title: Investigation of susceptibility genes triggering lachrymal/salivary gland lesion complications in Japanese patients with type 1 autoimmune pancreatitis.
abstract: Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS) with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA) that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs) in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group) and 53 type 1 AIP patients without (B group). The mean values of IgG and IG4 were both significantly different (P<0.05) between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001) were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021]) and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]). Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P = 0.00062, Pc = 0.003, OR = 2.98, 95%CI = 1.58–5.65) in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P = 0.00015, OR = 3.38, 95%CI = 1.77–6.45). In the LOC101928923 gene, the frequency of the minor T allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C allele of MPPED2 rs514644 carried a significantly increased risk of complications [corrected].These four genes may be linked with the onset of lachrymal/salivary gland lesions in type 1 AIP patients and require further study.
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Oguchi
authors.affiliation: Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hamano
authors.affiliation: Endoscopic Examination Center, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Arakura
authors.affiliation: Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.affiliation: Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.affiliation: Center for Health, Safety, and Environmental Management, Shinshu University, Matsumoto, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D007765:Lacrimal Apparatus / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000276:immunology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012469:Salivary Glands / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C561977:MPPED2 protein, human; D010727:Phosphoric Diester Hydrolases