Rare Genetic Variants Protecting Against Common Type 1 Diabetes
Nejentsev S, Walker N, Riches D, Egholm M, Todd JA
Science. 2009;324:387-389
Over the past year, new approaches in genome scanning have identified many common susceptibility variants for complex traits. However, enthusiasm has been tempered due to relative modest odds ratios seen with most of these variants, thereby leaving the majority of heritable risk unexplained. A potential explanation may be that rare variants, and not the common variants identified in genome-wide scans, confer the majority of risk for common diseases.
In their recent paper, Nejentsev and colleagues identified 4 rare genetic variants that independently protect against type 1 diabetes mellitus (T1DM). The alleles lie in a region containing functional elements of the gene interferon-induced helicase (IFIH1) on chromosome 2q24. The protective effect of the rare alleles was quite striking, with 1 variant cutting the risk of developing T1DM in half. This is one of the first studies to identify rare variants in a common disease.
The authors initially selected 10 genes previously known to associate with T1DM for further study. They resequenced 144 target regions that covered functional elements of the 10 genes, comprising a total of 31,000 base pairs. The initial scan was performed in 480 patients with T1DM and 480 controls; both groups were predominately of European descent. Using these data, 2 highly significant, rare single nucleotide polymorphisms (SNPs) in the IFIH1 gene were isolated and found to be protective.
An additional 20,000 cases and controls were then studied to replicate the protective effect of these 2 SNPs. The results of this second stage of testing validated the initial SNPs findings and revealed 2 additional rare SNPs and 1 common SNP in the same IFIH1 region. The 4 rare variants have predictable biologic responses, ranging from truncation of the IFIH1 protein to modifying essential splicing positions. Importantly, all 5 variants (4 rare, 1 common) were protective and their effect was independent of each other. Furthermore, the rare variants were found to have stronger protective effects than did the common SNP (odds ratio, 0.51-0.74 vs 0.86), underscoring the hypothesis that rare SNPs can have greater effects on phenotypic expression compared with common variants.
The IFIH1 gene is known to mediate immune activation in response to viral RNA from picornaviruses. Indeed, acute infection with enterovirus, a member of the picornavirus family, has been shown to predate autoantibody production and is commonly seen in patients recently diagnosed with T1DM and in prediabetics. Thus, one could extrapolate that regulation of IFIH1 gene expression through vaccination or targeted therapy might prevent the onset of juvenile or adult-onset T1DM through alteration in the immune response to these viruses. However, the safety of such an approach would have to be validated, as mice deficient of IFIH1 have been shown to be particularly susceptible to infection from picornaviruses.
The current study by Nejentsev and colleagues is a great example of how new resequencing technology can be used in conjunction with data obtained from previous genome-wide scans to identify rare variants and to shed light on disease processes that might have otherwise gone undetected. Because this was not a systematic assessment and the researchers only drilled down on 10 genes, one wonders how many rare variants might be found for T1DM and other complex traits, and what their effect might be on the risk for disease. Certainly, the 50% protection seen in this study was greater than the typical modest odds ratio of common SNPs that have thus far been reported. Whole genome sequencing will ultimately be necessary to provide a more comprehensive assessment. Nevertheless, identification of a mechanism to protect against the exciting advance for T1DM is an exciting advance. Could this be simulated by a small molecule or even a vaccine in the future?
Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
Nejentsev S, Walker N, Riches D, Egholm M, Todd JA
Science. 2009;324:387-389
Summary
Over the past year, new approaches in genome scanning have identified many common susceptibility variants for complex traits. However, enthusiasm has been tempered due to relative modest odds ratios seen with most of these variants, thereby leaving the majority of heritable risk unexplained. A potential explanation may be that rare variants, and not the common variants identified in genome-wide scans, confer the majority of risk for common diseases.
In their recent paper, Nejentsev and colleagues identified 4 rare genetic variants that independently protect against type 1 diabetes mellitus (T1DM). The alleles lie in a region containing functional elements of the gene interferon-induced helicase (IFIH1) on chromosome 2q24. The protective effect of the rare alleles was quite striking, with 1 variant cutting the risk of developing T1DM in half. This is one of the first studies to identify rare variants in a common disease.
The authors initially selected 10 genes previously known to associate with T1DM for further study. They resequenced 144 target regions that covered functional elements of the 10 genes, comprising a total of 31,000 base pairs. The initial scan was performed in 480 patients with T1DM and 480 controls; both groups were predominately of European descent. Using these data, 2 highly significant, rare single nucleotide polymorphisms (SNPs) in the IFIH1 gene were isolated and found to be protective.
An additional 20,000 cases and controls were then studied to replicate the protective effect of these 2 SNPs. The results of this second stage of testing validated the initial SNPs findings and revealed 2 additional rare SNPs and 1 common SNP in the same IFIH1 region. The 4 rare variants have predictable biologic responses, ranging from truncation of the IFIH1 protein to modifying essential splicing positions. Importantly, all 5 variants (4 rare, 1 common) were protective and their effect was independent of each other. Furthermore, the rare variants were found to have stronger protective effects than did the common SNP (odds ratio, 0.51-0.74 vs 0.86), underscoring the hypothesis that rare SNPs can have greater effects on phenotypic expression compared with common variants.
Viewpoint
The IFIH1 gene is known to mediate immune activation in response to viral RNA from picornaviruses. Indeed, acute infection with enterovirus, a member of the picornavirus family, has been shown to predate autoantibody production and is commonly seen in patients recently diagnosed with T1DM and in prediabetics. Thus, one could extrapolate that regulation of IFIH1 gene expression through vaccination or targeted therapy might prevent the onset of juvenile or adult-onset T1DM through alteration in the immune response to these viruses. However, the safety of such an approach would have to be validated, as mice deficient of IFIH1 have been shown to be particularly susceptible to infection from picornaviruses.
The current study by Nejentsev and colleagues is a great example of how new resequencing technology can be used in conjunction with data obtained from previous genome-wide scans to identify rare variants and to shed light on disease processes that might have otherwise gone undetected. Because this was not a systematic assessment and the researchers only drilled down on 10 genes, one wonders how many rare variants might be found for T1DM and other complex traits, and what their effect might be on the risk for disease. Certainly, the 50% protection seen in this study was greater than the typical modest odds ratio of common SNPs that have thus far been reported. Whole genome sequencing will ultimately be necessary to provide a more comprehensive assessment. Nevertheless, identification of a mechanism to protect against the exciting advance for T1DM is an exciting advance. Could this be simulated by a small molecule or even a vaccine in the future?
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