Association between Human Prothrombin Variant (T165M) and Kidney Stone Disease

• Published in: PloS one Vol. 7; no. 9; p. e45533
• Main Authors: Rungroj, Nanyawan, Sudtachat, Nirinya, Nettuwakul, Choochai, Sawasdee, Nunghathai, Praditsap, Oranud, Jungtrakoon, Prapaporn, Sritippayawan, Suchai, Chuawattana, Duangporn, Borvornpadungkitti, Sombat, Predanon, Chagkrapan, Susaengrat, Wattanachai, Yenchitsomanus, Pa-thai
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.09.2012; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Amino Acid Sequence; Amino Acid Substitution; Amino acids; Analysis; Base Sequence; Biology; C (programming language); Case-Control Studies; Codon; Computer programs; Disease; Exons; Female; Females; Fourier transforms; Gene Frequency; Gene Order; Gene sequencing; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genotype; Health risks; Homology; Hospitals; Humans; Hydrogen; Hydrogen bonds; Kidney Calculi - genetics; Kidney stones; Kidneys; Male; Medicine; Methionine; Middle Aged; Models, Molecular; Molecular Sequence Data; Mutagenesis; Nephrology; Patients; Peptide Fragments - chemistry; Peptide Fragments - genetics; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Population; Protein Conformation; Protein Precursors - chemistry; Protein Precursors - genetics; Proteins; Prothrombin; Prothrombin - chemistry; Prothrombin - genetics; R&D; Research & development; Risk analysis; Risk factors; Sequence Alignment; Sex Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Software; Stone; Threonine; Urine; Young Adult; Thailand; Bangkok Thailand
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0045533

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.