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=0.0018, 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=1.77-7.65). In the LOC101928923 gene, the frequency of the minor C 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. These four genes may be linked with the onset of lachrymal/salivary gland lesions in type 1 AIP patients and require further study.

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

“…(1) Genetic loci KLF7, FRMD4B, LOC101928923, MPPED2 in Japanese AIP associated with lacrimal/salivary gland lesions [14] Decreased MST 1 of regulatory T in Japanese AIP with extra-pancreatic lesions [17] FGFBP2 (fibroblast growth factor binding protein type 2): single base deletion in IgG4-RD [19] (2) Persistent exposure of intestinal commensal flora antigen in mouse AIP model Avirulent E. coli (as PAMP activator) induces anti-CA II, anti-LF and ANA in mouse AIP with salivary gland involvement [20] Commensal E. coli-derived membrane protein flagellin (FliC) induces AIP-like inflammation in mouse model [21] Intestinal microflora can activate TLRs and NLRs on basophils to promote Th2 skewing and IgG4 production in the presence of BAFF [22][23][24][25][26] (3) Intestinal dysbiosis-mediated AIP development via pDC activation Decrease in gut Bacteroides, Streptococcus and Clostridium species in patients with AIP, compared to chronic pancreatitis [28] Activation of pDC by innate immune responses against intestinal dysbiosis in experimental mouse AIP [29] BAFF-B cell-activating factor of TNF family; pDC-plasmacytoid dendritic cell; CA-carbonic anhydrase; LF-lactoferrin; ANA-antinuclear antibodies.…”

A high-throughput sequence analysis of Japanese patients revealed 11 candidate genes associated with type 1 autoimmune pancreatitis susceptibility

“…In contrast, our study used high-throughput sequencing. A recent genome-wide association study did not reveal the genes that are associated with AIP susceptibility [11] . The present study is therefore the first comprehensive analysis of the genes related to AIP susceptibility.…”

“…In this study, we also explored the genes that were associated with susceptibility to extra-pancreatic lesions, including sclerosing cholangititis, sialadenitis, dacryoadenitis, interstitial nephritis and lymph node swelling, and identified two candidates. Oguchi et al performed a genome-wide association study and extracted ten candidates associated with susceptibility to dacryoadenitis or sialadenitis in the Japanese patients with AIP, while no genes associated with all extra-pancreatic lesions was identified [11] . In this study, because sialadenitis and dacryoadenitis were only observed in two and three patients, respectively, we could not identified the genes that were specifically associated with dacryoadenitis or sialadenitis susceptibility in AIP patients.…”

“…Because multiple genes are usually associated with susceptibility to a multifactorial disease (including unknown genes), a high-throughput sequence analysis is necessary for the investigation of genes that confer AIP susceptibility. Oguchi et al performed a genome-wide association study to investigate genes that conferred susceptibility to the triggering of dacryoadenitis or sialadenitis in Japanese AIP patients; however, they did not show the genes that were associated with AIP susceptibility [11] . In the present study, we performed high-throughput sequencing with next generation sequencing, which targeted more than 1000 genes.…”

Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells

“…The protein encoded by the FRMD4B ( GRSP1 ) gene is a GRP1‐binding protein, which may act as a scaffolding protein, as it contains both two coiled coil domains and a FERM protein interaction domain 43 . Association of FRMD4B genetic variants had been reported in GWAS of advanced heart failure, 44 coeliac disease 45 and type 1 autoimmune pancreatitis 46 . Interestingly, GWAS of thiopurine metabolism in UK ALL97 patients identified an association with FRMD4B genetic variants 47 .…”