title: Cumulative effect of IFIH1 variants and increased gene expression associated with type 1 diabetes.
abstract: OBJECTIVE
  IFIH1 (Interferon Induced with Helicase C domain 1) gene encodes a sensor of double-stranded RNA, which initiates antiviral activity. Recent studies have indicated the association of rare and common IFIH1 variants with type 1 diabetes mellitus (T1D). The aim of this study was to investigate whether polymorphisms in the IFIH1 locus are a risk factor for T1D in Caucasian patients from Poland.
  
  
  METHODS
  We genotyped 514 T1D patients and 713 healthy control individuals for rs3747517, rs1990760, rs2111485 and rs13422767 variants. Cumulative genetic risk score (CGRS) was calculated using unweighted and weighted approaches. We also examined the expression of IFIH1 gene in a cohort of 90 T1D patients.
  
  
  RESULTS
  All studied polymorphisms showed significant association with type 1 diabetes. The risk alleles G of rs3747517, rs2111485, rs13422767 and A of rs1990760 were observed more frequently in T1D group with P values and allelic odds ratio OR (95%CI) < 0.0001, 1.742 (1.428-2.126); 0.001, 1.336 (1.125-1.588); < 0.0001, 1.799 (1.416-2.285); 0.0005, 1.359 (1.144-1.616), respectively. The risk for type 1 diabetes increased with the growing number of the risk alleles. OR (95%CI) for carriers of ≥ 6 risk alleles reached 2.387 (1.552-3.670) for unweighted CGRS and 3.132 (1.928-5.089) for weighted CGRS. Furthermore, IFIH1 gene expression levels in unstimulated peripheral blood mononuclear cells of T1D patients were significantly higher compared to healthy individuals (mean ± SEM mRNA copy number 163.8 ± 15.7 vs. 117.8 ± 7.2; P = 0.046).
  
  
  CONCLUSIONS
  This study confirms the association of the IFIH1 locus with susceptibility to T1D in the Polish population. The cumulative effect of rs3747517, rs1990760, rs2111485 and rs13422767 variants on type 1 diabetes risk was observed.
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. Electronic address: zurawek@man.poznan.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zurawek
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland; Department of Endocrinology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Fichna
authors.affiliation: Department of Paediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Fichna
authors.affiliation: Department of Paediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Bogda
authors.initials: B
authors.lastname: Skowronska
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dzikiewicz-Krawczyk
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland; Department of Paediatric Oncology, Haematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Januszkiewicz
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Nowak
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D016017:Odds Ratio; D011044:Poland; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
keywords: Cumulative effect of variants; Gene expression; IFIH1; T1D; Variants