title: PAX4 R192H and P321H polymorphisms in type 2 diabetes and their functional defects.
abstract: We have previously identified PAX4 mutations causing MODY9 and a recent genome-wide association study reported a susceptibility locus of type 2 diabetes (T2D) near PAX4. In this study, we aim to investigate the association between PAX4 polymorphisms and T2D in Thai patients and examine functions of PAX4 variant proteins. PAX4 rs2233580 (R192H) and rs712701 (P321H) were genotyped in 746 patients with T2D and 562 healthy normal control subjects by PCR and restriction-fragment length polymorphism method. PAX4 variant proteins were investigated for repressor function on human insulin and glucagon promoters and for cell viability and apoptosis upon high glucose exposure. Genotype and allele frequencies of PAX4 rs2233580 were more frequent in patients with T2D than in control subjects (P=0.001 and 0.0006, respectively) with odds ratio of 1.66 (P=0.001; 95% confidence interval, 1.22-2.27). PAX4 rs712701 was not associated with T2D but it was in linkage disequilibrium with rs2233580. The 192H/321H (A/A) haplotype was more frequent in T2D patients than in controls (9.5% vs 6.6%; P=0.009). PAX4 R192H, but not PAX4 P321H, impaired repression activities on insulin and glucagon promoters and decreased transcript levels of genes required to maintain β-cell function, proliferation and survival. Viability of β-cell was reduced under glucotoxic stress condition for the cells overexpressing either PAX4 R192H or PAX4 P321H or both. Thus these PAX4 polymorphisms may increase T2D risk by defective transcription regulation of target genes and/or decreased β-cell survival in high glucose condition.
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Jatuporn
authors.initials: J
authors.lastname: Sujjitjoon
authors.affiliation: Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Suwattanee
authors.initials: S
authors.lastname: Kooptiwut
authors.affiliation: Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Nalinee
authors.initials: N
authors.lastname: Chongjaroen
authors.affiliation: Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Namoiy
authors.initials: N
authors.lastname: Semprasert
authors.affiliation: Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Wanthanee
authors.initials: W
authors.lastname: Hanchang
authors.affiliation: Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.|Research Division, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Kanjana
authors.initials: K
authors.lastname: Chanprasert
authors.affiliation: Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Watip
authors.initials: W
authors.lastname: Tangjittipokin
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Pa-Thai
authors.initials: PT
authors.lastname: Yenchitsomanus
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Nattachet
authors.initials: N
authors.lastname: Plengvidhya
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose; D016022:Case-Control Studies; D002460:Cell Line; D002470:Cell Survival; D003062:Codon; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D016017:Odds Ratio; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D015533:Transcriptional Activation
chemical_list: D001786:Blood Glucose; D003062:Codon; D018398:Homeodomain Proteins; D007328:Insulin; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D005934:Glucagon