in which an individual's antibodies recognize and attack his or her tissues. Both genetic and environmental factors have been implicated in the disease, which is about nine times more common in women than men.

Past studies have turned up 15 to 20 lupus risk loci, including several SNPs affecting autoimmune genes. But almost all of this work has been done in individuals with European ancestry. And because lupus is more prevalent in some populations than others, researchers are keen to understand lupus genetics in individuals from different parts of the world.

In the first phase of their study, Chinese and Singaporean researchers assessed almost half a million SNPs in more than 2,200 Han Chinese individuals. In the process, they identified dozens of candidate SNPs. After verifying their initial findings in two Chinese validation groups, the team was left with 16 lupus-associated loci, including nine loci not linked to SLE in the past.

The findings highlight the importance of doing GWAS in non-European populations, the team noted, since some — but not all — of the Chinese SLE risk variants overlapped with those detected in Europeans.

"The genetic heterogeneity between ethnic populations has been suggested to be important in SLE risk, showing the need for further GWAS in non-European populations," senior author Xue-Jun Zhang, a researcher affiliated with Anhui Medical University and Huashan Hospital of Fudan University, and his colleagues wrote.

In the discovery arm of their study, the team genotyped 1,047 SLE cases and 1,205 healthy controls at 493,955 autosomal SNPs using the Illumina Human610-Quad BeadChips.

During their subsequent analyses, the researchers identified several loci, including one in the major histocompatibility complex, or MHC, region — a group of immune-related genes on chromosome 6 — containing13 SNPs.

To find non-MHC-related risk loci, the team selected 78 SNPs from outside this region and genotyped two other Han Chinese cohorts: one from central China containing 1,643 SLE cases and 5,930 healthy controls and another from southern China containing 1,509 cases and 1,120 controls.

Using this approach, they found another 16 SLE-related loci that are independent of the associations in the MHC region. Seven of the loci had been implicated in past lupus studies and nine were new.

Although more work is needed to understand the role that these genes play in SLE, if any, the team noted that several of the genes are involved in processes such as immune complex processing, interferon production, and immune signal transduction — similar to genes implicated in SLE risk in European populations.

On the other hand, the researchers did not see associations with dozens of other SNPs previously linked to lupus in European populations.

"The disparities of the GWAS findings between Chinese Han and European populations might suggest genetic heterogeneity of SLE between the two populations, especially in instances where risk alleles show a similar allele frequency in the two populations but association in only one population," they wrote. "Our study not only advances our understanding of the genetic basis of SLE susceptibility but also highlights the genetic heterogeneity of disease susceptibility between different ethnic populations."

In another online paper in Nature, a Genentech-led research team used custom Illumina Infinium II arrays to find previously overlooked SLE risk variants in individuals of European descent.

The researchers assessed an American group including 1,129 SLE cases and 2,991 controls and a Swedish group including 834 SLE cases and 1,338 controls using the custom array, which targeted roughly 12,000 variants, including nearly 2,400 regions that were nominally associated with lupus in a past GWAS as well as known lupus or autoimmune disease risk loci and ancestry markers.

In the process, they confirmed several previously identified SLE risk loci. The team also identified five new loci — affecting TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10 — that reached genome-wide significance, as well as 21 candidate SLE risk loci.

"This tells us about some of the basic pathways that underlie the disease," senior author Robert Graham, an immunology researcher at Genentech, told GenomeWeb Daily News.

Consistent with previous findings in lupus, risk loci were frequently at genes governing processes such as immunity and inflammation.

In addition, Graham noted, several of the variants detected have shown up in GWAS of other autoimmune diseases, such as type I diabetes and psoriasis. Such overlap between risk genes for various autoimmune diseases seems to be one of the emerging features of autoimmune diseases, he explained.

In general, Graham and his team hope to find lupus-related biological pathways that might make good targets for new SLE therapeutics. The researchers are also exploring the possibility of finding blood biomarkers for lupus and/or genetic variants for predicting SLE treatment outcomes.

In the future, the team plans to continue looking for additional lupus risk variants, including CNVs, Graham said. They are also exploring the possibility of using third-generation sequencing approaches, such as Complete Genomics', to look for rare variants.

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