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Association of brain-derived neurotrophic factor (Val66Met) genetic polymorphism with methamphetamine dependence in a Malaysian population

Sim MS, Mohamed Z, Hatim A, Rajagopal VL, Habil MH

Brain Res, 2010 Oct 21;1357:91-6.
PMID: 20736000 DOI: 10.1016/j.brainres.2010.08.053

Methamphetamine is a highly addictive psychostimulant that has surged in popularity worldwide in the last decade. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is widely expressed in the adult mammalian brain and plays an important role in the long-term survival, differentiation, and outgrowth of neurons. Previous studies suggested that the BDNF gene may be involved in the mechanisms underlying substance dependence. This study investigated the association of the BDNF gene Val66Met polymorphism with methamphetamine dependence and with psychosis in a Malaysian population with different ethnicities. The BDNF Val66Met polymorphism was genotyped by PCR-RFLP in 186 male methamphetamine-dependent subjects and in 154 male controls of four different ethnicities, namely, Malay, Chinese, Kadazan-Dusun, and Bajau. Our results showed that the distribution of the BDNF Val66Met genotype in Chinese subjects with methamphetamine dependence (OR=2.6, p=0.015) and methamphetamine psychosis (OR=0.2, p = 0.034) were significant compared with controls. The frequency of the 66Val allele in methamphetamine-dependent subjects was higher than that in the control group, suggesting that the 66Val carriers are more susceptible to methamphetamine dependence. However, 66Val allele frequency in other ethnicities was not significantly different from the controls. The results of the study also showed that in the Chinese methamphetamine-dependent subjects, there was a difference in allele frequency when comparing those who developed psychosis and those who did not. Our findings suggest that the BDNF Val66Met polymorphism may contribute to methamphetamine dependence and psychosis in the Chinese population but not in other Malaysian ethnicities.

Matched MeSH terms: Genetic Association Studies
Evaluation of association studies and meta-analyses of MTHFR gene polymorphisms in colorectal cancer

Haerian BS, Haerian MS

Pharmacogenomics, 2015;16(4):413-25.
PMID: 25823789 DOI: 10.2217/pgs.14.177

There is a discrepancy between the results of 89 original studies and 15 meta-analyses investigating the association of MTHFR rs1801133 and rs1801131 polymorphisms with colorectal cancer (CRC) risk. We examined this hypothesis through meta-analyses of both loci and their diplotypes as well as evaluation of previous meta-analyses. The present meta-analysis showed that rs1801133 and rs1801131 might be CRC susceptibility variants in Americans and Australians and rs1801133 in Brazilians and Japanese. A strong linkage disequilibrium was observed between both loci and their diplotypes were associated with CRC risk. Evaluation of 15 meta-analyses showed a high discrepancy among their findings, mainly caused by population stratification of original studies and data analysis strategies in meta-analysis. Population stratification was more dominant in the studies from Australia, America and Brazil leading to false positive or negative results. In conclusion, these loci alone might modify the development of CRC in some ethnicities.

Matched MeSH terms: Genetic Association Studies*
Fulltext Association of beta 2 adrenoceptor gene polymorphisms in Malaysian hypertensive subjects

Komara M, Vasudevan R, Ismail P, Bakar SA, Pishva SR, Heidari F

Genet. Mol. Res., 2014;13(2):2939-48.
PMID: 24782128 DOI: 10.4238/2014.April.16.2

The sympathetic nervous system plays a major role in blood pressure regulation. Beta 2 (β2) adrenoceptor gene polymorphisms have been associated with hypertension in different populations with conflicting results. We examined the association of three common polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile, of the β2 adrenoceptor gene in Malaysian hypertensive subjects. A total of 160 hypertensive and control subjects were recruited. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and anthropometric measurements were obtained from each subject. Biochemical analyses of lipid profiles were conducted with an autoanalyzer. DNA samples were extracted from blood and buccal cells. Genotyping was accomplished with polymerase chain reaction-restriction fragment length polymorphism. SBP, DBP, body mass index, and biochemical factors all differed significantly between case and control subjects (P < 0.05). The genotype frequencies of Arg16Arg, Arg16Gly, and Gly16Gly were 22.5, 70, and 7.5% among cases and 33.1, 63.1, and 3.8% among controls, respectively. The genotype frequencies of Gln27Gln, Gln27Glu, and Glu27Glu among cases were 41.1, 50, and 1.9% compared to 77.5, 20.6, and 1.9% among controls, respectively. In this study, the Gln27Glu polymorphism was significantly associated with Malaysian hypertensive subjects (P < 0.05). Therefore, the Gln27Glu polymorphism of the β2 adrenoceptor could be a risk factor associated with hypertension among Malaysians.

Matched MeSH terms: Genetic Association Studies*
Association of single nucleotide polymorphism rs6903956 on chromosome 6p24.1 with coronary artery disease and lipid levels in different ethnic groups of the Singaporean population

Tayebi N, Ke T, Foo JN, Friedlander Y, Liu J, Heng CK

Clin Biochem, 2013 Jun;46(9):755-9.
PMID: 23337689 DOI: 10.1016/j.clinbiochem.2013.01.004

A recent genome wide association study in the Chinese population has implicated rs6903956 within the ADTRP gene on chromosome 6p24.1 as a novel susceptibility locus for coronary artery disease (CAD). In this study, we evaluated the association of rs6903956 with CAD in the different ethnic groups of Singaporean population comprising Chinese, Malays and Asian Indians.

Matched MeSH terms: Genetic Association Studies
Fulltext Four novel p.N385K, p.V36A, c.1033-1034insT and c.1417-1418delCT mutations in the sphingomyelin Phosphodiesterase 1 (SMPD1) gene in patients with types A and B Niemann-Pick disease (NPD)

Manshadi MD, Kamalidehghan B, Keshavarzi F, Aryani O, Dadgar S, Arastehkani A, et al.

Int J Mol Sci, 2015 Mar 24;16(4):6668-76.
PMID: 25811928 DOI: 10.3390/ijms16046668

BACKGROUND: Types A and B Niemann-Pick disease (NPD) are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene.
METHODS: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis.
RESULTS: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous) showed the p.V36A mutation. One patient was homozygous for the c.1033-1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417-1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM) protein stability, which might be evidence to suggest the pathogenicity of these mutations.
CONCLUSION: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

Matched MeSH terms: Genetic Association Studies/methods
Fulltext The rs9340799 polymorphism of the estrogen receptor alpha (ESR1) gene and its association with breast cancer susceptibility

Tan SC, Low TY, Mohamad Hanif EA, Sharzehan MAK, Kord-Varkaneh H, Islam MA

Sci Rep, 2021 Sep 20;11(1):18619.
PMID: 34545128 DOI: 10.1038/s41598-021-97935-8

The ESR1 rs9340799 polymorphism has been frequently investigated with regard to its association with breast cancer (BC) susceptibility, but the findings have been inconclusive. In this work, we aimed to address the inconsistencies in study findings by performing a systematic review and meta-analysis. Eligible studies were identified from the Web of Science, PubMed, Scopus, China National Knowledge Infrastructure, VIP and Wanfang databases based on the predefined inclusion and exclusion criteria. The pooled odds ratio (OR) was then calculated under five genetic models: homozygous (GG vs. AA), heterozygous (AG vs. AA), dominant (AG + GG vs. AA), recessive (GG vs. AA + AG) and allele (G vs. A). Combined results from 23 studies involving 34,721 subjects indicated a lack of significant association between the polymorphism and BC susceptibility (homozygous model, OR = 1.045, 95% CI 0.887-1.231, P = 0.601; heterozygous model, OR = 0.941, 95% CI 0.861-1.030, P = 0.186; dominant model, OR = 0.957, 95% CI 0.875-1.045, P = 0.327; recessive model, OR = 1.053, 95% CI 0.908-1.222, P = 0.495; allele model, OR = 0.987, 95% CI 0.919-1.059, P = 0.709). Subgroup analyses by ethnicity, menopausal status and study quality also revealed no statistically significant association (P > 0.05). In conclusion, our results showed that the ESR1 rs9340799 polymorphism was not associated with BC susceptibility, suggesting its limited potential as a genetic marker for BC.

Matched MeSH terms: Genetic Association Studies
Molecular Characterisation of α- and β-Thalassaemia among Indigenous Senoi Orang Asli Communities in Peninsular Malaysia

Koh DXR, Raja Sabudin RZA, Mohd Yusoff M, Hussin NH, Ahmad R, Othman A, et al.

Ann. Hum. Genet., 2017 Sep;81(5):205-212.
PMID: 28620953 DOI: 10.1111/ahg.12201

Thalassaemia is a public health problem in Malaysia, with each ethnic group having their own common mutations. However, there is a lack on data on the prevalence and common mutations among the indigenous people. This cross-sectional study was performed to determine the common mutations of α- and β-thalassaemia among the subethnic groups of Senoi, the largest Orang Asli group in Peninsular Malaysia. Blood samples collected from six Senoi subethnic groups were analysed for full blood count and haemoglobin analysis (HbAn). Samples with abnormal findings were then screened for α- and β-globin gene mutations. Out of the 752 samples collected, 255 showed abnormal HbAn results, and 122 cases showing abnormal red cell indices with normal HbAn findings were subjected to molecular screening. DNA analysis revealed a mixture of α- and β-globin gene mutations with 25 concomitant cases. The types of gene abnormalities detected for α-thalassaemia were termination codon (T>C) Hb CS (αCS α), Cd59 (G>A) haemoglobin Adana (Hb Adana) (αCd59 α), initiation codon (ATG>A-G) (αIniCd α), two-gene deletion (-SEA ), and single-gene 3.7-kb deletion (-α3.7 ). For β-thalassaemia, there were Cd26 (G>A) Hb E (βE ), Cd19 (A>G) Haemoglobin Malay (Hb Malay) (βCd19 ), and IVS 1-5 (G>C) (βIVS 1-5 ).

Matched MeSH terms: Genetic Association Studies
Fulltext Association of TNF-α G308A gene polymorphism in essential hypertensive patients without type 2 diabetes mellitus

Ghodsian N, Akhlaghi M, Ramachandran V, Heidari F, Haghvirdizadeh P, Eshkoor SA, et al.

Genet. Mol. Res., 2015 Dec 29;14(4):18974-9.
PMID: 26782547 DOI: 10.4238/2015.December.29.4

This study aims to investigate the effects of tumor necrosis factor alpha (TNF-α) G308A gene polymorphism on essential hypertension (EHT) with or without type 2 diabetes mellitus (T2DM). The project was conducted on buccal epithelial and blood cells for case and control patients, respectively. Epithelial cells were obtained from the inner part of the cheeks. Techniques including DNA extraction, polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLP) were utilized to assess biomarkers of DNA damage. Our results demonstrated significant differences between wild and mutated genotypes among EHT patients without T2DM. We also found a significant association between wild and mutated allele frequencies in EHT patients (P < 0.05). Clinical characteristics between the groups (EHT with or without T2DM and controls) showed statistically significant association (P < 0.05). Overall, we show that G308A polymorphism of the TNF-αgene may be a significant genetic risk factor for EHT without T2DM patients in Malaysia.

Matched MeSH terms: Genetic Association Studies
Fulltext The associations between VDR BsmI polymorphisms and risk of vitamin D deficiency, obesity and insulin resistance in adolescents residing in a tropical country

Rahmadhani R, Zaharan NL, Mohamed Z, Moy FM, Jalaludin MY

PLoS One, 2017;12(6):e0178695.
PMID: 28617856 DOI: 10.1371/journal.pone.0178695

BACKGROUND: The vitamin D receptor (VDR) gene is expressed abundantly in different tissues; including adipocytes and pancreatic beta cells. The rs1544410 or BsmI single nucleotide polymorphism (SNP) in the intronic region of the VDR gene has been previously associated with vitamin D levels, obesity and insulin resistance.
AIMS: This study was aimed to examine the association between BsmI polymorphism and risk of vitamin D deficiency, obesity and insulin resistance in adolescents living in a tropical country.
METHODS: Thirteen-year-old adolescents were recruited via multistage sampling from twenty-three randomly selected schools across the city of Kuala Lumpur, Malaysia (n = 941). Anthropometric measurements were obtained. Obesity was defined as body mass index higher than the 95th percentile of the WHO chart. Levels of fasting serum vitamin D (25-hydroxyvitamin D (25(OH)D)), glucose and insulin were measured. HOMA-IR was calculated as an indicator for insulin resistance. Genotyping was performed using the Sequenom MassARRAY platform (n = 807). The associations between BsmI and vitamin D, anthropometric parameters and HOMA-IR were examined using analysis of covariance and logistic regression.
RESULT: Those with AA genotype of BsmI had significantly lower levels of 25(OH)D (p = 0.001) compared to other genotypes. No significant differences was found across genotypes for obesity parameters. The AA genotype was associated with higher risk of vitamin D deficiency (p = 0.03) and insulin resistance (p = 0.03) compared to GG. The A allele was significantly associated with increased risk of vitamin D deficiency compared to G allele (adjusted odds ratio (OR) = 1.63 (95% Confidence Interval (CI) 1.03-2.59, p = 0.04). In those with concurrent vitamin D deficiency, having an A allele significantly increased their risk of having insulin resistance compared to G allele (adjusted OR = 2.66 (95% CI 1.36-5.19, p = 0.004).
CONCLUSION: VDR BsmI polymorphism was significantly associated with vitamin D deficiency and insulin resistance, but not with obesity in this population.

Matched MeSH terms: Genetic Association Studies
Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia

Sivalingam M, Looi ML, Zakaria SZ, Hamidah NH, Alias H, Latiff ZA, et al.

Int J Lab Hematol, 2012 Aug;34(4):377-82.
PMID: 22335963 DOI: 10.1111/j.1751-553X.2012.01405.x

INTRODUCTION: To study the ß-gene mutations spectrum, the genotype/phenotype correlation, the modulatory effect of co-inherited factors such as α-gene mutations and of Xmn1 polymorphism in a large cohort of Malaysian patients.
METHODS: A total of 264 cases clinically diagnosed as Thalassemia major (TM) (111), Thalassemia intermedia (21), HbE-β Thalassemia (131), and 1 HbE homozygous were studied. The detection of α and ß gene mutations and characterization of Xmn1 polymorphism were performed by multiplex PCR, amplification refractory mutation system (ARMS), DNA sequencing, and restriction fragment length polymorphism (RFLP)-PCR.
RESULTS: A total of 19 ß Thalassemia mutations were characterized. CD26 and CD41/42 were the most common found in the Malay and Chinese population, respectively. The sensitivity of the clinical diagnosis for β TM, thalassemia intermedia, and HbE/β thalassemia was 94.0%, 15.2%, and 89.2%, respectively. Patients with Xmn1 heterozygosity [+/-] required less frequent transfusion compared with those without the polymorphism. Co-inheritance of α-thalassemia alleviates the severity of HbE-β thalassemia in our cohort.
CONCLUSION: Molecular analysis should be used for a better diagnosis and management of β thalassemia.

Matched MeSH terms: Genetic Association Studies*
Association of TGFβ1 and SMAD4 variants in the etiology of keloid scar in the Malay population

Emami A, Halim AS, Salahshourifar I, Yussof SJ, Khoo TL, Kannan TP

Arch. Dermatol. Res., 2012 Sep;304(7):541-7.
PMID: 22805880 DOI: 10.1007/s00403-012-1262-0

Keloid is a complex condition with environmental and genetic risk-contributing factors. Two candidate genes, TGFβ1 and SMAD4, located in the same signaling pathway are highly expressed in the keloid fibroblast cells. In a case-control design, TGFβ1 haplotypes showed association with the risk of keloid in the present study. The CC haplotype, composed of both c.29C>T and -509T>C variants, was observed more frequently among cases (Corrected p = 0.037, OR = 2.07, 95 % CI = 0.87-4.93), showing a 4.5-fold increased risk for keloid. The AG genotype of the SMAD4 c.5131A>G variant showed a trend of significance (p = 0.0573, OR = 1.75, 95 % CI = 0.99-3.13). Taken together, either of these variants is most probably causative at the expression level or is in linkage disequilibrium with other causative variants in a complex pattern together with the environmental factors that contribute to the condition. To the best of our knowledge, there is only one documented report on a relationship between TGFβ1 and keloid with no association within the Caucasian population, while there have not been any reports for SMAD4. Therefore, the present study is likely the first research showing a significant association between TGFβ1 variants and keloids in the Malay population.

Matched MeSH terms: Genetic Association Studies
Fulltext The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis

Au A, Griffiths LR, Cheng KK, Wee Kooi C, Irene L, Keat Wei L

Sci Rep, 2015 Dec 15;5:18224.
PMID: 26666837 DOI: 10.1038/srep18224

Both OLR1 and PCSK9 genes are associated with atherosclerosis, cardiovascular disease and ischemic stroke. The overall prevalence of PCSK9 rs505151 and OLR1 rs11053646 variants in ischemic stroke were 0.005 and 0.116, respectively. However, to date, association between these polymorphisms and ischemic stroke remains inconclusive. Therefore, this first meta-analysis was carried out to clarify the presumed influence of these polymorphisms on ischemic stroke. All eligible case-control and cohort studies that met the search terms were retrieved in multiple databases. Demographic and genotyping data were extracted from each study, and the meta-analysis was performed using RevMan 5.3 and Metafor R 3.2.1. The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed- and random-effect models. Seven case-control studies encompassing 1897 cases and 2119 controls were critically evaluated. Pooled results from the genetic models indicated that OLR1 rs11053646 dominant (OR = 1.33, 95% CI:1.11-1.58) and co-dominant models (OR = 1.24, 95% CI:1.02-1.51) were significantly associated with ischemic stroke. For the PCSK9 rs505151 polymorphism, the OR of co-dominant model (OR = 1.36, 95% CI:1.01-1.58) was found to be higher among ischemic stroke patients. In conclusion, the current meta-analysis highlighted that variant allele of OLR1 rs11053646 G > C and PCSK9 rs505151 A > G may contribute to the susceptibility risk of ischemic stroke.

Matched MeSH terms: Genetic Association Studies*
A New Zealand platform to enable genetic investigation of adverse drug reactions

Maggo SD, Chua EW, Chin P, Cree S, Pearson J, Doogue M, et al.

N Z Med J, 2017 Dec 01;130(1466):62-69.
PMID: 29197902

A multitude of factors can affect drug response in individuals. It is now well established that variations in genes, especially those coding for drug metabolising enzymes, can alter the pharmacokinetic and/or pharmacodynamic profile of a drug, impacting on efficacy and often resulting in drug-induced toxicity. The UDRUGS study is an initiative from the Carney Centre for Pharmacogenomics to biobank DNA and store associated clinical data from patients who have suffered rare and/or serious adverse drug reactions (ADRs). The aim is to provide a genetic explanation of drug-induced ADRs using methods ranging from Sanger sequencing to whole exome and whole genome sequencing. Participants for the UDRUGS study are recruited from various sources, mainly via referral through clinicians working in Canterbury District Health Board, but also from district health boards across New Zealand. Participants have also self-referred to us from word-of-mouth communication between participants. We have recruited various ADRs across most drug classes. Where possible, we have conducted genetic analyses in single or a cohort of cases to identify known and novel genetic association(s) to offer an explanation to why the ADR occurred. Any genetic results relevant to the ADR are communicated back to the referring clinician and/or participant. In conclusion, we have developed a programme for studying the genetic basis of severe, rare or unusual ADR cases resulting from pharmacological treatment. Genomic analyses could eventually identify most genetic variants that predispose to ADRs, enabling a priori detection of such variants with high throughput DNA tests.

Matched MeSH terms: Genetic Association Studies/methods
Fulltext Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing

Drew AP, Zhu D, Kidambi A, Ly C, Tey S, Brewer MH, et al.

Mol Genet Genomic Med, 2015 Mar;3(2):143-54.
PMID: 25802885 DOI: 10.1002/mgg3.126

Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.

Matched MeSH terms: Genetic Association Studies
Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms

Kaur M, Blair J, Devkota B, Fortunato S, Clark D, Lawrence A, et al.

Am J Med Genet A, 2023 Aug;191(8):2113-2131.
PMID: 37377026 DOI: 10.1002/ajmg.a.63247

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Matched MeSH terms: Genetic Association Studies
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: Genetic Association Studies
Fulltext Key glycolytic branch influences mesocarp oil content in oil palm

Ruzlan N, Low YSJ, Win W, Azizah Musa N, Ong AL, Chew FT, et al.

Sci Rep, 2017 Aug 29;7(1):9626.
PMID: 28852058 DOI: 10.1038/s41598-017-10195-3

The fructose-1,6-bisphosphate aldolase catalyzed glycolysis branch that forms dihydroxyacetone phosphate and glyceraldehyde-3-phosphate was identified as a key driver of increased oil synthesis in oil palm and was validated in Saccharomyces cerevisiae. Reduction in triose phosphate isomerase (TPI) activity in a yeast knockdown mutant resulted in 19% increase in lipid content, while yeast strains overexpressing oil palm fructose-1,6-bisphosphate aldolase (EgFBA) and glycerol-3-phosphate dehydrogenase (EgG3PDH) showed increased lipid content by 16% and 21%, respectively. Genetic association analysis on oil palm SNPs of EgTPI SD_SNP_000035801 and EgGAPDH SD_SNP_000041011 showed that palms harboring homozygous GG in EgTPI and heterozygous AG in EgGAPDH exhibited higher mesocarp oil content based on dry weight. In addition, AG genotype of the SNP of EgG3PDH SD_SNP_000008411 was associated with higher mean mesocarp oil content, whereas GG genotype of the EgFBA SNP SD_SNP_000007765 was favourable. Additive effects were observed with a combination of favourable alleles in TPI and FBA in Nigerian x AVROS population (family F7) with highest allele frequency GG.GG being associated with a mean increase of 3.77% (p value = 2.3E-16) oil content over the Family 1. An analogous effect was observed in yeast, where overexpressed EgFBA in TPI - resulted in a 30% oil increment. These results provide insights into flux balances in glycolysis leading to higher yield in mesocarp oil-producing fruit.

Matched MeSH terms: Genetic Association Studies
Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey PJ, Nones K, et al.

J Pathol, 2015 Nov;237(3):363-78.
PMID: 26172396 DOI: 10.1002/path.4583

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.

Matched MeSH terms: Genetic Association Studies
Fulltext Association between PDCD1 gene polymorphisms and risk of systemic lupus erythematosus in three main ethnic groups of the Malaysian population

Chua KH, Lian LH, Sim XJ, Cheah TE, Lau TP

Int J Mol Sci, 2015;16(5):9794-803.
PMID: 25938972 DOI: 10.3390/ijms16059794

The programmed cell death 1 (PDCD1) gene encodes for the PD-1 (programmed death 1) molecule, which negatively regulates self-reactive T- and B-cells in the maintenance of peripheral tolerance. A previous report had shown the development of lupus-like phenotypes in PD-1-deficient C57BL/6 mice, was suggestive to the role of PDCD1 in predisposing to systemic lupus erythematosus (SLE). Hence, we aimed to investigate the association between PDCD1 and SLE susceptibility in the Malaysian population. A TaqMan-based real-time PCR was employed to screen for PD1.1, PD1.3, PD1.5 and PD1.6 in both SLE and healthy control groups of 200 samples each. The observed frequency for PD1.5C/C genotype was significantly higher in Indian SLE patients and Malay controls (p < 0.01). On the other hand, the PD1.5C/T genotype might predispose the Malays to SLE, but confer a protective effect among the Indians (p < 0.01). The PD1.1, PD1.3 and PD1.6 were, however, not correlated to genetic predisposition of SLE in our Malaysian population. In conclusion, PD1.5 variant was significantly associated to SLE susceptibility in our Malaysian cohort. Our failure in replicating the association between other investigated PDCD1 variants and risk of getting SLE might due to ethnic and geographic variations in the distribution of these genetic variants.

Matched MeSH terms: Genetic Association Studies*
Fulltext Candidate Gene Association Studies of Anthracycline-induced Cardiotoxicity: A Systematic Review and Meta-analysis

Leong SL, Chaiyakunapruk N, Lee SW

Sci Rep, 2017 02 27;7(1):39.
PMID: 28232737 DOI: 10.1038/s41598-017-00075-1

Anthracyclines play an important role in the management of patients with cancer but the development of anthracycline-induced cardiotoxicity (ACT) remains a significant concern for most clinicians. Recently, genetic approach has been used to identify patients at increased risk of ACT. This systematic review assessed the association between genomic markers and ACT. A systematic literature search was performed in Medline, PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, AMED, EMBASE and HuGE Navigator from inception until May 2016. Twenty-eight studies examining the association of genetic variants and ACT were identified. These studies examined 84 different genes and 147 single nucleotide polymorphisms. Meta-analyses showed 3 risk variants significantly increased the risk for ACT; namely ABCC2 rs8187710 (pooled odds ratio: 2.20; 95% CI: 1.36-3.54), CYBA rs4673 (1.55; 1.05-2.30) and RAC2 rs13058338 (1.79; 1.27-2.52). The current evidence remains unclear on the potential role of pharmacogenomic screening prior to anthracycline therapy. Further research is needed to improve the diagnostic and prognostic role in predicting ACT.

Matched MeSH terms: Genetic Association Studies*

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