title: Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.
abstract: Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to create DNA pools for a genome wide association study (GWAS). GWAS findings were validated with individual HLA tag single nucleotide polymorphism (SNP) typing of 473 patients and 714 healthy controls. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%. This study confirmed that improvement of CD risk prediction sensitivity could be achieved by including non-HLA SNPs alongside HLA SNPs in genetic testing.
authors.affiliation: Department of Gastroenterology Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Paziewska
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Bozena
authors.initials: B
authors.lastname: Cukrowska
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Michalina
authors.initials: M
authors.lastname: Dabrowska
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Goryca
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Piatkowska
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kluska
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Mikula
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Karczmarski
authors.affiliation: Department of Gastroenerology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Oralewska
authors.affiliation: Department of Gastroenerology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rybak
authors.affiliation: Department of Gastroenerology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Socha
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Balabas
authors.affiliation: Department of Gastroenterology Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Zeber-Lubecka
authors.affiliation: Department of Gastroenterology Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Filip
authors.initials: F
authors.lastname: Ambrozkiewicz
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Konopka
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Trojanowska
authors.affiliation: The Faculty of Health Protection and Human Sciences, the State Higher School of Vocational Education, Ciechanow, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Zagroba
authors.affiliation: Department of Molecular Biology, The Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szperl
authors.affiliation: Department of Gastroenterology Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland; Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ostrowski
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity
chemical_list: D018797:Cell Cycle Proteins; D006680:HLA Antigens; C118481:MSH5 protein, human