TNFA Haplotype Genetic Testing Improves HLA in Estimating the Risk of Celiac Disease in Children.
BACKGROUND
TNF-α and IFN-γ play a role in the development of mucosal damage in celiac disease (CD). Polymorphisms of TNFA and IFNG genes, as well as of the TNFRSF1A gene, encoding the TNF-α receptor 1, might underlie different inter-individual disease susceptibility over a common HLA risk background. The aims of this study were to ascertain whether five SNPs in the TNFA promoter (-1031T>C,-857C>T,-376G>A,-308G>A,-238G>A), sequence variants of the TNFRSF1A gene and IFNG +874A>T polymorphism are associated with CD in a HLA independent manner.


METHODS
511 children (244 CD, 267 controls) were genotyped for HLA, TNFA and INFG (Real Time PCR). TNFRSF1A variants were studied (DHPLC and sequence).


RESULTS
Only the rare TNFA-1031C (OR=0.65, 95% CI:0.44-0.95), -857T (OR=0.42, 95% CI:0.27-0.65), -376A (OR=2.25, 95% CI:1.12-4.51) and -308A (OR=4.76, 95% CI:3.12-7.26) alleles were significantly associated with CD. One TNFRSF1A variant was identified (c.625+10A>G, rs1800693), but not associated with CD. The CD-correlated TNFA SNPs resulted in six haplotypes. Two haplotypes were control-associated (CCGG and TTGG) and three were CD-associated (CCAG, TCGA and CCGA). The seventeen inferred haplotype combinations were grouped (A to E) based on their frequencies among CD. Binary logistic regression analysis documented a strong association between CD and HLA (OR for intermediate risk haplotypes=178; 95% CI:24-1317; OR for high risk haplotypes=2752; 95% CI:287-26387), but also an HLA-independent correlation between CD and TNFA haplotype combination groups. The CD risk for patients carrying an intermediate risk HLA haplotype could be sub-stratified by TNFA haplotype combinations.


CONCLUSIONS
TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk.
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Elisa
E
Rossi
Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
Daniela
D
Basso
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Carlo-Federico
CF
Zambon
Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
Filippo
F
Navaglia
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Eliana
E
Greco
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Michela
M
Pelloso
Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy.
Serena
S
Artuso
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Andrea
A
Padoan
Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy.
Matilde
M
Pescarin
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Ada
A
Aita
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Dania
D
Bozzato
Department of Medicine-DIMED, University of Padova, Padova, Italy.
Stefania
S
Moz
Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy.
Mara
M
Cananzi
Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy.
Graziella
G
Guariso
Department of Medicine-DIMED, University of Padova, Padova, Italy; Department of Medicine-DIMED, University of Padova, Padova, Italy.
Mario
M
Plebani
D000293:Adolescent; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
D006680:HLA Antigens; C573415:IFNG protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma