Displaying publications 81 - 99 of 99 in total

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  1. Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia
    Chan SL, Suo C, Lee SC, Goh BC, Chia KS, Teo YY
    Pharmacogenomics J, 2012 Aug;12(4):312-8.
    PMID: 21383771 DOI: 10.1038/tpj.2011.7
    Genetic markers displaying highly significant statistical associations with complex phenotypes may not necessarily possess sufficient clinical validity to be useful. Understanding the contribution of these markers beyond readily available clinical biomarkers is particularly important in pharmacogenetics. We demonstrate the utility of genetic testing using the example of warfarin in a multi-ethnic setting comprising of three Asian populations that are broadly representative of the genetic diversity for half of the population in the world, especially as distinct interethnic differences in warfarin dose requirements have been previously established. We confirmed the roles of three well-established loci (CYP2C9, VKORC1 and CYP4F2) in explaining warfarin dosage variation in the three Asian populations. In addition, we assessed the relationship between ethnicity and the genotypes of these loci, observing strong correlations at VKORC1 and CYP4F2. Subsequently, we established the additional utility of these genetic factors in predicting warfarin dose beyond ethnicity and clinical biomarkers through performing a series of systematic cross-validation analyses of the relative predictive accuracies of various fixed-dose regimen, clinical and genetic models. Through a pharmacogenetics model for warfarin, we show the importance of genetic testing beyond readily available clinical biomarkers in predicting dose requirements, confirming the role of genetic profiling in personalized medicine.
    Matched MeSH terms: Ethnic Groups/genetics
  2. Distribution of PON1 polymorphisms PON1Q192R and PON1L55M among Chinese, Malay and Indian males in Singapore and possible susceptibility to organophosphate exposure
    Chia SE, Mohamed Ali S, Yap PH, Gan L, Ong YB, Chia KS
    Neurotoxicology, 2009 Mar;30(2):214-9.
    PMID: 19135476 DOI: 10.1016/j.neuro.2008.12.004
    Organophosphate (OP)-containing pesticides are widely used worldwide for domestic and industrial purposes. Studies on acute and chronic exposure to OPs have revealed numerous health effects attributed mainly to acetylcholinesterase (AChE) inhibition. The enzyme human serum paraoxonase (PON1) is involved in the detoxification of OP compounds. PON1 polymorphisms have been shown to affect susceptibility to OP exposure. We studied the effect of OP exposure on pest control workers and assessed the distribution of two common PON1 polymorphisms in our local population. The exposed group consisted of 103 workers from various pest control companies under the Singapore Pest Management Association while the 91 unexposed workers were from a lead stabilizer factory. For all workers, the mean age was 36.9 (20-70) years and the ethnic distribution was 38.1% Chinese, 44.3% Malay and 17.5% Indian. The mean+/-S.D. exposure duration among the pesticide workers was 10.4+/-8.4 years. The mean+/-S.D. RBC cholinesterase level was 18436.2+/-2078U/L and 18079.6+/-1576U/L for the exposed and unexposed groups, respectively (p=0.216). The mean+/-S.D. serum pseudocholinesterase was 11028.4+/-2867.4U/L and 9433.6+/-2022.6U/L in the exposed and unexposed groups, respectively (p<0.0001). Mean paraoxonase activity was similar among Chinese and Malays (266.5 and 266.3U/L, respectively) whereas that of the Indians was significantly lower (165.6U/L). Our study showed that cholinesterase levels among the exposed were not lower than those in the unexposed group. PON1 polymorphisms differed among ethnic groups, implying that ethnicity could be an important surrogate for identifying susceptible groups in case of OP exposure. Although OP poisoning is rare among occupationally exposed workers in Singapore, this information is useful for other developing countries that have large populations of Chinese, Malays and Indians where OP exposure could be very high especially in agricultural settings.
    Matched MeSH terms: Ethnic Groups/genetics*
  3. Cytogenetic abnormalities in de novo acute myeloid leukemia in adults: relation to morphology, age, sex and ethnicity - a single center study from Singapore
    Enjeti AK, Tien SL, Sivaswaren CR
    Hematol. J., 2004;5(5):419-25.
    PMID: 15448668
    Cytogenetic analysis performed at diagnosis is considered to be the most valuable prognostic factor in acute myeloid leukemia (AML). Large systematic studies of cytogenetic abnormalities in AML patients from Southeast Asia are not available. The karyotypic patterns in AML patients from a single center in Singapore were studied and compared with reports from other regions of the world to identify possible geographic heterogeneity.
    Matched MeSH terms: Ethnic Groups/genetics
  4. Fulltext A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
    Lou H, Lu Y, Lu D, Fu R, Wang X, Feng Q, et al.
    Am J Hum Genet, 2015 Jul 02;97(1):54-66.
    PMID: 26073780 DOI: 10.1016/j.ajhg.2015.05.005
    Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.
    Matched MeSH terms: Ethnic Groups/genetics*
  5. STR data for the AmpFlSTR Profiler loci from the three main ethnic population groups (Malay, Chinese and Indian) in Malaysia
    Lim KB, Jeevan NH, Jaya P, Othman MI, Lee YH
    Forensic Sci Int, 2001 Jun 01;119(1):109-12.
    PMID: 11348801
    Allele frequencies for the nine STRs genetic loci included in the AmpFlSTR Profiler kit were obtained from samples of unrelated individuals comprising 139-156 Malays, 149-153 Chinese and 132-135 Indians, residing in Malaysia.
    Matched MeSH terms: Ethnic Groups/genetics*
  6. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations
    Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, et al.
    Pharmacogenetics, 2002 Aug;12(6):437-50.
    PMID: 12172212
    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.
    Matched MeSH terms: Ethnic Groups/genetics*
  7. T cell receptor beta chain RFLP in Chinese, Indians and Malays from Singapore
    Tan JA, Tay JS, Aziz NB, Saha N
    Hum. Hered., 1996 Jul-Aug;46(4):236-8.
    PMID: 8807327
    Restriction fragment length polymorphism (RFLP) of the gene encoding the beta chain of the human T cell receptor (TcR) was studied in three ethnic groups in Singapore by Southern blotting. Polymorphism in the beta chain gene was identified in BglII-digested DNA samples using a 770-bp TcR beta cDNA clone containing the joining and constant region segments. The TcR beta/BglII polymorphism was studied in 136 Chinese, 93 Indian and 88 Malay samples. The frequency of the less frequent allele (TcR beta*2) in all the ethnic groups was significantly lower (0.15-0.29, p < 0.01) than that in the Caucasians (0.46). Indians had a significantly lower frequency of this allele (0.15) than the Chinese (0.29) and Malays (0.26).
    Matched MeSH terms: Ethnic Groups/genetics*
  8. Linkage disequilibrium between two loci (5' untranslated exon 1 and intron 5-DdeI) of the antithrombin III gene in three ethnic groups in Singapore
    Liu Y, Saha N, Low PS, Tay JS
    Hum. Hered., 1995 Jul-Aug;45(4):192-8.
    PMID: 7558050
    The distribution of two common DNA polymorphisms (5' untranslated exon 1 and intron 5-DdeI) of the antithrombin III (ATIII) gene was studied in three ethnic groups in Singapore: 251 Chinese, 221 Dravidian Indians and 102 Malays. The polymorphisms were identified by the polymerase chain reaction and size fractionation in agarose gels. The 5' untranslated to exon 1 polymorphism is a length polymorphism while the intron 5 polymorphism is a restriction site (DdeI) polymorphism. The frequency of the short fragment (S) of the 5' to exon 1 length polymorphism of the ATIII gene was found to be 0.37 in the Chinese, 0.54 in the Malays and 0.65 in the Dravidian Indians. For the Chinese, this was significantly lower compared to the Caucasians and Indians (p < 0.0001) and the Malays (p < 0.01). On the other hand, the frequencies of DdeI+ did not vary significantly among these three populations (p > 0.05). The distribution of different genotypes at these two loci of the ATIII gene was in Hardy-Weinberg equilibrium in all three ethnic groups. A strong linkage disequilibrium between these two polymorphisms was observed in all the ethnic groups and the estimated correlation coefficient (delta) was 0.42 in the Chinese (p < 0.001), 0.61 in the Dravidian Indians (p < 0.001) and 0.43 in the Malays (p < 0.001). The frequencies of haplotype S+, L+ and L- were, respectively, 0.37, 0.40 and 0.23 in the Chinese, 0.65, 0.18 and 0.16 in the Dravidian Indians and 0.54, 0.37 and 0.09 in the Malays.(ABSTRACT TRUNCATED AT 250 WORDS)
    Matched MeSH terms: Ethnic Groups/genetics*
  9. Recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history
    Kang PC, Phuah SY, Sivanandan K, Kang IN, Thirthagiri E, Liu JJ, et al.
    Breast Cancer Res Treat, 2014 Apr;144(3):635-42.
    PMID: 24578176 DOI: 10.1007/s10549-014-2894-x
    Although the breast cancer predisposition genes BRCA1 and BRCA2 were discovered more than 20 years ago, there remains a gap in the availability of genetic counselling and genetic testing in Asian countries because of cost, access and inaccurate reporting of family history of cancer. In order to improve access to testing, we developed a rapid test for recurrent mutations in our Asian populations. In this study, we designed a genotyping assay with 55 BRCA1 and 44 BRCA2 mutations previously identified in Asian studies, and validated this assay in 267 individuals who had previously been tested by full sequencing. We tested the prevalence of these mutations in additional breast cancer cases. Using this genotyping approach, we analysed recurrent mutations in 533 Malaysian breast cancer cases with <10 % a priori risk, and found 1 BRCA1 (0.2 %) and 5 BRCA2 (0.9 %) carriers. Testing in a hospital-based unselected cohort of 532 Singaporean breast cancer cases revealed 6 BRCA1 (1.1 %) and 3 BRCA2 (0.6 %) carriers. Overall, 2 recurrent BRCA1 and 1 BRCA2 mutations in Malays, 3 BRCA1 and 2 BRCA2 mutations in Chinese and 1 BRCA1 mutation in Indians account for 60, 24 and 20 % of carrier families, respectively. By contrast, haplotype analyses suggest that a recurrent BRCA2 mutation (c.262_263delCT) found in 5 unrelated Malay families has at least 3 distinct haplotypes. Taken together, our data suggests that panel testing may help to identify carriers, particularly Asian BRCA2 carriers, who do not present with a priori strong family history characteristics.
    Matched MeSH terms: Ethnic Groups/genetics
  10. HLA-A*31: 01 and HLA-B*15:02 association with Stevens-Johnson syndrome and toxic epidermal necrolysis to carbamazepine in a multiethnic Malaysian population
    Khor AH, Lim KS, Tan CT, Kwan Z, Tan WC, Wu DB, et al.
    Pharmacogenet Genomics, 2017 07;27(7):275-278.
    PMID: 28570299 DOI: 10.1097/FPC.0000000000000287
    The majority of the carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis CBZ-SJS/TEN are associated with HLA-B*15:02 in Asian populations where this allele is common. In contrast, the association with HLA-A*31:01 is only reported in Japanese and Europeans. This study aimed to further investigate the association with HLA-A*31:01 besides HLA-B*15:02 in a multiethnic Malaysian population. Twenty-eight CBZ-SJS/TEN cases and 227 CBZ-tolerant controls were recruited. Association was tested by comparing carrier frequencies of the alleles between cases and controls. Significant associations were detected between HLA-B*15:02 and CBZ-SJS/TEN in independent ethnic groups: Malays [P=2.00×10; odds ratio (OR): 49.0; 95% confidence interval (CI): 9.36-256.81], Chinese (P=0.0047; OR: 14.3; 95% CI: 2.38-86.03) and Indians (P=0.04; OR: 13.8; 95% CI: 1.51-124.99). Combined analysis of all ethnic groups showed a significant association with OR Cochran-Mantel-Haenszel (ORCMH) of 26.6 (95% CI: 12.80-55.25; PCMH=2.31×10). In Indians, HLA-A*31:01 was found to be associated significantly with CBZ-SJS/TEN (P=0.023; OR: 10.4; 95% CI: 1.64-65.79) and combined analyses of both variants, HLA-A*31:01 and HLA-B*15:02, increased the strength of the association (P=0.0068; OR: 14.3; 95% CI: 2.20-92.9). Besides HLA-B*15:02, our study found a new association between HLA-A*31:01 and CBZ-SJS/TEN in Indians.
    Matched MeSH terms: Ethnic Groups/genetics*
  11. Rubinstein-Taybi syndrome in diverse populations
    Tekendo-Ngongang C, Owosela B, Fleischer N, Addissie YA, Malonga B, Badoe E, et al.
    Am J Med Genet A, 2020 12;182(12):2939-2950.
    PMID: 32985117 DOI: 10.1002/ajmg.a.61888
    Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p 
    Matched MeSH terms: Ethnic Groups/genetics*
  12. Fulltext Bitter receptor gene (TAS2R38) P49A genotypes and their associations with aversion to vegetables and sweet/fat foods in Malaysian subjects
    Ooi SX, Lee PL, Law HY, Say YH
    Asia Pac J Clin Nutr, 2010;19(4):491-8.
    PMID: 21147709
    Recently, the bitter receptor gene (TAS2R38) was identified to be responsible for phenylthiocarbamide (PTC) bitter sensitivity. Its two predominant haplotypes at three Single Nucleotide Polymorphisms (SNPs) are found to be definitive for the PTC status, which the ProAlaVal and AlaValIle haplotypes are associated with tasters and non-tasters, respectively. TAS2R38 haplotypes have been reported to influence food preferences (like cruciferous vegetables and fat foods) and cardiovascular disease risk factors. We examined, in 215 Malaysian subjects (100 males, 115 females), the association of the P49A SNP of TAS2R38 with anthropometric measurements and aversion to a list of 36 vegetables, 4 soy products, green tea and 37 sweet/fat foods. The subjects were successfully genotyped as 110 PA, 81 PP and 24 AA (with the A49 allelic frequency of 0.37), by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Ethnicity (Malay, Chinese or Indian), but not gender, was associated with the P49A TAS2R38 genotypes (p<0.001). However, no significant differences in terms of Body Mass Index, Total Body Fat, waist circumference and Waist-Hip Ratio were found between the genotypes (p<0.05). Only aversions to green tea, mayonnaise and whipped cream, but not soy products, vegetables, and other sweet/fat foods, were associated with the P49A genotypes (p<0.05). Therefore, the P49A SNP of the bitter receptor gene TAS2R38 could not serve as a predictor of anthropometric measurements and aversion to vegetables or sweet/fat foods in the sampled Malaysian subjects, and this suggests the existence of other possible factors influencing food selection among Malaysians.
    Matched MeSH terms: Ethnic Groups/genetics
  13. Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data
    Yu CY, Ang GY, Subramaniam V, Johari James R, Ahmad A, Abdul Rahman T, et al.
    Genet Test Mol Biomarkers, 2017 Jul;21(7):409-415.
    PMID: 28525288 DOI: 10.1089/gtmb.2016.0235
    AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of a CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study was designed to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli.

    METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods.

    RESULTS: A total of 72 single nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population.

    CONCLUSION: The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in the Orang Asli of Peninsular Malaysia.

    Matched MeSH terms: Ethnic Groups/genetics
  14. Molecular basis of beta-thalassemia in the Maldives
    Furuumi H, Firdous N, Inoue T, Ohta H, Winichagoon P, Fucharoen S, et al.
    Hemoglobin, 1998 Mar;22(2):141-51.
    PMID: 9576331
    We have systematically analyzed beta-thalassemia genes using polymerase chain reaction-related techniques, dot-blot hybridization with oligonucleotide probes, allele specific-polymerase chain reaction, and sequencing of amplified DNA fragments from 41 unrelated patients, including 37 beta-thalassemia homozygotes, three with beta-thalassemia/Hb E, and one with beta-thalassemia/Hb S. Four different beta-thalassemia mutations were detected in 78 alleles. These are the IVS-I-5 (G-->C), codon 30 (AGG-->ACG) [also indicated as IVS-I (-1)], IVS-I-1 (G-->A), and codons 41/42 (-TTCT) mutations. The distribution of the beta-thalassemia mutations in the Maldives is 58 alleles (74.3%) with the IVS-I-5 (G-->C) mutation, 12 (15.4%) with the codon 30 (AGG-->ACG) mutation, seven (9%) with the IVS-I-1 (G-->A) mutation, and one with the codons 41/42 (-TTCT) mutation. The first three mutations account for 98.7% of the total number of beta-thalassemia chromosomes studied. These mutations are clustered in the region spanning 6 bp around the junction of exon 1 and the first intervening sequence of the beta-globin gene. These observations have significant implications for setting up a thalassemia prevention and control program in the Maldives. Analysis of haplotypes and frameworks of chromosomes bearing each beta-thalassemia mutation suggested that the origin and spread of these mutations were reflected by the historical record.
    Matched MeSH terms: Ethnic Groups/genetics
  15. Fulltext Germline APOBEC3B deletion is associated with breast cancer risk in an Asian multi-ethnic cohort and with immune cell presentation
    Wen WX, Soo JS, Kwan PY, Hong E, Khang TF, Mariapun S, et al.
    Breast Cancer Res, 2016 05 27;18(1):56.
    PMID: 27233495 DOI: 10.1186/s13058-016-0717-1
    BACKGROUND: APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system.

    METHODS: In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT.

    RESULTS: The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values 

    Matched MeSH terms: Ethnic Groups/genetics
  16. Fulltext Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D
    Shmukler BE, Kedar PS, Warang P, Desai M, Madkaikar M, Ghosh K, et al.
    Am J Hematol, 2010 Oct;85(10):824-8.
    PMID: 20799361 DOI: 10.1002/ajh.21836
    Familial distal renal tubular acidosis (dRTA) can be caused by mutations in the Cl2/HCO32 exchanger of the renal Type A intercalated cell, kidney AE1/SLC4A1. dRTA-associated AE1 mutations have been reported in families from North America, Europe, Thailand, Malaysia, Papua-New Guinea, Taiwan, and the Philippines, but not India. The dRTA mutation AE1 A858D has been detected only in the context of compound heterozygosity. We report here two unrelated Indian patients with combined hemolytic anemia and dRTA who share homozygous A858D mutations of the AE1/SLC4A1 gene. The mutation creates a novel restriction site that is validated for diagnostic screening.
    Matched MeSH terms: Ethnic Groups/genetics
  17. Fulltext Pathogenic nsSNPs that increase the risks of cancers among the Orang Asli and Malays
    Khoruddin NA, Noorizhab MN, Teh LK, Mohd Yusof FZ, Salleh MZ
    Sci Rep, 2021 Aug 09;11(1):16158.
    PMID: 34373545 DOI: 10.1038/s41598-021-95618-y
    Single-nucleotide polymorphisms (SNPs) are the most common genetic variations for various complex human diseases, including cancers. Genome-wide association studies (GWAS) have identified numerous SNPs that increase cancer risks, such as breast cancer, colorectal cancer, and leukemia. These SNPs were cataloged for scientific use. However, GWAS are often conducted on certain populations in which the Orang Asli and Malays were not included. Therefore, we have developed a bioinformatic pipeline to mine the whole-genome sequence databases of the Orang Asli and Malays to determine the presence of pathogenic SNPs that might increase the risks of cancers among them. Five different in silico tools, SIFT, PROVEAN, Poly-Phen-2, Condel, and PANTHER, were used to predict and assess the functional impacts of the SNPs. Out of the 80 cancer-related nsSNPs from the GWAS dataset, 52 nsSNPs were found among the Orang Asli and Malays. They were further analyzed using the bioinformatic pipeline to identify the pathogenic variants. Three nsSNPs; rs1126809 (TYR), rs10936600 (LRRC34), and rs757978 (FARP2), were found as the most damaging cancer pathogenic variants. These mutations alter the protein interface and change the allosteric sites of the respective proteins. As TYR, LRRC34, and FARP2 genes play important roles in numerous cellular processes such as cell proliferation, differentiation, growth, and cell survival; therefore, any impairment on the protein function could be involved in the development of cancer. rs1126809, rs10936600, and rs757978 are the important pathogenic variants that increase the risks of cancers among the Orang Asli and Malays. The roles and impacts of these variants in cancers will require further investigations using in vitro cancer models.
    Matched MeSH terms: Ethnic Groups/genetics*
  18. Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia
    Chai JF, Kao SL, Wang C, Lim VJ, Khor IW, Dou J, et al.
    J Clin Endocrinol Metab, 2020 Dec 01;105(12).
    PMID: 32936915 DOI: 10.1210/clinem/dgaa658
    CONTEXT: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.

    OBJECTIVE: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.

    DESIGN AND PARTICIPANTS: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.

    RESULTS: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P 

    Matched MeSH terms: Ethnic Groups/genetics
  19. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations
    Gan GG, Phipps ME, Lee MM, Lu LS, Subramaniam RY, Bee PC, et al.
    Ann Hematol, 2011 Jun;90(6):635-41.
    PMID: 21110192 DOI: 10.1007/s00277-010-1119-6
    Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.
    Study site: Anticoagulation clinic, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia
    Matched MeSH terms: Ethnic Groups/genetics*
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