Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis

Masanao Matsushita, Hiroshi Miyakawa, Atsushi Tanaka, Minako Hijikata, Kentaro Kikuchi, Hirotoshi Fujikawa, Junya Arai, Shigehiko Sainokami, Kunihiko Hino, Itaru Terai, Shunji Mishiro, M. Eric Gershwin

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9% vs. 17.0%, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95% confidence interval (CI)=1.34-4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.

Original languageEnglish (US)
Pages (from-to)251-257
Number of pages7
JournalJournal of Autoimmunity
Volume17
Issue number3
DOIs
StatePublished - Nov 1 2001

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Mannose-Binding Lectin
Biliary Liver Cirrhosis
Single Nucleotide Polymorphism
Genotype
Polymerase Chain Reaction
Mucosal Immunity
Genetic Promoter Regions
Restriction Fragment Length Polymorphisms
Haplotypes
Cluster Analysis
Exons
Odds Ratio
Confidence Intervals

Keywords

  • Innate immune system
  • Mannose-binding lectin (MBL)
  • Primary biliary cirrhosis (PBC)
  • Single nucleotide polymorphism (SNP)

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis. / Matsushita, Masanao; Miyakawa, Hiroshi; Tanaka, Atsushi; Hijikata, Minako; Kikuchi, Kentaro; Fujikawa, Hirotoshi; Arai, Junya; Sainokami, Shigehiko; Hino, Kunihiko; Terai, Itaru; Mishiro, Shunji; Gershwin, M. Eric.

In: Journal of Autoimmunity, Vol. 17, No. 3, 01.11.2001, p. 251-257.

Research output: Contribution to journalArticle

Matsushita, M, Miyakawa, H, Tanaka, A, Hijikata, M, Kikuchi, K, Fujikawa, H, Arai, J, Sainokami, S, Hino, K, Terai, I, Mishiro, S & Gershwin, ME 2001, 'Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis', Journal of Autoimmunity, vol. 17, no. 3, pp. 251-257. https://doi.org/10.1006/jaut.2001.0538
Matsushita, Masanao ; Miyakawa, Hiroshi ; Tanaka, Atsushi ; Hijikata, Minako ; Kikuchi, Kentaro ; Fujikawa, Hirotoshi ; Arai, Junya ; Sainokami, Shigehiko ; Hino, Kunihiko ; Terai, Itaru ; Mishiro, Shunji ; Gershwin, M. Eric. / Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis. In: Journal of Autoimmunity. 2001 ; Vol. 17, No. 3. pp. 251-257.
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abstract = "Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9{\%} vs. 17.0{\%}, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95{\%} confidence interval (CI)=1.34-4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.",
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AU - Kikuchi, Kentaro

AU - Fujikawa, Hirotoshi

AU - Arai, Junya

AU - Sainokami, Shigehiko

AU - Hino, Kunihiko

AU - Terai, Itaru

AU - Mishiro, Shunji

AU - Gershwin, M. Eric

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AB - Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9% vs. 17.0%, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95% confidence interval (CI)=1.34-4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.

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