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A polymorphism of the interferon-gamma-inducible protein 30 gene is associated with hyperglycemia in severely obese individuals

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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

References

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed  CAS  Google Scholar 

  • Alberti KG, Zimmet P, Shaw J (2006) Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23:469–480

    Article  PubMed  CAS  Google Scholar 

  • Anis AH, Zhang W, Bansback N, Guh DP, Amarsi Z, Birmingham CL (2010) Obesity and overweight in Canada: an updated cost-of-illness study. Obes Rev 11:31–40

    Article  PubMed  CAS  Google Scholar 

  • Arunachalam B, Phan UT, Geuze HJ, Cresswell P (2000) Enzymatic reduction of disulfide bonds in lysosomes: characterization of a gamma-interferon-inducible lysosomal thiol reductase (GILT). Proc Natl Acad Sci USA 97:745–750

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Bluher M (2010) The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 21:38–43

    Article  PubMed  Google Scholar 

  • Bouchard L, Tchernof A, Deshaies Y, Marceau S, Lescelleur O, Biron S, Vohl MC (2007) ZFP36: a promising candidate gene for obesity-related metabolic complications identified by converging genomics. Obes Surg 17:372–382

    Article  PubMed  Google Scholar 

  • Bouchard L, Faucher G, Tchernof A, Deshaies Y, Lebel S, Hould FS, Marceau P, Vohl MC (2009a) Comprehensive genetic analysis of the dipeptidyl peptidase-4 gene and cardiovascular disease risk factors in obese individuals. Acta Diabetol 46:13–21

    Article  PubMed  CAS  Google Scholar 

  • Bouchard L, Faucher G, Tchernof A, Deshaies Y, Marceau S, Lescelleur O, Biron S, Bouchard C, Perusse L, Vohl MC (2009b) Association of OSBPL11 gene polymorphisms with cardiovascular disease risk factors in obesity. Obesity (Silver Spring) 17(7):1466–1472. doi:10.1038/oby.2009.71

    Google Scholar 

  • Cameron AJ, Dunstan DW, Owen N, Zimmet PZ, Barr EL, Tonkin AM, Magliano DJ, Murray SG, Welborn TA, Shaw JE (2009) Health and mortality consequences of abdominal obesity: evidence from the AusDiab study. Med J Aust 191:202–208

    PubMed  Google Scholar 

  • Collins DS, Unanue ER, Harding CV (1991) Reduction of disulfide bonds within lysosomes is a key step in antigen processing. J Immunol 147:4054–4059

    PubMed  CAS  Google Scholar 

  • Expert Panel on Detection EaToHBCiA (2001) Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285:2486–2497

    Article  Google Scholar 

  • Hajer GR, van Haeften TW, Visseren FL (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29:2959–2971

    Article  PubMed  CAS  Google Scholar 

  • Hastings KT, Cresswell P (2011) Disulfide reduction in the endocytic pathway: immunological functions of gamma-interferon-inducible lysosomal thiol reductase. Antioxid Redox Signal. doi:10.1089/ars.2010.3684

  • Karelis AD, St Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET (2004) Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 89:2569–2575

    Article  PubMed  CAS  Google Scholar 

  • Konig IR, Ziegler A (2003) Group sequential study designs in genetic-epidemiological case–control studies. Hum Hered 56:63–72

    Article  PubMed  Google Scholar 

  • Lahiry P, Pollex RL, Hegele RA (2008) Uncloaking the genetic determinants of metabolic syndrome. J Nutrigenet Nutrigenomics 1:118–125

    Article  PubMed  CAS  Google Scholar 

  • Lindholm E, Melander O, Almgren P, Berglund G, Agardh CD, Groop L, Orho-Melander M (2006) Polymorphism in the MHC2TA gene is associated with features of the metabolic syndrome and cardiovascular mortality. PLoS One 1:e64

    Article  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Marceau P, Hould FS, Simard S, Lebel S, Bourque RA, Potvin M, Biron S (1998) Biliopancreatic diversion with duodenal switch. World J Surg 22:947–954

    Article  PubMed  CAS  Google Scholar 

  • Maric M, Arunachalam B, Phan UT, Dong C, Garrett WS, Cannon KS, Alfonso C, Karlsson L, Flavell RA, Cresswell P (2001) Defective antigen processing in GILT-free mice. Science 294:1361–1365

    Article  PubMed  CAS  Google Scholar 

  • Martinez A, Sanchez-Lopez M, Varade J, Mas A, Martin MC, de Las Heras V, Arroyo R, Mendoza JL, Diaz-Rubio M, Fernandez-Gutierrez B, de la Concha EG, Urcelay E (2007) Role of the MHC2TA gene in autoimmune diseases. Ann Rheum Dis 66:325–329

    Article  PubMed  CAS  Google Scholar 

  • Mathieu P, Poirier P, Pibarot P, Lemieux I, Despres JP (2009) Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension 53:577–584

    Article  PubMed  CAS  Google Scholar 

  • Mathieu P, Lemieux I, Despres JP (2010) Obesity, inflammation, and cardiovascular risk. Clin Pharmacol Ther 87:407–416

    Article  PubMed  CAS  Google Scholar 

  • Singh R, Cresswell P (2010) Defective cross-presentation of viral antigens in GILT-free mice. Science 328:1394–1398

    Article  PubMed  CAS  Google Scholar 

  • Sobell JL, Heston LL, Sommer SS (1993) Novel association approach for determining the genetic predisposition to schizophrenia: case–control resource and testing of a candidate gene. Am J Med Genet 48:28–35

    Article  PubMed  CAS  Google Scholar 

  • Teran-Garcia M, Bouchard C (2007) Genetics of the metabolic syndrome. Appl Physiol Nutr Metab 32:89–114

    Article  PubMed  CAS  Google Scholar 

  • The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26(Suppl 1):S5–S20

    Google Scholar 

  • Vohl MC, Sladek R, Robitaille J, Gurd S, Marceau P, Richard D, Hudson TJ, Tchernof A (2004) A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes Res 12:1217–1222

    Article  PubMed  CAS  Google Scholar 

  • Vohl MC, Houde A, Lebel S, Hould FS, Marceau P (2005) Effects of the peroxisome proliferator-activated receptor-gamma co-activator-1 Gly482Ser variant on features of the metabolic syndrome. Mol Genet Metab 86:300–306

    Article  PubMed  CAS  Google Scholar 

  • WHO (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894:i–xii, 1–253

  • Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610–617

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Nutraceuticals and Functional Foods (INAF), Pavillon des Services, Laval University, local 2729K, Quebec, G1V 0A6, Canada

    V. Turcot, G. Faucher, L. Pérusse & Marie-Claude Vohl

  2. Molecular Endocrinology and Genomics, CHUQ, Laval University, Quebec, Canada

    V. Turcot, G. Faucher, A. Tchernof & Marie-Claude Vohl

  3. Department of Biochemistry, Faculty of Medicine and Health Sciences, University of Sherbrooke, and ECOGENE-21 Research Center, Chicoutimi Hospital, Quebec, Canada

    L. Bouchard

  4. Quebec Heart and Lung Institute, Faculty of Medicine, Laval University, Quebec, Canada

    Y. Deshaies, P. Marceau, F. S. Hould & S. Lebel

  5. Department of Preventive Medicine, Laval University, Quebec, Canada

    L. Pérusse

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  1. V. Turcot
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  2. L. Bouchard
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  3. G. Faucher
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  4. A. Tchernof
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  5. Y. Deshaies
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  6. L. Pérusse
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  7. P. Marceau
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  8. F. S. Hould
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  9. S. Lebel
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  10. Marie-Claude Vohl
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Correspondence to Marie-Claude Vohl.

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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

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