Genetic Polymorphism In Exon Research Articles

Genetic Polymorphisms in Exon 5 and Intron 5 and 7 of AIRE Are Associated with Rheumatoid Arthritis Risk in a Hungarian Population.

Rheumatoid arthritis (RA) is chronically persistent synovitis and systemic inflammation. Although multiple contributors are detected, only one is pivotal in the neonatal period: the negative selection of autoimmune naïve T-cells by the autoimmune regulator (AIRE) transcriptional factor. Single-nucleotide polymorphisms (SNPs) in the DNA-binding site of AIRE may determine its function and expression. We intended to analyse site-specific allelic polymorphisms in two exon (rs878081 and rs1055311) and three intron (rs1003853, rs2075876, and rs1003854) loci with an RA risk. Our analytical case-control study analysed 270 RA patients and 322 control subjects in five different genetic models using quantitative real-time PCR (qPCR) with TaqMan® assays. Statistically significant differences were found between the odds of allelic polymorphisms in the loci of rs878081, rs1003854, and rs1003853 among the controls and RA patients, and the disease activity seemed to be significantly associated with the genotypic subgroups of rs878081 and rs1055311. Our in silico analysis supported this, suggesting that allele-specific alterations in the binding affinity of transcriptional factor families might determine RA activity. Our findings highlight the involvement of neonatal self-tolerance in RA pathogenesis, providing novel insights into disease development and paving the way for an analysis of further site-specific genetic polymorphisms in AIRE to expand the intervention time for RA.

Identification of Polymorphisms of the CSN2 Gene Encoding β-Casein in Greek Local Breeds of Cattle.

This e research focused on the detection and identification of genetic polymorphisms in exon 7 of the β-casein CSN2 gene in blood samples from Greek Holstein cows and from local breeds of cattle, such as Vrachykeratiki, Katerinis, and Sykias. For this purpose, DNA was isolated from 780 blood samples obtained from Greek Holstein cows, 86 from three local breeds of cattle, namely Brachyceros, Katerinis, and Sykias, and 14 from Greek buffalo. The desired region of exon 7 was amplified by PCR, resulting in 121 and 251 bp products in bovine and buffalo samples. The PCR product was digested with restriction fragment length polymorphism (RFLP) on agarose gels. The restriction enzymes DdeI and TaqI were used. All of the blood samples had the amplified size. The results showed that 74.4% of the Greek Holstein cows had the A2A2 β-casein genotype, the three native breads Vrachykeratiki had 57.7%, and the other two had 100% of the A2A2 β-casein. From the 14 Greek buffalo, 100% had the A2A2 β-casein.

Association of the polymorphism Exon 1 (A/O) region of the mannose-binding lectin gene and periportal fibrosis regression in schistosomiasis after specific treatment.

INTRODUCTION: We evaluated the association between genetic polymorphisms in exon 1 (A/O alleles) and promoter regions at positions -550 (H/L variant, rs11003125) and -221 (X/Y variant, rs7096206) MBL2 and periportal fibrosis regression. METHODS: This was a retrospective cohort study involving 114 Brazilians infected with Schistosoma mansoni, who were subjected to follow-up for three years after specific treatment for schistosomiasis to estimate the probability of periportal fibrosis regression. RESULTS: A risk association was observed between polymorphism at the exon 1 MBL2 and periportal fibrosis regression. CONCLUSIONS: This study suggests that the polymorphism of exon 1 MBL2 may potentially be used to predict periportal fibrosis regression in this population.

Identification of Polymorphisms of Gene CSN2 of B Casein in Greek Cow Breeds (Holstein) by Restriction Fragment Length Polymorphism

The research focused to detect and identify genetic polymorphisms in exon 7 of the β-casein CSN2 gene in blood samples from Greek Holstein cows. For this purpose, DNA was extracted from 120 blood samples of cows. The desired region of exon 7 was amplified by PCR, resulting in a 121 bp product. The PCR product was digested by restriction fragment length polymorphism (RFLP) method. The results suggest that the A1A2 genotype prevails over the others. Specifically, of the 120 cattle, 72 showed triple bands of 121 bp, 86 bp, and 35 bp indicating the A1A2 genotype. The 42 cattle showed a single band at 121 bp, indicating that they carried the A1A1 genotype. The remaining 6 showed only two bands of 86 and 35 bps, indicating that they carried the A2A2 genotype. In the total population of heterozygotes A1A2-0.60 were the most frequent, while homozygotes A2A2-0.06 were the least frequent ones. This suggests a slight superiority of allele A-0.65.

DNA polymorphism of FSHR gene and its association with infertility traits in Egyptian buffaloes

The objectives of this study were to detect genetic polymorphism in exon 10 of Follicle Stimulating Hormone Receptor gene (FSHR) by using RFLP and direct sequence methods, also to investigate their possible association with infertility traits in Egyptian buffaloes. A total number of 50 female Egyptian buffaloes at Mahallet Mousa experimental farms in Kafr El-sheikh province were investigated. Animals were divided into three groups: normal fertile (20 animals), infertile due to anestrum (15 animals) and infertile due to repeat breeding (15 animals). Genomic DNA was extracted from blood samples, then PCR was performed with annealing temperatures of 57oC to amplify 231 bp of FSHR exon 10 gene. The amplicons were digested with Hin1II (NlaIII) restriction enzyme. The results showed that all the investigated buffaloes were monomorphic and genotyped as A/A genotype. Moreover, the monomorphism of buffaloes FSHR exon 10 gene was confirmed by sequencing three samples from each buffaloes’ group. It seems that FSHR gene are highly conserved in the investigated buffalo’s population.

PCR-RFLP Polymorphism of Growth Hormone Gene and Its Association with Growth and Morphometric Traits in Ganjam and Baigani Goats of Odisha

Background: Growth Hormone (GH) gene codes for the growth hormone, an anabolic hormone synthesized and secreted by the somatotroph cells of pituitary. Growth hormone influences many processes such as growth, lactation, reproduction and metabolism. Genetic variation in the gene are utilized as markers for selecting animals that are superior in terms growth, production and reproduction traits. Information available on the polymorphism of growth hormone gene of Ganjam and Baigani goats of Odisha is scanty. The current investigation was done to explore the genetic variation of this gene and its association with morphometric traits. Methods: Genetic polymorphism in exon 2 and 3 of Growth hormone gene in Ganjam goat and Baigani goat was explored with sample size of 100 goats for each. The goats belonged to three locations: Khallikote, Rambha, Chattrapur of Ganjam district. The goats were recorded for their body weights, morphometric traits and morphological traits. Genomic DNA was isolated, the target segment comprising exons 2 and 3 was amplified and PCR-RFLP was carried out using Hae III restriction enzyme. Genotypes were scored. Result: PCR of the locus resulted in 422 bp PCR product. PCR-RFLP using Hae III restriction enzyme yielded only two variants in both the populations. The variant A had only one restriction recognition site on the target gene segment yielding two bands with size of 366bp and 56bp whereas the variant B did not have any restriction site with single band of 422bp. Three genotypes AA, AB and BB were found in both the population. In both the population, the gene and genotype frequency were significantly deviated from the Hardy Weinberg Equilibrium frequency. There was a significant difference in the genotype frequencies of growth hormone gene between Ganjam and Baigani goats. The AB genotype had higher mean value for all morphometric traits than AA and BB genotype though the differences were not found to be significant.

Molecular Analysis of Leptin Gene Polymorphism in Achai, Sahiwal Cattle and Nili-ravi Buffalo Breeds of Pakistan

Pakistan is blessed with rich sheep genetic resources and being a source of milk, meat and wool sheep breeds are reared across the country. Despite its great economic importance very limited work has been done in Pakistan on sheep genetic exploration. Leptin hormone plays important role in milk yield, body weight, energy balance, feed intake, immune function and fertility performance in animals. The current study was carried out to investigate genetic polymorphism in exon III of Leptin gene (LEP) in indigenous animal breeds (Nilli-ravi buffalo, Sahiwal and Achai cattle) of Pakistan using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). PCR-RFLP analysis revealed that all the three studied animals breeds were polymorphic for i>LEP gene (having all the three genotypes AA, AB and BB) with frequency of 60%, 33% and 7% in Nili-ravi buffalo, 55%, 41% and 4% in Achai cattle and 52%, 45% and 3% in Sahiwal cattle breed. The genotype BB is highly desirable in cattle and buffalo breeds but its frequency is very low in our indigenous population. Studying genetic polymorphism of milk protein is important due to its application in dairy industry and these in formations could further be utilized for future breeding programs particularly for the enrichment of the rare genotype.

Single nucleotide polymorphism of candidate genes in non-descript local goats of Sri Lanka

In the present study, genetic polymorphism in exon 4 of kappa casein (k-CSN3), exon 2-3 of alpha lactalbumin (LALBA) and exon 1 of gonadotropin releasing hormone receptor (GnRHR) genes were analyzed as candidate genes for milk production, milk quality and prolificacy in non-descriptive local goats in Sri Lanka. Altogether eleven, one and three single nucleotide polymorphisms (SNPs) were identified in k-CSN3, LALBA and GnRHR gene fragments, respectively utilizing the DNA sequencing technique for the first time in Sri Lanka. Seven polymorphic sites out of eleven in k-CSN3 gene fragment and the recorded variable site in LALBA gene fragment were homozygous while all three polymorphic sites in GnRHR gene fragment were heterozygous. Two of the SNPs recorded in the present study are known to be unique for Sri Lankan non-descript goat population at G203T and A730G in k-CSN3 and GnRHR genes, respectively. The study records another two SNPs in GnRHR gene, which are already known to be correlated with higher fecundity in goats (G757A and G891T). Results of the present study will be extremely important in future attempts to develop markers to improve the milk production, milk composition and litter size of non-descript local goats in Sri Lanka.

Single nucleotide polymorphism of candidate genes in non-descript local goats of Sri Lanka

In the present study, genetic polymorphism in exon 4 of kappa casein (k-CSN3), exon 2–3 of alpha lactalbumin (LALBA) and exon 1 of gonadotropin releasing hormone receptor (GnRHR) genes were analyzed as candidate genes for milk production, milk quality and prolificacy aiming to provide information for future studies on genetic improvements in non-descriptive local goats in Sri Lanka. Altogether eleven, thirteen and three single nucleotide polymorphisms (SNPs) were identified in k-CSN3, LALBA and GnRHR gene fragments respectively utilizing the DNA sequencing technique in Sri Lanka. Seven polymorphic sites out of eleven in k-CSN3 gene fragment and the recorded polymorphic site in exon 3 of LALBA gene fragment were homozygous while all three polymorphic sites in GnRHR gene fragment were heterozygous. Two of the SNPs recorded in the present study are found to unique for Sri Lankan non-descript goat population at G203T and A730G in k-CSN3 and GnRHR genes respectively. The study records another two SNPs in GnRHR gene which are already known to be correlated with higher fecundity in goats (G757A and G891T). Results of the present study will be extremely important in future attempts to indicate markers to improve the milk production, composition of milk and litter size of non-descript local goats in Sri Lanka.

Comparative screening of single nucleotide polymorphisms in β-casein and κ-casein gene in different livestock breeds of India

sThe most polymorphic milk protein gene is β-casein; 13 protein variants are known in cattle. Milk protein genetic polymorphism has received considerable research interest in recent years because of possible associations between milk protein and economically important traits in livestock. The present study was undertaken to explore the genetic polymorphisms in exon 7 of β-casein and exon 4 of κ-casein genes in Arunachali yaks (Bos grunniens), Sahiwal (Bos indicus) cattle, malpura sheep (Ovis aries) and Gaddi goat (Capra hircus). Results of the study revealed presence of 11 SNP variants in all livestock species. Four SNPs were observed in Bos indicus; two SNPs in Bos grunniens; three SNPs in Ovis aries and three SNPs in Capra hircus. These variations are found to be synonymous in nature as these variations do not result in their corresponding amino acids. A total of five polymorphic sites have been described at the κ-casein (CSN3) locus in the Indian domestic Gaddi goat (Capra hircus) when compared with exotic goat (X60763) while sequence analysis of κ-casein gene in sheep showed three novel nucleotide changes in malpura sheep when compared with the exotic sheep (AY237637). These results highlight the importance of taking into consideration the CSN3 SNPs when performing selection for milk composition in dairy livestock breeds.

Association between multidrug resistance 1 gene polymorphisms and genetic susceptibility to sporadic colorectal adenocarcinoma

Objective To investigate the association between genetic polymorphism in exon 26 C3435T and exon 21 G2677T/A of the multidrug resistance 1 (MDR1) gene and the sporadic colorectal adenocarcinoma.Methods A total of 123 patients with colorectal adenocarcinoma and 86 healthy subjects as controls were included.Snapshot SNP typing was used to determine the allele and genotype frequencies of MDR1 C3435T,and G2677T/A.Results There was no significant difference in the distribution of MDR1 C3435T and G2677T/A alleles and genotypes frequencies between control group and case group.When stratified by clinicopathological features such as lesion distribution,differentiation degree and Duke' s stage in the patients with colorectal adenocarcinoma,the statistically significant differences were found in the frequency of C3435T genotype between patients with colon adenocarcinoma (CC 22.2％,CT 63.4％,and TT 14.8 ％) and rectal adenocarcinoma (CC 50.7％,CT 31.9％,and TT 17.4％) (P ＜ 0.01).The frequency of 3435T allele was decreased significantly in patiens with rectal adenocarcinoma (33.3％) as compared with colon adenocarcinoma (46.3％,P ＜0.05).And the frequency of 2677GT genotype was decreased significantly in patients with moderately-differentiated (26.9％) as compared with well-differentiated (46.4％) and poorly-differentiated (47.1％,P ＜ 0.05).Furthermore,the frequency of 2677GT genotype was increased significantly in patients with colon adenocarcinoma (46.3％) as compared with rectal adenocarcinoma (24.6％,P ＜ 0.05),and the frequency of 2677G allele was decreased significantly in patiens with poorly differentiated adenocarcinoma (3.7％) as compared with moderately-differentiated (28.5％) and well-differentiated adenocarcinoma (11.0％,P ＜ 0.05).Conclusion MDR1 C3435T and G2677T/A polymorphisms were found to be not associated with colorectal adenocarcinoma. Key words: Colorectal carcinoma; Multidrug resistance gene; Polymorphism

Relationship between genetic polymorphism of multidrug resistance 1 gene and the risk of childhood acute lymphocytic leukemia

To investigate the relationship between genetic polymorphism in exon 12 C1236T, exon 21 G2677T/A and exon 26 C3435T of the multidrug resistance 1 (MDR1) gene and the risk of childhood acute lymphocytic leukemia (ALL). A total of 176 patients with ALL and a cohort of 170 matched healthy subjects were included. SNaPshot SNP typing was used to determine the genotypes of MDR1 C1236T, G2677T/A, C3435T. Based on the clinical data, the relationship between genetic polymorphism of MDR1 and the risk of childhood ALL was analyzed. There was significant difference in the distribution of genotype of MDR1 C3435T between the group of controls and cases. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (P = 0.000; OR = 4.504). The data show evidence of pairwise linkage disequilibrium between the three common SNPs (C1236T-G2677T/A-C3435T). The haplotypes of TTT, TGC, CGC and CAC were predominant. The haplotype CGT distributed significantly differently between the groups of controls and cases (P = 0.034). The frequency of the haplotype TTT/TTT in the high risk group was higher than the other groups (P = 0.037). The present findings suggest that 3435C→T polymorphism in MDR1 gene may be a genetic susceptibility factor for ALL. The haplotype of MDR1 (C1236T-G2677T/A-C3435T) could be the clinical parameter at diagnosis.

A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations

BackgroundThe present study aimed to investigate the genetic polymorphisms in exon 4 of the NOD2 gene in tuberculosis patients and healthy controls, in order to clarify whether polymorphisms in the NOD2 gene is associated with tuberculosis.MethodsA case-control study was performed on the Chinese Han, Uygur and Kazak populations. Exon 4 of the NOD2 gene was sequenced in 425 TB patients and 380 healthy controls to identify SNPs.ResultsThe frequency of T/G genotypes for the Arg587Arg (CGT → CGG) single nucleotide polymorphism (SNP) in NOD2 was found to be significantly higher in the Uygur (34.9%) and Kazak (37.1%) populations than the Han population (18.6%). Also, the frequency of G/G genotypes for the Arg587Arg SNP was significantly higher in the Uyghur (8.3%) and Kazak (5.4%) populations than the Han population (0.9%). Meanwhile, no significant difference was found in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Uyghur and Kazak populations (P > 0.05) whereas, a significant difference was observed in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Han population (P < 0.01). The odd ratio of 2.16 (95% CI = 1.31-3.58; P < 0.01) indicated that the Arg587Arg SNP in NOD2 may be associated with susceptibility to tuberculosis in the Chinese Han population.ConclusionsOur study is the first to demonstrate that the Arg587Arg SNP in NOD2 is a new possible risk factor for tuberculosis in the Chinese Han population, but not in the Uyghur and Kazak populations. Our results may reflect racial differences in genetic susceptibility to tuberculosis.

Distribution of the AMPD1 C34T polymorphism in Polish power-oriented athletes

The aims of this study were to determine the distribution of the AMPD1 genotype among groups of high-level Polish power-oriented athletes, and to investigate potential associations between genetic polymorphism in exon 2 of the AMPD1 gene and power-oriented athlete status. Altogether, 158 male Polish power-oriented athletes were genotyped by PCR-RFLP. The genetic control group comprised 160 unrelated male volunteers. We observed significant differences in genotype distribution when all 158 athletes (89.25% CC, 10.75% CT, 0.00% TT; P = 0.0025) were compared with controls (75.00% CC, 23.75% CT, 1.25% TT). A significant deficiency of the T allele was noted in all subgroups (short-distance runners: 5.21%, P = 0.032; short-distance swimmers: 5.56%, P = 0.031; weightlifters: 5.36%, P = 0.024) compared with controls (13.13%), while this trend was even stronger when the frequency of the T allele was compared between controls and all 158 athletes (5.38%, P = 0.0007). Our results indicate a lower frequency of the AMPD1 exon 2 T34 allele in elite Polish power-oriented athletes. Our data suggest that the C allele may help athletes to attain elite status in power-oriented sports.

Genetic polymorphism in exon 2 of cathepsin D is not associated with vascular dementia

Cathepsin D, the most abundant lysosomal and endosomal aspartyl protease, shows beta and gamma secretase activity in vitro by cleaving the amyloid precursor protein (APP) into amyloid beta protein (Aβ). Polymorphism at position 224, C224T, on exon 2 of cathepsin D gene (CTSD) has been associated with an increased risk for Alzheimer's disease (AD) by some investigators, but there have been contrary findings by others. However, an association between CTSD polymorphism and vascular dementia (VaD) has not been reported thus far. To investigate whether a polymorphism at CTSD C224T is associated with VaD in the Korean population. We compared the genotype and allele frequencies at this polymorphism site in clinically assessed 162 VaD patients with those in 197 healthy Koreans. The major genotype frequency at CTSD C224T in normal controls was higher in the Asian population than in various European populations. Our study does not show a significant difference in genotype (P=0.3071) and allele (P=0.2291) frequencies of CTSD C224T between VaD and normal controls. This was the first genetic association study of CTSD in a VaD population.

Presence of the CYP2B6 516G&gt; T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients

BackgroundThe 516G > T polymorphism in exon 4 of the CYP2B6 gene has been associated with increased plasma Efavirenz (EFV) concentrations. EFV concentrations greater than the recommended therapeutic range have been associated with the increased likelihood of developing adverse CNS effects. The aims of this study were to a) determine the presence of the 516G > T and other CYP2B6 exon 4 polymorphisms in a South African group of HIV-infected individuals b) investigate the relationship between the EFV plasma concentrations, the CYP2B6 516G > T polymorphism and the occurrence of CNS related side effects in this group of patients and c) develop and validate a rapid method for determination of EFV in plasma.MethodData from 80 patients is presented. Genetic polymorphisms in exon 4 of the CYP2B6 gene were identified using PCR amplification of this region followed by sequencing of the amplification products. EFV concentrations were analysed by UPLC-MS/MS. Assessment of the presence of CNS related side effects following EFV initiation were elicited with the use of a questionnaire together with physical examination.ResultsPlasma EFV concentrations displayed high inter-individual variability amongst subjects with concentrations ranging from 94 μg/l to 23227 μg/l at 2 weeks post initiation of treatment. For the 516G > T polymorphism the following frequencies were observed 23% of patients were TT homozygous, 36% GG and 41% GT. The TT homozygous patients had significantly higher EFV concentrations vs. those with the wild (GG) genotype (p < 0.05). Patients who experienced no side effects had significantly lower EFV plasma concentrations vs. the group of patients which experienced the most severe side effects (p < 0.05).ConclusionThe significant association between the 516G > T polymorphism and plasma EFV concentrations has been demonstrated in this study. A rapid and sensitive method for the measurement of plasma EFV concentration was developed and validated.

Absence of association between two insertion/deletion coding genetic polymorphisms of TIM‐1 gene and asthma in Chinese Han population

TIM-1, a member of T-cell immunoglobulin domain and mucin domain (TIM) gene family, was implicated as an asthma susceptibility gene in previous studies. TIM-1 was expressed on CD4(+) T cells after activation and its expression was sustained preferentially in T-helper type 2 (T(H)2) but not in T(H)1 cells, therefore TIM-1 became a good candidate gene for atopic diseases. Recent studies indicated that two insertion/deletion (ins/del) coding genetic polymorphisms in exon 4 of TIM-1 were associated with asthma susceptibility in some but not in all populations. In order to investigate the relationship between TIM-1 genetic polymorphisms and asthma in Chinese Han population, we performed a case-control study for two insertion/deletion polymorphisms in TIM-1 exon 4 (5383_5397ins/del and 5509_5511delCAA) and a single nucleotide polymorphism (SNP) in intron 8 (IVS 8+9 G/A) between a healthy control group of 309 people and an asthma patient group of 352 people recruited from Chinese Han population. The polymorphisms were genotyped and the allele and genotype frequencies were analysed, but none of the three polymorphisms showed association with asthma susceptibility in single-locus association analyses. Linkage disequilibrium (LD) analyses demonstrated that the two insertion/deletion polymorphisms were in strong LD but the haplotypes constructed from these two polymorphisms showed no significant association with asthma. In conclusion, our findings suggest that 5383_5397ins/del, 5509_5511delCAA and SNP IVS 8+9 G/A polymorphisms are not associated with asthma susceptibility in Chinese Han population.

Factors Affecting the Maintenance Stable Warfarin Dosage in Hong Kong Chinese Patients

Multiple factors can affect the anticoagulation effect of warfarin. The objective of this study was to determine the relationship between different clinical factors and outcomes of warfarin therapy in Hong Kong Chinese patients. The study was conducted at the anticoagulation clinic of the Prince of Wales Hospital from 1 April to 31 December 2003. Clinical data collected included demographics, indications of warfarin, dietary vitamin K consumption, and drug-drug interactions. Blood samples were obtained for the genetic polymorphism analysis of CYP 2 C 9. Linear and multiple regression analysis were used for statistical analysis to determine the correlation between variables and the importance of various factors as the determinants of warfarin dosage requirement. A total of 63 patients were recruited. The mean warfarin dosage was 3.30+/-2.23 mg/day. The warfarin dosage ranged from 0.75 to 12 mg/day. The mean age was 59+/-14 years old. Age, dietary vitamin K consumption, chronic heart failure, atrial fibrillation, hypertension, smoking and drinking status were found to be factors statistically significant affecting warfarin dosage. We detected no single nucleotide polymorphism in CYP 2 C 9 exon 4. Age, dietary vitamin K consumption, warfarin indication for atrial fibrillation, co-morbid with CHF, smoking and drinking status were found to be the factors that affected the warfarin requirement in Hong Kong Chinese patients. However, the genetic polymorphism in exon 4 of CYP 2 C 9 may not be associated with the warfarin sensitivity in this patient population.

Digoxin pharmacokinetics and MDR1 genetic polymorphisms.

The effect of MDR1 C3435T single nucleotide polymorphism (SNP) in exon 26 on digoxin pharmacokinetics has recently been challenged. OBJECTIVE. To clarify the relationships between MDR1 genetic polymorphisms in exon 26 (C3435T) and 21 (G2677T/A) and digoxin pharmacokinetics. MDR1 genotypes for C3435T and G2677T/A SNPs were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics had been measured over 48 h. A significant relationship was observed between C3435T SNP and digoxin AUCs ( p<0,05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT and CC subjects and a trend for higher 48 h digoxin urinary recoveries (TT>CT>CC). Similar results, although not statistically significant, were observed from the MDR1 G2677T/A SNP. Our results confirm that the MDR1 C3435T single nucleotide polymorphism (SNP) significantly affects digoxin disposition kinetics, with homozygous TT subjects presenting the highest plasma concentrations.

Genetic and phenotypic polymorphisms of the A subunit of Coagulation factor XIII in Japanese population.

To clarify whether genetic polymorphisms in exon 14 of Coagulation factor XIII A-subunit gene (FXIIIA) affect phenotype expressions, we studied genetic polymorphisms in exon 14 of FXIIIA in a Japanese population and the relationship between the genetic polymorphisms and phenotype expression. Genetic polymorphisms in exon 14 of FXIIIA of 144 unrelated Japanese were analyzed by single-strand conformation polymorphism. Plasma FXIIIA antigen concentrations, FXIII activities, and phenotype were also determined by two-dimensional electrophoresis. The frequencies of the three genotypes, the homozygote (AD), the homozygote (BC) and the heterozygote (AD/BC), were 77.1, 0.7, and 22.2%, respectively. The gene frequencies of AD and BC were 0.88 and 0.12. We detected AD (GTT x GAG) and BC (ATT x CAG) at codon 650 and 651 of exon 14. There were no significant differences of FXIIIA antigen concentrations and FXIII activities between these genotypes. We detected three pl differences among them as being pls of 5.3, 5.6, 5.8 in the homozygote (AD) and the heterozygote (AD/BC), and a pl of 5.8 in the homozygote (BC). These polymorphisms affected isoelectric mobility, but did not affect protein levels, enzyme activities, or the molecular weight of FXIII.