Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in malaria endemic regions and is estimated to affect more than 400 million people worldwide. Deficient subjects are mostly asymptomatic but clinical manifestations range from neonatal jaundice due to acute hemolytic anemia to chronic non-spherocytic hemolytic anemia. To date, biochemical parameters allowed more than 400 different G6PD variants to be distinguished thereby suggesting a vast genetic heterogeneity. So far, only a small portion of this heterogeneity has been confirmed at the DNA level with the identification of about 90 different point mutations in the G6PD coding sequence. To determine the molecular background of G6PD deficiency in Southeast Asian countries, we conducted molecular analyses of G6PD patients from the Philippines, Malaysia, Singapore, Vietnam and Indonesia. The most prevalent mutation identified differs from country to country, thus suggesting independent mutational events of the G6PD gene.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
We determined whether single nucleotide polymorphisms (SNPs; rs1761667 and rs1527483) in the fatty acid translocase CD36 gene - a receptor for fatty acids - is associated with oral fat perception (OFP) of different fat contents in custards and commercially-available foods, and obesity measures in Malaysian subjects (n=313; 118 males, 293 ethnic Chinese; 20 ethnic Indians). A 170-mm visual analogue scale was used to assess the ratings of perceived fat content, oiliness and creaminess of 0%, 2%, 6% and 10% fat content-by-weight custards and low-fat/regular versions of commercially-available milk, mayonnaise and cream crackers. Overall, the subjects managed to significantly discriminate the fat content, oiliness and creaminess between low-fat/regular versions of milk and mayonnaise. Females rated the perception of fat content and oiliness of both milks higher, but ethnicity, obesity and adiposity status did not seem to play a role in influencing most of OFP. The overall minor allele frequencies for rs1761667 and rs1527483 were 0.30 and 0.26, respectively. Females and individuals with rs1527483 TT genotype significantly perceived greater creaminess of 10% fat-by-weight custard. Also, individuals with rs1527483 TT genotype and T allele significantly perceived greater fat content of cream crackers, independent of fat concentration. rs1761667 SNP did not significantly affect OFP, except for cream crackers. Both gene variants were also not associated with obesity measures. Taken together, this study supports the notion that CD36 - specifically rs1527483, plays a role in OFP, but not in influencing obesity in Malaysian subjects. Besides, gender is an important factor for OFP, where females had higher sensitivity.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
Non-syndromic cleft lip, with or without cleft palate, is a heterogeneous, complex disease with a high incidence in the Asian population. Several association studies have been done on cleft candidate genes, but no reports have been published thus far on the Orofacial Cleft 1 (OFC1) genomic region in an Asian population. This study investigated the association between the OFC1 genomic region and non-syndromic cleft lip with or without cleft palate in 90 Malay father-mother-offspring trios. Results showed a preferential over-transmission of a 101-bp allele of marker D6S470 in the allele- and haplotype-based transmission disequilibrium test (TDT), as well as an excess of maternal transmission. However, no significant p-value was found for a maternal genotype effect in a log-linear model, although single and double doses of the 101-bp allele showed a slightly increased cleft risk (RR = 1.37, 95% CI, 0.527-3.4, p-value = 0.516). Carrying two copies of the 101-bp allele was significantly associated with an increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035). In conclusion, we report evidence of the contribution of the OFC1 genomic region to the etiology of clefts in a Malay population.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
Despite the tremendous growth of the DNA sequencing data in the last decade, our understanding of the human genome is still in its infancy. To understand the implications of genetic variants in the light of population genetics and molecular evolution, we developed a database, PGG.SNV ( https://www.pggsnv.org ), which gives much higher weight to previously under-investigated indigenous populations in Asia. PGG.SNV archives 265 million SNVs across 220,147 present-day genomes and 1018 ancient genomes, including 1009 newly sequenced genomes, representing 977 global populations. Moreover, estimation of population genetic diversity and evolutionary parameters is available in PGG.SNV, a unique feature compared with other databases.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
A total of 627 subjects comprising 455 Chinese, 127 Dravidian Indians and 45 Malays were investigated for serum Apo A-IV polymorphism. The frequency of Apo A-IV*2 was found to be significantly higher (p less than 0.001) in Indians (0.043) compared to that in the Chinese (0.010) and Malays (0.011). The frequency of A-IV*3 was found to be around 0.02 in all the ethnic groups. A low frequency of A-IV*4 (less than 0.01) was observed in the Chinese and Indians. The phenotypic distribution of Apo A-IV was at Hardy-Weinberg equilibrium in the three ethnic groups.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
The distribution of red cell phosphoglucomutase (PGM) subtypes was determined by starch-gel electrophoresis and isoelectric focusing in a group of 2,484 unrelated individuals from ten Mongoloid populations of East Asia. The sample comprised 998 Chinese from various localities--Singapore, 325; Malaysia, 270; Taiwan, 276; Hong Kong, 67; Fouzhou, 60--as well as 342 Koreans; 252 Filipinos; 529 Thais; 336 Malays, and 27 Indonesians. Altogether 15 phenotypes controlled by four common and five rare alleles at the PGM1 locus were observed in these populations. The frequency of the most frequent allele (PGM1+) varied from 0.56 to 0.74, with the highest frequency observed in the Singapore Chinese and the lowest in the Malays. Within the Chinese from different localities a significant degree of heterogeneity was observed at the PGM1 locus. The rare allele (PGM17)6 was observed only among the Chinese, Thais, and Malays, while the PGM1 was lacking in the Filipinos. A new allele with ahigh pI (6.5) was observed in a low frequency in all the populations but the Malays.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
DNA samples were extracted from six prehistoric human remains, found on the Malay Peninsula, dating to the Paleolithic and the Neolithic periods. Nucleotide sequences of mitochondrial DNA were determined by the polymerase chain reaction-direct sequencing method. A phylogenetic tree between prehistoric and present humans was constructed based on the nucleotide sequence data. Mitochondrial DNA phylogenetic relationships and ethnoarchaeological evidence suggest that there is a continuity beetween the pre-Neolithic humans and the present Semang and that the Neolithic humans in this area might be an ancestral group of the Senoi.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
The primary focus of this article is on the so-called negritos of Peninsular Malaysia and southern Thailand, but attention is also paid to other parts of Southeast Asia. I present a survey of current views on the "negrito" phenotype--is it single or many? If the phenotype is many (as now seems likely), it must have resulted from parallel evolution in the several different regions where it has been claimed to exist. This would suggest (contrary to certain views that have been expressed on the basis of very partial genetic data) that the phenotype originated recently and by biologically well-authenticated processes from within the neighboring populations. Whole-genome and physical-anthropological research currently support this view. Regardless of whether the negrito phenotype is ancient or recent-and to the extent that it retains any valid biological reality (which is worth questioning)-explanations are still needed for its continued distinctiveness. In the Malay Peninsula, a distinctive "Semang" societal pattern followed by most, but not all, so-called negritos may have been responsible for this by shaping familial, breeding, and demographic patterns to suit the two main modes of environmental appropriation that they have followed, probably for some millennia: nomadic foraging in the forest, and facultative dependence on exchange or labor relations with neighboring populations. The known distribution of "negritos" in the Malay Peninsula is limited to areas within relatively easy reach of archaeologically authenticated premodern transpeninsular trading and portage routes, as well as of other non-negrito, Aslian-speaking populations engaged in swidden farming. This suggests that their continued distinctiveness has resulted from a wish to maintain a complementary advantage vis-à-vis other, less specialized populations. Nevertheless, a significant degree of discordance exists between the associated linguistic, societal-tradition, and biological patterns which suggests that other factors have also been at play.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
Southeast Asia houses various culturally and linguistically diverse ethnic groups. In Malaysia, where the Malay, Chinese, and Indian ethnic groups form the majority, there exist minority groups such as the "negritos" who are believed to be descendants of the earliest settlers of Southeast Asia. Here we report patterns of genetic substructure and admixture in two Malaysian negrito populations (Jehai and Kensiu), using ~50,000 genome-wide single-nucleotide polymorphism (SNP) data. We found traces of recent admixture in both the negrito populations, particularly in the Jehai, with the Malay through principal component analysis and STRUCTURE analysis software, which suggested that the admixture was as recent as one generation ago. We also identified significantly differentiated nonsynonymous SNPs and haplotype blocks related to intracellular transport, metabolic processes, and detection of stimulus. These results highlight the different levels of admixture experienced by the two Malaysian negritos. Delineating admixture and differentiated genomic regions should be of importance in designing and interpretation of molecular anthropology and disease association studies.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
Anatomically modern hunter-gatherers expanded from Africa into Southeast Asia at least 50,000 years ago, where they probably encountered and interacted with populations of Homo erectus and Homo floresiensis and the recently discovered Denisovans. Simulation studies suggest that these hunter-gatherers may well have followed a coastal route that ultimately led to the settlement of Sahul, while archaeology confirms that they also crossed significant seas and explored well into the interior. They also adapted to marked environmental changes that alternated between relatively cool and dry conditions and warmer, wetter interludes. During the former, the sea fell by up to 120 m below its present level, which opened up a vast low-lying area known as Sundaland. Three principal alignments can be identified: the first involved the occupation of rock shelters in upland regions, the second has identified settlement on broad riverine floodplains, and the last concentrated on the raised beaches formed from about five millennia ago when the sea level was elevated above its present position. This cultural sequence was dislocated about 4 kya when rice and millet farmers infiltrated the lowlands of Southeast Asia ultimately from the Yangtze River valley. It is suggested that this led to two forms of interaction. In the first, the indigenous hunter-gatherers integrated with intrusive Neolithic communities and, while losing their cultural identity, contributed their genes to the present population of Southeast Asia. In the second, hunter-gatherers withdrew to rainforest refugia and, through selective pressures inherent in such an environment, survived as the small-bodied, dark-skinned humans found to this day in the Philippines, Peninsular Malaysia and Thailand, and the Andaman Islands. Beyond the impact of expansive rice farmers in Melanesia and Australia, hunter-gatherers continued to dominate until they encountered European settlement.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
In this survey, we have successfully genotyped 22 single nucleotide polymorphisms in the 13 cytokine genes for five Malay subethnic groups (Kelantan, Acheh, Mandailing, Minangkabau and Patani Malays) using polymerase chain reaction-sequence-specific primer cytokine genotyping kit (Invitrogen, Carlsbad, CA, USA). Most of the cytokine genes showed similar pattern of allelic spectra with wild-type alleles (e.g. ILIa-889/C, ILIB+3962/C and IL6 nt565/G) that represent more than 80% in the studied Malay subethnic groups. These newly observed cytokine alleles and subsequent analyses clearly indicate genetic contribution from Asia in the studied Malay subethnic groups with evidence of admixture from neighbouring populations in Patani Malays. The cytokine data sets for the five Malay subethnic groups deposited in this report can also be used as reference standard for searching suitable donor for allograft transplant and diseases association study. This is particularly relevance as our analyses showed differences between the Malay subethnic groups and other populations screened for cytokine genes.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
Epstein-Barr virus (EBV) is associated with cancers, including lymphomas and nasopharyngeal carcinoma (NPC). To date, risk variants for NPC were mainly identified from Chinese populations, which dominated the world's total number of cases. Although Southeast Asia (SEA) countries have among the world's top yet intriguingly diverse NPC age-standardized incidence rates across subpopulations, data on EBV from SEA remains scarce. In this study, we examined 83 NPC patients of different ancestries for the presence of risk haplotypes associated with the Southern Chinese NPC and generated and analyzed 67 EBV sequences (from tissue, patient-derived xenografts and lymphoblastoid cell lines of 60 NPC patients) together with 838 published EBV genomes. Our study revealed that NPC patients of non-Chinese ancestry had fewer risk variants and haplotypes that are associated with Southern Chinese NPC and clustered distinctly from lymphomas, Southern Chinese NPC, and non-cancer controls. The distribution of non-synonymous variants was similar among NPC patients of Chinese ancestry, irrespective of geographical location. Meanwhile, non-synonymous variants in genes related to packaging, latency, and structural proteins such as BPLF1, LF3, and LMP1 varied across different ancestries. Our findings suggest possibilities of EBV adaptation to host genetics for NPC pathogenesis and warrant further research for the understudied NPC subpopulations.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
Genome-wide association studies have identified SV2C as a Parkinson's disease (PD) risk locus, with a common missense variant p.Asp543Asn in the synaptic vesicle glycoprotein 2C (SV2C) protein significantly associated with PD. We examined if other rare SV2C variants also influence PD risk. We analyzed sequencing data of 9810 East Asian individuals comprising 4298 patients and 5512 controls and identified 55 rare nonsynonymous variants. There was no significant association of rare nonsynonymous or loss-of-function variants with PD. Our findings show that besides p.Asp543Asn, other rare coding variants in SV2C do not play a major role in PD susceptibility in East Asia.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
CYP2C9 enzyme contributes to the metabolism of several pharmaceuticals and xenobiotics and yet displays large person-to-person and interethnic variation. Understanding the mechanisms of CYP2C9 variation is thus of immense importance for personalized medicine and rational therapeutics. A genetic variant of P450 (cytochrome) oxidoreductase (POR), a CYP450 redox partner, is reported to influence CYP2C9 metabolic activity in vitro. We investigated the impact of a common variant, POR*28, on CYP2C9 metabolic activity in humans. 148 healthy Swedish and 146 healthy Korean volunteers were genotyped for known CYP2C9 defective variant alleles (CYP2C9*2, *3). The CYP2C9 phenotype was determined using a single oral dose of 50 mg losartan. Excluding oral contraceptive (OC) users and carriers of 2C9*2 and *3 alleles, 117 Korean and 65 Swedish were genotyped for POR*5, *13 and *28 using Taqman assays. The urinary losartan to its metabolite E-3174 metabolic ratio (MR) was used as an index of CYP2C9 metabolic activity. The allele frequency of the POR*28 variant allele in Swedes and Koreans was 29% and 44%, respectively. POR*5 and *13 were absent in both study populations. Considering the CYP2C9*1/*1 genotypes only, the CYP2C9 metabolic activity was 1.40-fold higher in carriers of POR*28 allele than non-carriers among Swedes (p = 0.02). By contrast, no influence of the POR*28 on CYP2C9 activity was found in Koreans (p = 0.68). The multivariate analysis showed that ethnicity, POR genotype, and smoking were strong predictors of CYP2C9 MR (p < 0.05). This is the first report to implicate the importance of POR*28 genetic variation for CYP2C9 metabolic activity in humans. These findings contribute to current efforts for global personalized medicine and using medicines by taking into account pharmacogenetic and phenotypic variations.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
CHEK2 is a protein kinase that is involved in cell-cycle checkpoint control after DNA damage. Germline mutations in CHEK2 gene have been associated with increase in breast cancer risk. The aim of this study is to identify the CHEK2 gene germline mutations among high-risk breast cancer patients and its contribution to the multiethnic population in Malaysia. We screened the entire coding region of CHEK2 gene on 59 high-risk breast cancer patients who tested negative for BRCA1/2 germline mutations from UKM Medical Centre (UKMMC), Hospital Kuala Lumpur (HKL) and Hospital Putrajaya (HPJ). Sequence variants identified were screened further in case-control cohorts consisting of 878 unselected invasive breast cancer patients (180 Malays, 526 Chinese and 172 Indian) and 270 healthy individuals (90 Malays, 90 Chinese and 90 Indian). By screening the entire coding region of the CHEK2 gene, two missense mutations, c.480A>G (p.I160M) and c.538C>T (p.R180C) were identified in two unrelated patients (3.4%). Further screening of these missense mutations on the case-control cohorts unveiled the variant p.I160M in 2/172 (1.1%) Indian cases and 1/90 (1.1%) Indian control, variant p.R180C in 2/526 (0.38%) Chinese cases and 0/90 Chinese control, and in 2/180 (1.1%) of Malay cases and 1/90 (1.1%) of Malay control. The results of this study suggest that CHEK2 mutations are rare among high-risk breast cancer patients and may play a minor contributing role in breast carcinogenesis among Malaysian population.
Matched MeSH terms: Asian Continental Ancestry Group/genetics
The study aimed to investigate the association between the interferon regulatory factor 5 (IRF5) gene polymorphisms and the onset of Crohn's disease (CD) in a Malaysian cohort.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
CYP2E1 PstI polymorphism G-1259C (rs3813867) genotype distributions vary significantly among different populations and are associated with both diseases, like cancer, and adverse drug effects. To date, there have been limited genotype distributions and allele frequencies of this polymorphism reported in the three major indigenous ethnic groups (KadazanDusun, Bajau, and Rungus) in Sabah, also known as North Borneo. The aim of this study was to investigate the genotype distributions and allele frequencies of the CYP2E1 PstI polymorphism G-1259C in these three major indigenous peoples in Sabah. A total of 640 healthy individuals from the three dominant indigenous groups were recruited for this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at G-1259C polymorphic site of CYP2E1 gene was performed using the Pst I restriction enzyme. Fragments were analyzed using agarose gel electrophoresis and confirmed by direct sequencing. Overall, the allele frequencies were 90.3% for c1 allele and 9.7% for c2 allele. The genotype frequencies for c1/c1, c1/c2 and c2/c2 were observed as 80.9%, 18.8%, and 0.3%, respectively. A highly statistical significant difference (p<0.001) was observed in the genotype distributions between indigenous groups in Sabah with all Asian and non-Asian populations. However, among these three indigenous groups, there was no statistical significant difference (p>0.001) in their genotype distributions. The three major indigenous ethnic groups in Sabah show unique genotype distributions when compared with other populations. This finding indicates the importance of establishing the genotype distributions of CYP2E1 PstI polymorphism in the indigenous populations.
Matched MeSH terms: Asian Continental Ancestry Group/genetics*
The dysbindin-1 (dystrobrevin-binding protein-1 [DTNBP-1]) gene has repeatedly been shown to be associated with psychotic disorder across diverse populations. In this study, we attempted to investigate the association of the rs3213207 (P1635) genetic polymorphism of the DTNBP1 gene with methamphetamine dependence and with methamphetamine-induced psychosis, manic episodes, and panic disorder in a male Malaysian population.
Matched MeSH terms: Asian Continental Ancestry Group/genetics