Papers by Umamaheswaran Gurusamy
Genome Medicine
Background High sequence identity between segmental duplications (SDs) can facilitate copy number... more Background High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood. Methods We employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints. Results In total, we discovere...
Supplementary figures<br><b>Single molecule support images for 1000 Genomes Project a... more Supplementary figures<br><b>Single molecule support images for 1000 Genomes Project and the California Initiative to Advance Precision Medicine samples</b>. Optical mapping of the haplotype contigs represented in blue and optical mapping molecules are represented as yellow lines. The red rectangle box depicts the haplotype.
Genetic Testing and Molecular Biomarkers, 2011
In association with candidate genes, the observed trait may be due to either one of the variant a... more In association with candidate genes, the observed trait may be due to either one of the variant alleles or the interaction of variant alleles at different loci, which are in linkage disequilibrium. Aim: The objective of this study was to investigate the baseline allele and genotype frequencies, linkage disequilibrium (LD) patterns, and haplotype structures of common variants of the CYP2C8, CYP2C9, and ADRB1 genes located on chromosome 10. Methods: Two hundred and forty-five healthy subjects were recruited from South India and were compared with the HapMap Project's population for LD pattern, allele and genotype frequencies, and haplotype structures. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism and TaqMan assay on real-time polymerase chain reaction. Results: A significant ethnic difference was found in the LD patterns among the variant alleles between the South Indian population and other major ethnic groups, namely African, European, Chinese, and Japanese. Conclusion: This study established the normative allele and genotype frequencies, haplotype structure, and LD patterns of common variants of the CYP2C8, CYP2C9, and ADRB1 genes in a South Indian population (Tamilian). The data may be helpful to plan candidate gene-trait association studies in this population.
International Journal of Human Genetics, 2011
Genetic variants of renin angiotensin system (RAS) gene play a significant role in the pathogenes... more Genetic variants of renin angiotensin system (RAS) gene play a significant role in the pathogenesis of essential hypertension and cardiovascular diseases. In the present study, we investigated the association of RAS gene polymorphisms with hypertension by analyzing the polymorphisms ACE ID, AGT T207M, M268T and AGT1R A1166C in 462 hypertensive patients and 444 healthy subjects. Genotyping was determined by allele specific PCR, PCR-RFLP and RT-PCR Taqman assay. The ACE ID heterozygous (OR=1.5: 95% CI: 1.0-2.3, p<0.05) and ACE DD homozygous genotype (OR=1.7: 95% CI: 1.2-2.8, p<0.01) was found to be significantly associated with hypertension. There was no significant association between AGT T207M, M268T and AGT1R A1166C gene polymorphisms and hypertension. Gender-specific analysis showed ACE ID heterozygous genotypes were positively associated with hypertension among male hypertensives (OR=1.9: 95% CI: 1.1-2.6, p<0.01). Significant gene-gene interaction was observed between ACE ID and AGT M268T polymorphisms (OR=2.0; 95% CI: 1.2-3.5, p<0.01). Our results suggest that ACE ID polymorphism is associated with hypertension. Further, gene-gene interaction between ACE ID and AGT M268T gene polymorphisms further modified the risk of essential hypertension.
Molecular Biology Reports, 2014
Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis ... more Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.
Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in gen... more Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in genomic disorders, such as the 3q29 deletion syndrome. At the 3q29 region, non-allelic homologous recombination (NAHR) between paralogous copies of segmental duplications (SDs) leads to a recurrent ∼1.6 Mbp deletion or duplication, causing neurodevelopmental and psychiatric phenotypes. However, risk factors contributing to NAHR at this locus are not well understood. In this study, we used an optical mapping approach to identify structural variations within the 3q29 interval. We identified 18 novel haplotypes among 161 unaffected individuals and used this information to characterize this region in 18 probands with either the 3q29 deletion or 3q29 duplication syndrome. A significant amount of variation in haplotype prevalence was observed between populations. Within probands, we narrowed down the breakpoints to a ∼5 kbp segment within the SD blocks in 89% of the 3q29 deletion and duplication ...
Blood
Objectives: 1)To determine the influence of DHFR gene polymorphisms on outcome of methotrexate-ba... more Objectives: 1)To determine the influence of DHFR gene polymorphisms on outcome of methotrexate-based maintenance therapy in patients with acute lymphoblastic leukemia (ALL) 2)To compare the relapse free survival between DHFR genotype 3)To establish the normal allele and genotype frequencies of the DHFR polymorphisms in the South Indian population Methods: A total of thirty one patients with ALL were included for the study. A total of 85 healthy volunteers from the South India were recruited to establish the allelic frequencies of the A-317G & C-680A variants of DHFR gene. DNA was extracted by phenol chloroform method and genotyping was done by allelic discrimination method. Patients were followed up for two years for the outcome. Results: Homozygous mutant genotype carriers (GG) were at two-fold increased risk of relapse when compared to the other genotypes (AA & AG) [Relative risk= 2.6; 95% CI, 1.260 to 5.365, P<0.05]. Relapse-free survival rate was lower in GG genotype carriers...
International Journal of Human Genetics, Mar 1, 2011
The Indian Journal of Medical Research
Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorpti... more Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.
Molecular Biology Reports
Myocardial infarction (MI) is a complex multi-factorial, polygenic disorder which results from an... more Myocardial infarction (MI) is a complex multi-factorial, polygenic disorder which results from an interaction between a person's genetic makeup and various environmental factors. Nitric oxide (NO), a potent vasodilator produced by endothelial cells, plays an important role in the regulation of blood pressure, regional blood flow and also inhibits platelet aggregation, vascular smooth muscle cell proliferation and leukocyte adhesion to vascular endothelium. Our aim was to analyze the association of NOS3 (endothelial nitric oxide synthase 3) 894G>T and -786T>C gene polymorphisms and MI risk in the South Indian population. A total of 287 MI patients, 279 risk control patients and 321 healthy controls were recruited for the retrospective study. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). There was no significant association observed between NOS3 894G>T, -786T>C polymorphisms and MI. A significant difference was...
OBJECTIVE: To investigate for association of ischemic stroke to total plasma homocysteine levels ... more OBJECTIVE: To investigate for association of ischemic stroke to total plasma homocysteine levels and the C677T and A1298C SNP mutations in the South Indian Tamil population. BACKGROUND: Association of Ischemic stroke and other vascular diseases with plasma homocysteine levels and MTHFR polymorphisms vary in different populations. South Indian Tamilian population is deemed to have distinct genetic identity. DESIGN/METHODS: Case-control design. The association of Plasma homocsyteine levels(micromoles/l) between ischemic stroke (N=126) and control groups (MI=71, PVD=22, non-vascular cerebraldisease=23,non-vascular healthy=75) groups were tested using analysis of variance. The comparison of frequencies and association with haplotypes involving C677T and A1296C allelic combinations were also tested between the groups. The observed and expected genotype frequencies compared to test for deviations from Hardy-Weinberg equilibrium.The odds ratios and 95% confidence intervals were calculated ...
Objectives: To determine the influence of Dihydro Folate Reductase (DHFR) gene polymorphisms on r... more Objectives: To determine the influence of Dihydro Folate Reductase (DHFR) gene polymorphisms on relapse in Acute Lymphoblastic Leukemia patients (ALL) treated with methotrexate-based maintenance therapy and to establish the normal allele and genotype frequencies of the DHFR in healthy South Indian population. Materials and Methods: A total of 85 healthy volunteers were recruited to establish the allelic frequencies of A-317G and C-680A in DHFR gene. A total of twenty eight patients with ALL were included in this study. Healthy volunteers and Patients’ DNA were extracted from WBC by phenol chloroform and they were tested for the presence of variants rs408626 and rs442767 in DHFR gene by allelic specific discrimination method. Study subjects were followed for two years for the outcome. Results: The genotype frequencies of A-317G and C-608A variants in healthy volunteers were AA = 51.76%, AG = 37.64%, GG = 10.58%; CC = 0%, AC = 20.98%, AA = 79.01% respectively. In the patient group, A-...
Background: Tamoxifen is used as an adjuvant hormonal therapy in breast cancer. It is converted t... more Background: Tamoxifen is used as an adjuvant hormonal therapy in breast cancer. It is converted to the active metabolite endoxifen by cytochrome P450 enzymes CYP2D6 and CYP2C19. Variations in activity of CYP2C19, leading to reduced endoxifen levels, may be a reason for recurrence of tumor with adjuvant tamoxifen. Previous studies on the role of CYP2C19 genotype on tamoxifen therapy gave conflicting results and no such study has been performed in Indian population. Therefore, this study was done to evaluate the influence of CYP2C19 genetic polymorphisms on the recurrence of breast cancer in patients receiving tamoxifen. Methods: Patients receiving adjuvant tamoxifen were recruited for the study. Genotyping was carried out for CYP2C19 alleles 2*, *17 by PCR-RFLP. Carriers of CYP2C19*2 allele have a poor metabolizer phenotype and the association between *2 allele carriers and recurrence of tumor was assessed. Subjects with *17 allele (*1/*17, *17/*17) have an ultrarapid metabolizer phe...
The Journal of asthma : official journal of the Association for the Care of Asthma, Jan 19, 2015
Genetic mutations in the β2 receptor could alter its functioning and the response to β2 agonists.... more Genetic mutations in the β2 receptor could alter its functioning and the response to β2 agonists. The study was done to find out the effect of two commonly occurring polymorphisms-Arg16Gly and Gln27Glu, on cause of asthma and on response to nebulized salbutamol in South Indian subjects of asthma. After baseline measurements of Forced Expiratory Volume in 1st second (FEV1), Forced Vital Capacity (FVC) and Peak Expiratory Flow Rate (PEFR), five mg of nebulized salbutamol was administered and spirometry was repeated. The increase in these parameters was calculated and patients were included for genotyping if the percentage increase in FEV1 was ≥12%. The frequencies of these polymorphisms in patients were compared with those of healthy volunteers. 112 patients and 127 healthy volunteers were genotyped. The frequencies of the polymorphisms were found to be similar to previously published Dravidian population frequencies. The frequencies of genotypes in asthmatics were similar to healthy ...
Handbook of Pharmacogenomics and Stratified Medicine, 2014
ABSTRACT
ABSTRACT Background: In postmenopausal women with endocrine responsive breast cancer, treatment w... more ABSTRACT Background: In postmenopausal women with endocrine responsive breast cancer, treatment with letrozole has shown better clinical outcome than tamoxifen in early and advanced stage of the disease. Intriguingly, in spite of these advances as anti-estrogen drug, a significant proportion of tumor demonstrates resistance and responds differently with letrozole medication. Genetic variations of CYP19A1 gene may influence inter-individual variation in letrozole efficacy. Therefore, the aim of the study was to evaluate the impact of CYP19A1 polymorphisms on the clinical outcomes of adjuvant letrozole in 191 HR+ BC patients had been on or received letrozole (2.5mg, OD). Methods: DNA was extracted by phenol-chloroform method and genotyping of CYP19A1 SNPs (rs4646, rs10046, rs700519, rs700518, rs727479, rs4775936, rs10459592, rs1062033, rs749292, rs6493497 &amp; rs7176005) was performed by RT-PCR with TaqMan assays. The patients were followed up until there was evidence of disease recurrence or death. Data was analyzed by SPSS v19.0 and Haploview v4.2 was used to measure the linkage disequilibrium between polymorphisms. Results: The mean (± SD) age of the study cohort was 56.92 ± 9.65. Of the 191 patients, 8.4% had both local and distant recurrence of BC. There was a significant difference in the proportions of allele and genotype frequencies for rs4646 polymorphism of CYP19A1 gene alone between recurrence and non-recurrence groups. The carriers of two copies (homozygous) of the variant allele ‘T’ were at 6.69 (95% CI 1.55-28.90, P&lt;0.010) fold increased risk for recurrence. We investigated the clinical efficacy of letrozole in the association of 21 specific haplotypes derived with a frequency of &gt;1% from 11 CYP19A1 SNPs tested. Of those, haplotype T-C-C-A-T-C-T-C-G-C-G was significantly associated with higher odds of recurrence risk (P = 5.2821E-5). Further, Kaplan-Meier estimates indicate that the patients carrying homozygous condition for ‘T’ allele of rs4646 polymorphism had significantly shorter RFS (100.71 ± 4.59 months vs. 210.93 ± 6.63 months, P&lt;0.024). Conclusions: First study to assess the association between CYP19A1 variants and letrozole efficacy in adjuvant setting. Our results suggest that the polymorphisms of CYP19A1 gene may be considered a pharmacogenetic marker to predict the risk of relapse and the survival outcome in South Indian women with HR+ BC.
ABSTRACT Objective: To study the effect of HTR-2C (5HT2C receptor) genetic polymorphism on risper... more ABSTRACT Objective: To study the effect of HTR-2C (5HT2C receptor) genetic polymorphism on risperidone-induced weight gain in patients with schizophrenia and acute psychosis. Materials and Methods: Seventy one patients diagnosed with schizophrenia or acute psychosis who had been started on risperidone therapy were recruited and followed up for 3 months to assess weight gain and clinical improvement reflected in BPRS (Brief Psychiatric Rating Scale) scores. Genotyping was done by standard Real-Time PCR for -759C&gt;T polymorphism of HTR-2C gene. Results: Prevalence of weight gain was 43.6% (31 patients). The presence of mutant T allele of -759C&gt;T polymorphism of HTR-2C gene showed a protective effect on the development of weight gain defined as ≥5% increase from baseline weight. (P-0.0003 OR-0.15, 95% CI-0.054 to 0.439) Heterozygous mutant (CT) and homozygous mutant (T and TT) genotypes also showed a protective effect for the occurrence of weight gain compared to the wild type (OR-0.18, 95% CI: 0.046 to 0.704 and OR-0.13,95% CI: 0.040 to 0.473 respectively). Higher baseline weight, height and the presence of T allele were found to affect the outcome of weight gain by binary logistic regression. Protective effect of T allele remained significant even after adjusting for baseline weight and height (OR-0.07, 95% CI: 0.018 to 0.300). Conclusion: The presence of T allele of -759C&gt;T polymorphism of HTR-2C gene and the variant genotypes (Heterozygous and homozygous mutants) have a protective effect on the development of weight gain in patients with schizophrenia and acute psychosis on risperidone therapy, which remained significant even after adjusting for weight and height.
Molecular Biology Reports, 2014
Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis ... more Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.
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Papers by Umamaheswaran Gurusamy