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Type 1 Diabetes Resequencing Study Finds Protective Variants

NEW YORK (GenomeWeb News) – By re-sequencing a handful of candidate genes from previous genome-wide association studies, University of Cambridge and Roche 454 researchers have identified four rare variants and one common variant in an antiviral gene called IFIH1 that protect against type 1 diabetes or T1D. Since the variants appear to curb the gene's activity, the team proposes that functional IFIH1 may contribute to T1D.

The team used Roche 454 sequencing to re-sequence ten GWAS candidate gene exons and splice sites in nearly 500 individuals with T1D and as many control individuals. They identified four rare variants that lowered T1D risk, which they subsequently validated in more than 30,000 individuals, including more than 3,000 families. One common variant also showed independent association with T1D. The research appeared online today in Science Express.

"Not only has this proved that IFIH1 is involved in T1D, it also gave us clues to understand the mechanism," lead author Sergey Nejentsev, a medical researcher affiliated with the University of Cambridge's Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, said in a statement. "This experiment shows the way to identify causative genes contributing to various common diseases."

Type 1 diabetes is a complex autoimmune disease in which the body's own immune cells attack and destroy insulin-producing cells in the pancreas. It seems to be caused by a combination of genetic and environmental factors. Previous genetic association studies have implicated 15 loci in the human genome with T1D risk.

But because of linkage disequilibrium in the genome, it's often tricky to tell which GWAS genes are actually the culprits. In addition, significant associations land in parts of the genome with no known function.

In an effort to identify new variants and evaluate those implicated in previous research, Nejentsev and his colleagues used the Roche 454 Genome Sequencer FLX system to sequence the exons and splice sites for ten candidate genes — PTPN22, PTPN2, IFIH1, SH2B3, CLEC16A, IL2RA, FOXP3, AIRE, KCNJ11 and IAN4L1 — in 480 individuals with T1D and 480 healthy controls, all from Great Britain.

The team got 31,000 bases of sequence data from 144 regions after generating 9.4 million reads, each about 250 bases long. They subsequently identified 212 SNPs in these genes: 33 common SNPs and 179 rare SNPs, including 156 rare SNPs that hadn't been identified previously.

"Our goal was not only to discover new rare variants but also to test their association with T1D in the same experiment, comparing allele frequency in DNA pools of patients and controls," the authors explained.

The researchers first confirmed previous associations between common SNPs and T1D before focusing on the rare variants. Of these rare SNPs, the two that were most strongly associated with T1D fell in a gene called IFIH1.

IFIH1 codes for a cytoplasmic protein that recognizes RNA viruses called picornaviruses and participates in the production of interferons in response to these viruses. Intriguingly, prior studies have shown that individuals who are newly diagnosed with T1D are more likely to carry enteroviruses — a group of picornaviruses including coxsackie viruses, polioviruses, and echoviruses — than individuals in the general population.

While the researchers didn't see clear associations between T1D and rare variants in other genes, they found possible associations with SNPs in a gene called CLEC16A.

Consequently, the researchers focused on two SNPs in IFIH1 and two SNPs in CLEC16A, testing these associations in 8,379 individuals with T1D, 10,575 controls, and 3,165 European and American families with one or more children with T1D and their parents.

Neither CLEC16A SNP was validated. But both of the IFIH1 variants remained associated with T1D, prompting the team to follow up on other IFIH1 SNPs they'd found in their re-sequencing work. In so doing, they turned up two more rare IFIH1 variants that were associated with T1D.

Altogether, the researchers reported that four rare IFIH1 variants and one common variant were independently associated with T1D. And, they noted, the four rare protective variants all appear to inactivate or otherwise mute IFIH1 activity, either by truncating the gene, altering its splicing, or affecting a highly conserved amino acid. That, in turn, suggests that the common form of IFIH1 may contribute to T1D.

In a statement issued today, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory researcher John Todd, who was the senior author on the paper, said that the results likely represent a small but important part of the larger T1D picture.

Since the researchers have not yet re-sequenced all of the genes that have been implicated in T1D in the past, including FAP, GCA, and KCNH7, they conceded that it's possible that there are additional genes that contain rare T1D-associated variants.

"We have been able to pinpoint one particular gene among a long list of candidates," Todd said in a statement. "Now we and others can begin to study the biology of IFIH1 in the context of type 1 diabetes knowing that it is part of the cause of the disease."

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