title: Association between human prothrombin variant (T165M) and kidney stone disease.
abstract: We previously reported the association between prothrombin (F2), encoding a stone inhibitor protein - urinary prothrombin fragment 1 (UPTF1), and the risk of kidney stone disease in Northeastern Thai patients. To identify specific F2 variation responsible for the kidney stone risk, we conducted sequencing analysis of this gene in a group of the patients with kidney stone disease. Five intronic SNPs (rs2070850, rs2070852, rs1799867, rs2282687, and rs3136516) and one exonic non-synonymous single nucleotide polymorphism (nsSNP; rs5896) were found. The five intronic SNPs have no functional change as predicted by computer programs while the nsSNP rs5896 (c.494 C>T) located in exon 6 results in a substitution of threonine (T) by methionine (M) at the position 165 (T165M). The nsSNP rs5896 was subsequently genotyped in 209 patients and 216 control subjects. Genotypic and allelic frequencies of this nsSNP were analyzed for their association with kidney stone disease. The frequency of CC genotype of rs5896 was significantly lower in the patient group (13.4%) than that in the control group (22.2%) (P = 0.017, OR 0.54, 95% CI 0.32-0.90), and the frequency of C allele was significantly lower in the patient group (36.1%) than that in the control group (45.6%) (P = 0.005, OR 0.68, 95% CI 0.51-0.89). The significant differences of genotype and allele frequencies were maintained only in the female group (P = 0.033 and 0.003, respectively). The effect of amino-acid change on UPTF1 structure was also examined by homologous modeling and in silico mutagenesis. T165 is conserved and T165M substitution will affect hydrogen bond formation with E180. In conclusion, our results indicate that prothrombin variant (T165M) is associated with kidney stone risk in the Northeastern Thai female patients.
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Nanyawan
authors.initials: N
authors.lastname: Rungroj
authors.forename: Nirinya
authors.initials: N
authors.lastname: Sudtachat
authors.forename: Choochai
authors.initials: C
authors.lastname: Nettuwakul
authors.forename: Nunghathai
authors.initials: N
authors.lastname: Sawasdee
authors.forename: Oranud
authors.initials: O
authors.lastname: Praditsap
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Jungtrakoon
authors.forename: Suchai
authors.initials: S
authors.lastname: Sritippayawan
authors.forename: Duangporn
authors.initials: D
authors.lastname: Chuawattana
authors.forename: Sombat
authors.initials: S
authors.lastname: Borvornpadungkitti
authors.forename: Chagkrapan
authors.initials: C
authors.lastname: Predanon
authors.forename: Wattanachai
authors.initials: W
authors.lastname: Susaengrat
authors.forename: Pa-Thai
authors.initials: PT
authors.lastname: Yenchitsomanus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D016022:Case-Control Studies; D003062:Codon; D005091:Exons; D005260:Female; D005787:Gene Frequency; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007669:Kidney Calculi / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics; D011516:Prothrombin / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D012737:Sex Factors; D055815:Young Adult
chemical_list: D003062:Codon; D010446:Peptide Fragments; D011498:Protein Precursors; C029733:prothrombin fragment 1; D011516:Prothrombin