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Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

ABSTRACT: Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nation, but little is known about the population genetics of the major Sri Lankan ethnic groups. The objective of this study was to investigate the diversity of pharmacogenomic variants in the major Sri Lankan ethnic groups.We examined the allelic diversity of more than 7000 variants in genes involved in drug biotransformation and response in the three major ethnic populations of Sri Lanka (Sinhalese, Sri Lankan Tamils, and Moors), and compared them with other South Asian, South East Asian, and European populations using Wright's Fixation Index, principal component analysis, and STRUCTURE analysis.We observed overall high levels of similarity within the Sri Lankan populations (median FST=0.0034), and between Sri Lankan and other South Asian populations (median FST=0.0064). Notably, we observed substantial differentiation between Sri Lankan and European populations for important pharmacogenomic variants related to warfarin (VKORC1 rs9923231) and clopidogrel (CYP2C19 rs4986893) response.These data expand our understanding of the population structure of Sri Lanka, provide a resource for pharmacogenomic research, and have implications for the clinical use of genetic testing of pharmacogenomic variants in these populations.

SUBMITTER: Chan SL

PROVIDER: S-EPMC4890825 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

Chan Sze Ling SL Samaranayake Nilakshi N Ross Colin J D CJ Toh Meng Tiak MT Carleton Bruce B Hayden Michael R MR Teo Yik Ying YY Dissanayake Vajira H W VH Brunham Liam R LR

Pharmacogenetics and genomics 20160101 1

<h4>Background</h4>Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nat ...[more]

PMID: 26444257

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Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) is an enzyme that plays an important role in many cellular functions. Deficiency of this enzyme results from point mutations in the coding region of the G6PD gene. G6PD-deficiency is important in malaria, as certain anti-malarial drugs could induce haemolysis in such patients and mutations in this gene may influence the susceptibility or resistance to the disease. Detailed information on genetic variations in the G6PD gene for Sri Lankan populations is yet to be revealed. This study describes a set of G6PD mutations present in a Sri Lankan population and their association with uncomplicated malaria.MethodsDNA was extracted from 1,051 individuals. Sixty-eight SNPs in the region of the G6PD gene were genotyped. A database created during the 1992-1993 malaria epidemic for the same individuals was used to assess the associations between the G6PD SNPs and parasite density or disease severity of uncomplicated malaria infections. Linkage disequilibrium for SNPs and haplotype structures were identified.ResultsSeventeen genetic variants were polymorphic in this population. The mutant allele was the major allele in 9 SNPs. Common G6PD variants already described in Asians or South-Asians seemed to be absent or rare in this population. Both the severity of disease in uncomplicated malaria infections and parasitaemia were significantly lower in males infected with Plasmodium falciparum carrying the ancestral allele of rs915942 compared to those carrying the mutant allele. The parasite density of males infected with P. falciparum was significantly lower also in those who possessed the mutant alleles of rs5986877, rs7879049 and rs7053878. Two haplotype blocks were identified, where the recombination rates were higher in males with no history of malaria when compared to those who have experienced the disease in the past.ConclusionsThis is the most detailed survey of G6PD SNPs in a Sri Lankan population undertaken so far that enabled novel description of single nucleotide polymorphisms within the G6PD gene. A few of these genetic variations identified, demonstrated a tendency to be associated with either disease severity or parasite density in uncomplicated disease in males. Known G6PD gene polymorphisms already described from elsewhere were either absent or rare in the local study population.

Project description:PurposeSeveral single nucleotide polymorphisms (SNPs) have been reported to be associated with clinicopathological profiles in sporadic breast cancer based on studies conducted on major population groups. The knowledge of the effects of these common genetic variants in South Asian populations remains limited. The present study aimed to investigate the association between a selected set of SNPs and the clinicopathological profiles in sporadic breast cancer in Sri Lankan women.MethodsA total of 350 postmenopausal women with histologically confirmed invasive breast cancer were genotyped for 58 SNPs located in 36 breast cancer related genes. The clinicopathological factors that were investigated included age of onset, tumor histologic grade, and lymph node involvement, as well as estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status. Association testing was performed using logistic regression models adjusted for confounding factors.ResultsSeven SNPs showed significant associations with clinicopathological profiles in breast cancer. The G allele of BRCA1:rs799917 (p=0.047; β [standard error; SE]=-1.069 [0.537]) and the G allele of NQO2:rs17136117 (p=0.040, β [SE]=1.901 [0.923]) were found to be associated with age of onset between 50 and 59 years. The C allele of CDH1:rs13689 (odds ratio [OR], 2.121; p=0.033) was found to be associated with ER-positive breast cancer. The A allele of AKT1:rs1130214 (OR, 2.095; p=0.011) and the C allele of NQO2:rs2071002 (OR, 1.632; p=0.045) were associated with HER2-positive breast cancer. The C allele of BRCA2:rs15869 (OR, 1.600; p=0.041) and the C allele of CCND1:rs7177 (OR, 1.555; p=0.041) were associated with high tumor histologic grade.ConclusionThe common genetic variants identified in the AKT1, BRCA1, BRCA2, CCND1, CDH1, and NQO2 genes could serve as potential clinical and prognostic biomarkers in sporadic breast cancer patients. Further studies are required to validate our current findings in other populations.

Project description:Extreme environmental conditions are a major challenge in livestock production. Changes in climate, particularly those that contribute to weather extremes like drought or excessive humidity, may result in reduced performance and reproduction and could compromise the animal’s immune function. Animal survival within extreme environmental conditions could be in response to natural selection and to artificial selection for production traits that over time together may leave selection signatures in the genome. The aim of this study was to identify selection signatures that may be involved in the adaptation of indigenous chickens from two different climatic regions (Sri Lanka = Tropical; Egypt = Arid) and in non-indigenous chickens that derived from human migration events to the generally tropical State of São Paulo, Brazil. To do so, analyses were conducted using fixation index (Fst) and hapFLK analyses. Chickens from Brazil (n = 156), Sri Lanka (n = 92), and Egypt (n = 96) were genotyped using the Affymetrix Axiom®600k Chicken Genotyping Array. Pairwise Fst analyses among countries did not detect major regions of divergence between chickens from Sri Lanka and Brazil, with ecotypes/breeds from Brazil appearing to be genetically related to Asian-Indian (Sri Lanka) ecotypes. However, several differences were detected in comparisons of Egyptian with either Sri Lankan or Brazilian populations, and common regions of difference on chromosomes 2, 3 and 8 were detected. The hapFLK analyses for the three separate countries suggested unique regions that are potentially under selection on chromosome 1 for all three countries, on chromosome 4 for Sri Lankan, and on chromosomes 3, 5, and 11 for the Egyptian populations. Some of identified regions under selection with hapFLK analyses contained genes such as TLR3, SOCS2, EOMES, and NFAT5 whose biological functions could provide insights in understanding adaptation mechanisms in response to arid and tropical environments.

Project description:BACKGROUND:The development of relatively cheap and high throughput methods of genotyping and phenotyping plants offers the opportunity to explore local germplasm more thoroughly than before and should accelerate the identification of sources of genetic variation suitable for breeding. In this study, 135 Sri Lankan accessions, mostly identified as landraces, for which data was available at the International Rice Research Institute on drought scores were genotyped using a 384 SNP array and assessed for root depth using a newly developed buried herbicide method. Roots of 36 accessions were assessed using hydroponics and 12 using soil-filled rhizotrons to establish if variation in herbicide score could be attributed to root traits. RESULTS:Population structure based on the SNPs using STRUCTURE revealed six groups, being tropical japonica, aus and four indica subpopulations. Three of these indica subpopulations do not seem to be represented in the Rice Diversity Panel I (RDP1) of 372 global rice accessions and appear to represent genetic diversity so far poorly studied by the global scientific community. The herbicide score was highly discriminatory between landraces and correlated very strongly with hydroponic and rhizotron root traits. The mean herbicide score strongly differentiated between landraces according to the province and the latitude from which they were collected. It also differed between subpopulations, being high in indica 2 and tropical japonica and low in indica 1 and aus. Drought scores suggest that indica 2 is more drought resistant than the other groups. Correlations indicate that those landraces with high herbicide scores are more drought resistant in the vegetative stage. The landrace Niyan Wee, whose name in Sinhalese means "drought rice" belongs to the indica 2 subgroup, has high herbicide scores and deep roots. CONCLUSIONS:Niyan Wee and other cultivars within the indica 2 subgroup should be a valuable source of breeding for drought resistance at least partly because of their superior root traits, not normally associated with the indica rice cultivars.

Project description:IntroductionMost studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.MethodologyLead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population.ResultsOf the 36 SNPs passing quality control, sixteen showed nominal (p<0.05) association in Sri Lankan samples, fifteen of those directionally-consistent with the original signal. Overall, these association findings were robust to analyses that accounted for membership of ethnolinguistic subgroups. Overall, the odds ratios for 31 of the 36 SNPs were directionally-consistent with those observed in Europeans (p?=?3.2×10(-6)). Allelic odds ratios and risk allele frequencies in Sri Lankan subjects were not systematically different to those reported in Europeans. Genetic risk score and risk of T2D were strongly related in Sri Lankans (per allele OR 1.10 [95%CI 1.08-1.13], p?=?1.2×10(-17)).ConclusionOur data indicate that most T2D-risk variants identified in Europeans have similar effects in South Asians from Sri Lanka, and that systematic difference in common variant associations are unlikely to explain inter-ethnic differences in prevalence or presentation of T2D.

Project description:Background:Obtaining reliable food portion size estimations in dietary surveys found to be a difficult task. A food atlas is a set of photograph series depicting different amounts of a particular food, usually bound together in a single volume that can be used to describe portion sizes. By this paper we aim to explain the methods used in developing a photographic food atlas for Sri Lankan adults and to discuss its usage, advantages and limitations. Methods:Foods that are commonly consumed in Sri Lanka were recognized by a local nutritional survey, market survey and interviewing nutrition experts. In obtaining food items, certain dishes were prepared according to a standard recipe book while other items were purchased from recognized restaurants and the local market. White color crockery or/with blue color board was used to present the food items and they were photographed by a professional photographer employing a camera setup recommended for food photography. Three types of photographs have been used to illustrate the food items; serial, range and guide. Mainly the serial photographs were taken using two cameras: one fixed at an angle of 5° to capture aerial views, and the other placed at an angle of 45° to represent the view of a person of average height, sitting at a table, looking at a plate on the table in front of him. The liquid portion series were photographed at an angle of 90° to get life-size images. The range and guide photographs were taken free hand so that all the items could be captured in the best way possible. Results:A total of 125 foods that are commonly consumed by Sri Lankan adults were selected to be depicted in the atlas; serial photographs of increasing portion sizes (n = 88 foods); range photographs depicting a range of sizes/varieties of a particular food, (n = 11), and guide photographs which represent the brands/types of a certain food item/category available in the market (n = 26). Conclusion:The food atlas will be a valuable resource for dietary surveys in Sri Lanka as well as in other South Asian countries where similar foods are consumed.

Dataset Information

Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

Publications

Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

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