Currently, Dr. Raychaudhuri and his colleagues are using fine-mapping techniques to study shared loci for rheumatoid arthritis and type 1 diabetes, and finding genetic hits for causal variants in genes associated with both of these diseases that share a pathophysiology but target different organs.
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Explore This IssueMarch 2018
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“We think that genetics can be useful strategy to validate drug targets. Rare coding variants can be very useful,” he said.
‘We need strategies to come up with better drug targets, & possibly, genetics is one way to get there.’ —Soumya Raychaudhuri, MD, PhD
Genetics in Lupus Risk
Rheumatology researchers are also using genomic analysis to learn more about risk loci associated with systemic lupus erythematosus (SLE), said Edward K. Wakeland, PhD, chair of the Department of Immunology at University of Texas Southwestern, Dallas. Genetics and genome-wide association study research has revealed more than 50 risk loci for lupus in many ethnic groups, including non-HLA associations, he said.5
“Some loci clearly have the strongest associations with SLE, such as HLA, ILR5 and STAT4. These are loci that have been seen through the years and continue to be prominent, not only in individuals of European descent, but in other ethnicities,” said Dr. Wakeland. Researchers have identified 38 risk loci for SLE that have genome-wide significance, mostly in people of European descent. Fewer loci reach that level of significance in African-American or Hispanic patient cohorts, which are smaller, but more genomic studies of these populations, which are significantly impacted by lupus and other autoimmune diseases, should tell us more, he said.
Researchers are now searching for risk alleles in lupus. Through genetics and genome-wide association study analysis, they try to identify endophenotypes important to SLE risk. “These individual loci are considered to contribute one piece overall to disease. If we could precisely identify the disease allele, and their functional characteristics, this may provide insight into what endophenotypes are interacting to mediate the disease process,” he said.
In a 2016 study, Dr. Wakeland and his colleagues analyzed the nature of risk alleles found in 28 SLE risk loci on the LD block, which have been defined in various ethnic groups.6
“We looked at the tagging SNP identifying the entire segment of the genome that is encompassed by the LD block that this SNP marks,” he said. Using a targeted sequencing strategy, they searched the LD block for causal variants associated with the endophenotype targeted by that particular risk allele. The study included 1,775 samples from 773 SLE patients and 579 healthy controls. “We found strong association even in this small cohort, and looking at these individual markers, saw a variety of SNPs in each locus,” he said. Functional variants in TNFAIP3 and ITGAM had high association with lupus autoimmunity. They also searched for lupus risk alleles, and noticed a higher frequency of SLE cases located on the haplotype 2 region of their genomic map. In the locus for STAT4, which is strongly associated with SLE risk, they found the major tagging SNPs. STAT1 is located in an adjacent locus to STAT4, but not on the LD block. Regulation of both STAT1 and STAT4 is mediated within this portion of the genome, and researchers found that variants of STAT4 and STAT1 are upregulated in association with a lupus risk haplotype.