Abstract
A previous expression profiling of visceral adipose tissue (VAT) revealed that the immune response gene interferon-gamma-inducible protein 30 (IFI30) gene was 1.72-fold more highly expressed in non-diabetic severely obese men with the metabolic syndrome as compared to those without. Given the importance of low-grade inflammation in obesity-related metabolic complications, we hypothesized that variants in the IFI30 gene are associated with cardiovascular disease (CVD) risk factors. A detailed genetic investigation was performed at the IFI30 locus by sequencing its promoter, exons and intron–exon junction boundaries using DNA of 25 severely obese men. Among the 21 sequence-derived single-nucleotide polymorphisms (SNPs), 5 tagged SNPs (covering 100% of the common SNPs identified) were genotyped in two independent samples of severely obese patients (total n = 1,283). Using a multistage experimental design, chi-square analyses and logistic regressions were performed to compare genotype frequencies and compute odds-ratios (OR) for low and high CVD risk groups (dyslipidemia, hyperglycemia/diabetes and hypertension). A significant association was observed with the non-synonymous SNP rs11554159 (p.R76Q), where GA individuals showed lower risk (OR = 0.67; P = 0.0009) for hyperglycemia/diabetes as compared to homozygotes for the major allele (GG). No association was observed between rs11554159 and VAT IFI30 mRNA levels (P = 0.81), and the expression levels were not correlated with fasting plasma glucose levels (P = 0.31) in 112 non-diabetic severely obese women. The localization of rs11554159 near the active site of IFI30 suggests a functional effect of this SNP. This study showed a novel association between rs11554159 (p.R76Q) polymorphism at the IFI30 locus and the risk of hyperglycemia/diabetes in severely obese individuals.
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Abbreviations
- BMI:
-
Body mass index
- bp:
-
Base pair
- CRP:
-
C-reactive protein
- CVD:
-
Cardiovascular disease
- GILT:
-
Gamma-interferon-inducible lysosomal thiol reductase
- GLM:
-
General linear model
- HDL:
-
High-density lipoprotein
- IDF:
-
International Diabetes Federation
- IFI30:
-
Interferon-gamma-inducible protein 30
- LD:
-
Linkage disequilibrium
- LDL:
-
Low-density lipoprotein
- LS:
-
Least square
- MAF:
-
Minor allele frequency
- MHC:
-
Major histocompatibility complex
- MS:
-
Metabolic syndrome
- NCEP-ATPIII:
-
National Cholesterol Education Program-Adult Treatment Panel III
- qRT-PCR:
-
Quantitative real-time reverse transcriptase polymerase chain reaction
- OR:
-
Odds-ratio
- SNPs:
-
Single-nucleotide polymorphisms
- T2D:
-
Type 2 diabetes
- TSS:
-
Translation start site
- UTR:
-
Untranslated region
- VAT:
-
Visceral adipose tissue
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Acknowledgments
This study was supported by a grant from the Canadian Institutes of Health Research (CIHR: MOP-200609). The severely obese cohort was supported, over the years, by the Laval University Merck-Frosst/CIHR Research Chair in Obesity. We express our gratitude to surgeons Simon Marceau, Simon Biron, Odette Lescelleur and Laurent Berthio of the Quebec Heart and Lung Institute who have sampled adipose tissues for this project. Many thanks are also expressed to Fanny Therrien and Caroline Nadeau for their help in adipose tissue banking management. Valérie Turcot received studentship awards from the Canadian Institutes of Health Research and the Fonds de la Recherche en Santé du Québec. André Tchernof is a research scholar from the Fonds de la Recherche en Santé du Québec. Marie-Claude Vohl is Tier 1 Canada Research Chair in Genomics Applied to Nutrition and Health.
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The authors declare that they have no conflict of interest.
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Turcot, V., Bouchard, L., Faucher, G. et al. A polymorphism of the interferon-gamma-inducible protein 30 gene is associated with hyperglycemia in severely obese individuals. Hum Genet 131, 57–66 (2012). https://doi.org/10.1007/s00439-011-1043-4
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DOI: https://doi.org/10.1007/s00439-011-1043-4