Genetic Determinants of Enterovirus Infections: Polymorphisms in Type 1 Diabetes and Innate Immune Genes in the MIDIA Study.
Enteroviruses have been suggested as triggers of type 1 diabetes (T1D). We aimed to assess whether established T1D susceptibility single nucleotide polymorphisms (SNPs) and candidate SNPs in innate immune genes were associated with the frequency of enterovirus infection in otherwise healthy children. Fifty-six established T1D SNPs and 97 other candidate immunity SNPs were typed in 419 children carrying the T1D high-risk genotype, HLA-DR4-DQ8/DR3-DQ2 genotype, and 373 children without this genotype. Enteroviral RNA was detected using real-time polymerase chain reaction, with primers detecting essentially all enterovirus serotypes, in 7,393 longitudinal stool samples collected monthly (age range 3-36 months). The most significant association was with two T1D SNPs, rs12150079 (ZPBP2/ORMDL3/GSDMB region) (enterovirus frequency: AA 7.3%, AG 8.7%, GG 9.7%, RR = 0.86, overall p = 1.87E-02) and rs229541 (C1QTNF6/SSTR3/RAC2) (enterovirus frequency: CC 7.8%, CT 9.7%, TT 9.4%, RR = 1.13, overall p = 3.6E-02), followed by TLR8 (rs2407992) (p = 3.8E-02), TLR3 (1914926) (p = 4.9E-02), and two other T1D SNPs (IFIH1 rs3747517, p = 4.9E-02 and PTPN22, rs2476601, p = 5.3E-02). However, the quantile-quantile plot of p-values with confidence intervals for all 153 SNPs did not reveal clear evidence for rejection of the complete null hypothesis. Among a number of SNPs in candidate genes, we found no evidence for strong associations with enterovirus presence in stool samples from Norwegian children.
1 Norwegian Institute of Public Health , Oslo, Norway .
Elisabet
E
Witsø
2 Department of Pediatrics, University Hospital Motol, and 2nd Faculty of Medicine, Charles University in Prague , Prague, Czech Republic .
Ondrej
O
Cinek
1 Norwegian Institute of Public Health , Oslo, Norway .
German
G
Tapia
3 Department of Pediatrics E, Copenhagen Diabetes Research Centre (CPH-DIRECT), Herlev University Hospital , Herlev, Denmark .
Caroline A
CA
Brorsson
1 Norwegian Institute of Public Health , Oslo, Norway .
Lars C
LC
Stene
1 Norwegian Institute of Public Health , Oslo, Norway .|4 Department of Global Public Health and Primary Care, University of Bergen , Bergen, Norway .
Håkon K
HK
Gjessing
1 Norwegian Institute of Public Health , Oslo, Norway .
Trond
T
Rasmussen
5 Hagedorn Research Institute , Gentofte, Denmark .
Regine
R
Bergholdt
3 Department of Pediatrics E, Copenhagen Diabetes Research Centre (CPH-DIRECT), Herlev University Hospital , Herlev, Denmark .|6 Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark .
Flemming M
FM
Pociot
7 Department of Pediatric Research, Oslo University Hospital , Oslo, Norway .
Kjersti S
KS
Rønningen
D002675:Child, Preschool; D004770:Enterovirus / Q000302:isolation & purification; D004769:Enterovirus Infections / Q000453:epidemiology / Q000235:genetics*; D005243:Feces / Q000821:virology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
D012367:RNA, Viral