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GWAS IDs New Atopic Dermatitis Risk Loci in Japanese Population

NEW YORK (GenomeWeb News) – A Japanese genome-wide association study on a form of eczema called atopic dermatitis has uncovered eight new loci linked to risk for the chronic inflammatory skin condition in that population.

As they reported online yesterday in Nature Genetics, researchers at the Riken Center for Genomics Medicine and other centers in Japan did genome-wide association and validation analyses using data for more than 3,300 Japanese individuals with atopic dermatitis and nearly 14,500 unaffected controls. In addition to confirming atopic dermatitis associations at seven known sites in the genome, the study pointed to eight previously unknown loci with significant ties to the disease.

At these newly identified risk regions, the team tracked down genes in immunity, inflammation, apoptosis, and skin-related pathways that are suspected of contributing to the condition. The search also led to parts of the genomes with apparent ties to asthma or other allergies.

"These findings suggest that atopic dermatitis and asthma or allergic rhinitis have overlapping susceptibility regions," senior author Mayumi Tamari, a respiratory diseases researcher at the Riken Center, and co-authors wrote, "and that these regions contain common genetic factors for many allergic diseases."

Past studies have shown that loss-of-function alterations in a filaggrin skin protein-coding gene called FLG are among the strongest genetic contributors to atopic dermatitis — a chronic condition characterized by itchy, inflamed, and sensitive skin that's prone to bacterial and other infections.

But GWAS have uncovered half a dozen more loci that are associated with atopic dermatitis risk in European and Chinese populations, prompting Tamari and colleagues to extend the search for atopic dermatitis culprits to Japanese populations.

"To gain a better understanding of the contribution of complex genetic effects to the pathogenesis of atopic dermatitis," they explained, "it is important to identify additional susceptibility loci and validate the association of previously reported loci in different ancestry groups."

For their initial GWAS, the researchers used Illumina arrays to genotype 1,472 Japanese individuals with atopic dermatitis and 7,971 unaffected controls from the same population.

Using this data, the team uncovered atopic dermatitis ties for seven loci linked to the disease in past studies of European and Chinese populations.

And based on patterns at more than 600,000 SNPs that were genotyped in the Japanese cases and controls, researchers identified three dozen new candidate variants at sites on chromosomes 2, 6, and 11. Follow-up testing on another 1,856 cases and 7,021 controls verified the associations for 11 variants at these loci.

Meanwhile, the team's combined analyses of data from the discovery and validation groups added to the tally of atopic dermatitis-associated loci, bringing the number of genomic sites reaching genome-wide significance up to eight. These included the chromosome 2, 6, and 11 loci, along with sites on chromosomes 3, 7, 10, and 20.

For their subsequent analyses, the researchers looked at types of genes found in and around these regions. There, they found immune-related genes — including signals in major histocompatibility regions — along with genes involved in processes such as the regulation of apoptosis, inflammation, vitamin D production, and skin cell organization.

Because variants in some of the same genes had been reported in conditions such as bronchial asthma, the team also looked at whether SNP at any of the new or known atopic dermatitis loci corresponded with asthma risk in individuals who had both conditions.

For those co-morbid cases, researchers reported, the strongest association fell in a chromosome 2 region containing the interleukin cytokine receptor gene IL1RL1.

Authors of the study say their findings "advance the understanding of the genetic basis of atopic dermatitis." Still, they noted, "[f]urther studies are needed to better understand the genetic etiology and pathophysiology of atopic dermatitis."

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