Search

Aims: To determine the breath alcohol elimination rate (AER) and Widmark factor derived from the maximum breath alcohol concentration (rpeak BrAC) in Chinese and Indians in Singapore, and to evaluate the contribution of genetic and non-genetic factors to variability of AER and rpeak BrAC. Methods: A total of 180 subjects ingested a vodka–orange juice mixture, together with a standardized meal and underwent a series of BrAC measurements. Results: Significant inter-ethnic differences in AER and rpeak BrAC were observed in females and males, respectively. Alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase (ALDH2) genotypes were identified as significant predictors for AER among males, accounting for 8.5% (P = 0.048) and 23.4% (P < 0.001) of the variance, respectively. ADH1B genotype was identified as a significant predictor for rpeak BrAC among males, accounting for 17.1% of the variance (P = 0.001). In females, however, none of the genotypes were found to be significant predictors for breath AER, and rpeak BrAC. Conclusion: ALDH2 and/or ADH1B genotypes in males, but not in females, appear to contribute, albeit modestly, to variability in AER and rpeak BrAC. The median AER in Chinese males, Indian males, Chinese females and Indian females is 6.6 μg dl−1 h−1 [99% confidence interval (CI), 5.6–7.5 μg dl−1 h−1], 6.2 μg dl−1 h−1 (99% CI, 5.5–7.0 μg dl−1 h−1), 8.6 μg dl−1 h−1 (99% CI, 7.4–9.7 μg dl−1 h−1) and 7.4 μg dl−1 h−1 (99% CI, 6.2–8.4 μg dl−1 h−1), respectively. The median rpeak BrAC in Chinese males, Indian males, Chinese females and Indian females is 0.0229 (99% CI, 0.0216–0.0268), 0.0209 (99% CI, 0.0190–0.0237), 0.0214 (99% CI, 0.0185–0.0254) and 0.0199 (99% CI, 0.0187–0.0227), respectively. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of this study were to examine the effects of ethnicity, gender and a proton pump inhibitor (PPI), omeprazole, on the human gut microbiome. PPIs are commonly used for the treatment of acid-related disorders. We hypothesised that PPI therapy might perturb microbial communities and alter the gut microbiome., Methods: Healthy subjects of Chinese (n = 12), Malay (n = 12) and Indian (n = 10) ancestry, aged 21-37 years, were enrolled. They provided a baseline stool sample (Day 1) and were then given a course of omeprazole at therapeutic dose (20 mg daily) for seven days. Stool samples were collected again on Day 7 and 14 (one week after stopping omeprazole). Microbial DNA was extracted from the stool samples, followed by polymerase chain reaction, library construction, 16S rRNA sequencing using Illumina MiSeq, and statistical and bioinformatics analyses., Results: The findings showed an increase in species richness (p = 0.018) after omeprazole consumption on Day 7, which reverted to baseline on Day 14. There were significant increases in the relative abundance of Streptococcus vestibularis (p = 0.0001) and Veillonella dispar (p = 0.0001) on Day 7, which diminished on Day 14. Faecalibacterium prausnitzii, Sutterella stercoricanis and Bacteroides denticanum were characteristic of Chinese, Malays and Indians, respectively. Lactobacillaceae and Bacteroides xylanisolvens were the signature taxa of male and female subjects, respectively., Conclusion: The study demonstrated alterations in the gut microbiome following omeprazole treatment. This may explain the underlying pathology of increased risk of Clostridium difficile infections associated with omeprazole therapy., (Copyright: © Singapore Medical Association.)

HNF4α (encoded by gene NR2A1) is a dominant transcriptional regulator of various drug disposition genes. It forms a circuitry of molecular cross-talk with other nuclear receptors such as PXR and CAR to synergistically initiate transcription. This study reports on the frequency, linkage disequilibrium pattern and tag-SNP selection of NR2A1 polymorphisms in three local Asian populations, namely Chinese, Malays and Indians (n = 56 subjects each). A total of 69 polymorphisms were identified in the genomic region of NR2A1, of which thirty-three were novel polymorphisms with low allelic frequencies (<0.02). The exonic region of NR2A1 was highly conserved with only 4 novel and 1 reported SNPs identified at low allelic frequencies of less than 0.02. Based on the criteria of MAF ≥ 0.05 and R(2) ≥ 0.80, there were 19, 20 and 22 tag-SNPs selected to represent the genetic polymorphisms of NR2A1 in Chinese, Malays and Indians, respectively. In-silico predictions suggested that some of these polymorphic variants may exert functional effects through affecting the binding sites of transcription and splicing factors. Our study provides valuable information on the genetic variability of NR2A1 which would be useful for pharmacogenetics studies in the local Asian populations.

MCT4 (SLC16A3) is the third member of the monocarboxylate transporter (MCT) family and is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study aimed to identify genetic variations of the SLC16A3 gene that may be present in the ethnic Chinese (n = 95) and Indian (n = 96) groups of the Singaporean population. The genetic variations in the promoter, coding region and exon-intron junctions of the SLC16A3 gene encoding the MCT4 transporter were screened by DNA sequencing. A total of 46 genetic variants were detected in the SLC16A3 gene, of which 33 are novel. Of these variants, 22 are located in the promoter regions, 2 in the 5' untranslated region (UTR), 10 in the coding exons (5 nonsynonymous and 5 synonymous variations), 6 in 3'UTR and 6 in the intron. Of the 5 nonsynonymous variants, only 44C>T (Ala15Val) was predicted by PolyPhen and SIFT as having a potentially damaging effect on protein function, whereas 55G>A (Gly19Ser), 574G>A (Val192Met) and 916G>A (Gly306Ser) had conflicting results between the SIFT and PolyPhen algorithms. Finally, 641C>T (Ser214Phe) was predicted to be a tolerated variant.

Research on the role of copy number variations (CNVs) in the genetic risk of diseases in Asian populations has been hampered by a relative lack of reference CNV maps for Asian populations outside the East Asians. In this article, we report the population characteristics of CNVs in Chinese, Malay, and Asian Indian populations in Singapore. Using the Illumina Human 1M Beadchip array, we identify 1,174 CNV loci in these populations that corroborated with findings when the same samples were typed on the Affymetrix 6.0 platform. We identify 441 novel loci not previously reported in the Database of Genomic Variations (DGV). We observe a considerable number of loci that span all three populations and were previously unreported, as well as population-specific loci that are quite common in the respective populations. From this we observe the distribution of CNVs in the Asian Indian population to be considerably different from the Chinese and Malay populations. About half of the deletion loci and three-quarters of duplication loci overlap UCSC genes. Tens of loci show population differentiation and overlap with genes previously known to be associated with genetic risk of diseases. One of these loci is the CYP2A6 deletion, previously linked to reduced susceptibility to lung cancer., ((c) 2010 Wiley-Liss, Inc.)

CYP1A2 play an important role in the metabolism of many carcinogens and clinically important drugs. CYP1A2 activity has been found to be influenced by the presence of polymorphic variants which were reported to display wide interethnic variation. This study investigates the frequency distribution and linkage disequilibrium patterns of CYP1A2 genetic polymorphisms, and characterize their haplotype structures in three healthy Asian populations in Singapore (Chinese, Malay, and Indian). The entire CYP1A2 gene was screened in 126 healthy subjects from all three ethnic groups (N=42 each). A total of 25 polymorphisms was identified, of which nine were novel. The polymorphisms, -2467delT and -163C>A were detected at high frequencies in all Asian ethnic groups. Significant interethnic differences were observed in the genotypic frequency distribution of IVS2-99G>A (P<0.01) and 1548C>T (P=0.05) across the three ethnic groups while -163C>A (P=0.02) was found to differ between Chinese and Malays. Haplotype analyses revealed four to six major haplotypes in each ethnic population which accounted for more than 60% of the cumulative haplotype frequencies. Future studies should be done to investigate the functional roles of these haplotypes.

The Singapore Genome Variation Project (SGVP) provides a publicly available resource of 1.6 million single nucleotide polymorphisms (SNPs) genotyped in 268 individuals from the Chinese, Malay, and Indian population groups in Southeast Asia. This online database catalogs information and summaries on genotype and phased haplotype data, including allele frequencies, assessment of linkage disequilibrium (LD), and recombination rates in a format similar to the International HapMap Project. Here, we introduce this resource and describe the analysis of human genomic variation upon agglomerating data from the HapMap and the Human Genome Diversity Project, providing useful insights into the population structure of the three major population groups in Asia. In addition, this resource also surveyed across the genome for variation in regional patterns of LD between the HapMap and SGVP populations, and for signatures of positive natural selection using two well-established metrics: iHS and XP-EHH. The raw and processed genetic data, together with all population genetic summaries, are publicly available for download and browsing through a web browser modeled with the Generic Genome Browser.

Objectives: The aims of this study were to characterize the population frequency of PEPT2 (SLC15A2) polymorphic variants in three Asian ethnic populations, namely Chinese, Malay and Asian Indian, and to investigate the associations of ethnicity (Chinese vs. Asian Indian), PEPT2 haplotype and cephalexin pharmacokinetics in healthy Asian subjects., Methods: PEPT2 polymorphisms were screened from a cohort of 96 Chinese, 96 Malay and 96 Asian Indian subjects. Cephalexin (1000 mg, orally) pharmacokinetics was characterized in an additional 15 Chinese and 15 Asian Indian healthy subjects. These 30 subjects were subsequently genotyped for their PEPT2 polymorphisms., Results: In total, ten common single nucleotide polymorphisms (SNPs) were detected in the three populations, forming two PEPT2 haplotypes. There were significant ethnic differences in PEPT2 haplotype distribution: the frequencies of the *1 and *2 alleles were 0.307 and 0.693 in the Chinese population, 0.495 and 0.505 in the Malay population and 0.729 and 0.271 in Asian Indian population, respectively. The C (max) of cephalexin was significantly lower in the Chinese (29.80 +/- 4.09 microg ml(-1)) population than in the Asian Indian one (33.29 +/- 4.97 microg ml(-1); P = 0.045). This difference could be explained by the higher average body weight of the Chinese population. There was no other significant difference in cephalexin pharmacokinetics between either ethnic or PEPT2 genotype groups., Conclusion: PEPT2 polymorphism distributions differ significantly between Chinese, Malay and Asian Indian populations. However, cephalexin pharmacokinetics is not meaningfully different between Chinese and Asian Indians. The association between the PEPT2 haplotype and cephalexin pharmacokinetics could not be confirmed, and future studies under better controlled conditions are needed.

OATP1B1 is a liver-specific transporter that mediates the uptake of various endogenous and exogenous compounds including many clinically used drugs from blood into hepatocytes. This study aims to identify genetic variations of SLCO1B1 gene in three distinct ethnic groups of the Singaporean population (n=288). The coding region of the gene encoding the transporter protein was screened for genetic variations in the study population by denaturing high-performance liquid chromatography and DNA sequencing. Twenty-five genetic variations of SLCO1B1, including 10 novel ones, were found: 13 in the coding exons (9 nonsynonymous and 4 synonymous variations), 6 in the introns, and 6 in the 3' untranslated region. Four novel nonsynonymous variations: 633A>G (Ile211Met), 875C>T (Ala292Val), 1837T>C (Cys613Arg), and 1877T>A (Leu626Stop) were detected as heterozygotes. Among the novel nonsynonymous variations, 633A>G, 1837T>C, and 1877T>A were predicted to be functionally significant. These data would provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OATP1B1 in Asians.

The human concentrative nucleoside transporter (hCNT2), also known as SLC28A2, plays an important role in the cellular uptake across intestinal membrane of some naturally occurring nucleosides and nucleoside analogs. This study aims to determine the genetic variability of hCNT2 (SLC28A2) in three major Asian ethnic groups residing in Singapore: Chinese, Malay and Indian, and functionally characterize the variants of hCNT2. Healthy participants (n=96) from each group were screened for genetic variations in the exons of hCNT2 (SLC28A2) using denaturing high performance liquid chromatography and sequencing analyses. A total of 23 polymorphisms were identified in the exonic and flanking intronic regions, and ethnic differences in single nucleotide polymorphism frequencies were evident. Five novel nonsynonymous variants (L12R, R142H, E172D, E385K, M612T) were constructed by mutagenesis and functionally characterized in U-251 cells. Expression of these variants in U-251 cells revealed that all except E385K can uptake various substrates of hCNT2: inosine, ribavirin and uridine.

Aims: To determine and compare the distribution of the FcgammaRIIIa 176 F/V polymorphism across three ethnically distinct populations (Chinese, Asian Indians and Malays) in Singapore., Methods: The FcgammaRIIIa 176 F/V polymorphism was genotyped by direct sequencing from genomic DNA samples obtained from normal healthy Chinese, Asian Indians and Malays (n = 192 from each population)., Results: The allelic frequencies of the high binding affinity FcgammaRIIIa 176 V allele for Chinese, Asian Indians and Malays were 35%, 33% and 46%, respectively (F allele frequencies were 65%, 67% and 54%, respectively). Genotype distributions were found to conform to the Hardy-Weinberg law (P > 0.05) in each group. chi(2) comparisons revealed significant differences in the genotype distributions of the FcgammaRIIIa 176 V/F polymorphism of Malays from the other two populations (Chinese and Asian Indians). However, no significant difference in the genotype distributions of the FcgammaRIIIa 176 V/F polymorphism was observed between Chinese and Asian Indian populations., Conclusions: The genotype distributions of the FcgammaRIIIa 176 V/F polymorphism in healthy Malays are significantly different from both Chinese and Indians. These observations provide the fundamentals on which future disease associations may be built and also present important implications for the design of therapeutic regimens amongst various ethnic groups.

The MDR1 multidrug transporter plays a key role in determining drug bioavailability, and differences in drug response exist amongst different ethnic groups. Numerous studies have identified an association between the MDR1 single nucleotide polymorphism (SNP) exon 26 3435C>T and differences in MDR1 function. We performed a haplotype analysis of the MDR1 gene in three major ethnic groups (Chinese, Malays and Indians) by examining 10 intragenic SNPs. Four were polymorphic in all three ethnic groups: one occurring in the non-coding region and three occurring in coding exons. All three coding SNPs (exon 12 1236C>T, exon 21 2677G>T/A and exon 26 3435C>T) were present in high frequency in each ethnic group, and the derived haplotype profiles exhibited distinct differences between the groups. Fewer haplotypes were observed in the Malays (n = 6) compared to the Chinese (n = 10) and Indians (n = 9). Three major haplotypes (> 10% frequency) were observed in the Malays and Chinese; of these, two were observed in the Indians. Strong linkage disequilibrium (LD) was detected between the three SNPs in all three ethnic groups. The strongest LD was present in the Chinese, followed by Indians and Malays, with the corresponding LD blocks estimated to be approximately 80 kb, 60 kb and 40 kb, respectively. These data strongly support the hypothesis that strong LD between the neutral SNP exon 26 3435C>T and a nearby unobserved causal SNP underlies the observed associations between the neutral SNP and MDR1 functional differences. Furthermore, strong LD between exon 26 3435T and different unobserved causal SNPs in different study populations may provide a plausible explanation for conflicting reports associating the same exon 26 3435T allele with different MDR1 functional changes.