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Fulltext The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2

Pekar JE, Magee A, Parker E, Moshiri N, Izhikevich K, Havens JL, et al.

Science, 2022 Aug 26;377(6609):960-966.
PMID: 35881005 DOI: 10.1126/science.abp8337

Understanding the circumstances that lead to pandemics is important for their prevention. We analyzed the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted "A" and "B." Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October to 8 December), and the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans before November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

Matched MeSH terms: Genetic Variation
Fulltext Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel

Kountouris P, Stephanou C, Lederer CW, Traeger-Synodinos J, Bento C, Harteveld CL, et al.

Hum Mutat, 2022 Aug;43(8):1089-1096.
PMID: 34510646 DOI: 10.1002/humu.24280

Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, and HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.

Matched MeSH terms: Genetic Variation
Fulltext Geographical distribution and genetic diversity of Plasmodium vivax reticulocyte binding protein 1a correlates with patient antigenicity

Park JH, Kim MH, Sutanto E, Na SW, Kim MJ, Yeom JS, et al.

PLoS Negl Trop Dis, 2022 Jun;16(6):e0010492.
PMID: 35737709 DOI: 10.1371/journal.pntd.0010492

Plasmodium vivax is the most widespread cause of human malaria. Recent reports of drug resistant vivax malaria and the challenge of eradicating the dormant liver forms increase the importance of vaccine development against this relapsing disease. P. vivax reticulocyte binding protein 1a (PvRBP1a) is a potential vaccine candidate, which is involved in red cell tropism, a crucial step in the merozoite invasion of host reticulocytes. As part of the initial evaluation of the PvRBP1a vaccine candidate, we investigated its genetic diversity and antigenicity using geographically diverse clinical isolates. We analysed pvrbp1a genetic polymorphisms using 202 vivax clinical isolates from six countries. Pvrbp1a was separated into six regions based on specific domain features, sequence conserved/polymorphic regions, and the reticulocyte binding like (RBL) domains. In the fragmented gene sequence analysis, PvRBP1a region II (RII) and RIII (head and tail structure homolog, 152-625 aa.) showed extensive polymorphism caused by random point mutations. The haplotype network of these polymorphic regions was classified into three clusters that converged to independent populations. Antigenicity screening was performed using recombinant proteins PvRBP1a-N (157-560 aa.) and PvRBP1a-C (606-962 aa.), which contained head and tail structure region and sequence conserved region, respectively. Sensitivity against PvRBP1a-N (46.7%) was higher than PvRBP1a-C (17.8%). PvRBP1a-N was reported as a reticulocyte binding domain and this study identified a linear epitope with moderate antigenicity, thus an attractive domain for merozoite invasion-blocking vaccine development. However, our study highlights that a global PvRBP1a-based vaccine design needs to overcome several difficulties due to three distinct genotypes and low antigenicity levels.

Matched MeSH terms: Genetic Variation
Fulltext Psychosocial outcome and health behaviour intent of breast cancer patients with BRCA1/2 and PALB2 pathogenic variants unselected by a priori risk

Padmanabhan H, Hassan NT, Wong SW, Lee YQ, Lim J, Hasan SN, et al.

PLoS One, 2022;17(2):e0263675.
PMID: 35167615 DOI: 10.1371/journal.pone.0263675

There is an increasing number of cancer patients undertaking treatment-focused genetic testing despite not having a strong family history or high a priori risk of being carriers because of the decreasing cost of genetic testing and development of new therapies. There are limited studies on the psychosocial outcome of a positive result among breast cancer patients who are at low a priori risk, particularly in women of Asian descent. Breast cancer patients enrolled under the Malaysian Breast Cancer Genetic Study between October 2002 and February 2018 were tested for BRCA1, BRCA2 and PALB2 genes. All 104 carriers identified were invited by a research genetic counsellor for result disclosure. Of the 104 carriers, 64% (N = 66) had low a priori risk as determined by PENN II scores. Psychosocial, risk perception and health behaviour measures survey were conducted at baseline (pre-result disclosure), and at two to six weeks after result disclosure. At baseline, younger carriers with high a priori risk had higher Cancer Worry Scale scores than those with low a priori risk but all scores were within acceptable range. Around 75% and 55% of high a priori risk carriers as well as 80% and 67% of low a priori risk carriers had problems in the "living with cancer" and "children" psychosocial domains respectively. All carriers regardless of their a priori risk demonstrated an improved risk perception that also positively influenced their intent to undergo risk management procedures. This study has shown that with sufficient counselling and support, low a priori risk carriers are able to cope psychologically, have improved perceived risk and increased intent for positive health behaviour despite having less anticipation from a family history prior to knowing their germline carrier status.

Matched MeSH terms: Genetic Variation
Fulltext Comparative Phylogeography and Phylogeny of Pennah Croakers (Teleostei: Sciaenidae) in Southeast Asian Waters

Lim HC, Habib A, Chen WJ

Genes (Basel), 2021 11 29;12(12).
PMID: 34946874 DOI: 10.3390/genes12121926

A broad-scale comparative phylogeographic and phylogenetic study of pennah croakers, mainly Pennahia anea, P. macrocephalus, and P. ovata was conducted to elucidate the mechanisms that may have driven the diversification of marine organisms in Southeast Asian waters. A total of 316 individuals from the three species, and an additional eight and six individuals of P. argentata and P. pawak were employed in this study. Two genetically divergent lineages each of P. argentata and P. anea (lineages L1 and L2) were respectively detected from the analyses based on mitochondrial cytochrome b gene data. Historical biogeography analysis with a multi-gene dataset revealed that Pennahia species most likely originated in the South China Sea and expanded into the eastern Indian Ocean, East China Sea, and northwestern Pacific Ocean through three separate range expansions. The main diversifications of Pennahia species occurred during Miocene and Pliocene periods, and the occurrences of lineage divergences within P. anea and P. argentata were during the Pleistocene, likely as a consequence of cyclical glaciations. The population expansions that occurred after the sea level rise might be the reason for the population homogeneity observed in P. macrocephalus and most P. anea L2 South China Sea populations. The structure observed between the two populations of P. ovata, and the restricted distributions of P. anea lineage L1 and P. ovata in the eastern Indian Ocean, might have been hampered by the northward flowing ocean current at the Malacca Strait and by the distribution of coral reefs or rocky bottoms. While our results support S. Ekman's center-of-origin hypothesis taking place in the South China Sea, the Malacca Strait serving as the center of overlap is a supplementary postulation for explaining the present-day high diversity of pennah croakers centered in these waters.

Matched MeSH terms: Genetic Variation
Fulltext Emergence of B.1.524(G) SARS-CoV-2 in Malaysia during the third COVID-19 epidemic wave

Tan KK, Tan JY, Wong JE, Teoh BT, Tiong V, Abd-Jamil J, et al.

Sci Rep, 2021 11 11;11(1):22105.
PMID: 34764315 DOI: 10.1038/s41598-021-01223-4

The COVID-19 pandemic first emerged in Malaysia in Jan 2020. As of 12th Sept 2021, 1,979,698 COVID-19 cases that occurred over three major epidemic waves were confirmed. The virus contributing to the three epidemic waves has not been well-studied. We sequenced the genome of 22 SARS-CoV-2 strains detected in Malaysia during the second and the ongoing third wave of the COVID-19 epidemic. Detailed phylogenetic and genetic variation analyses of the SARS-CoV-2 isolate genomes were performed using these newly determined sequences and all other available sequences. Results from the analyses suggested multiple independent introductions of SARS-CoV-2 into Malaysia. A new B.1.524(G) lineage with S-D614G mutation was detected in Sabah, East Malaysia and Selangor, Peninsular Malaysia on 7th October 2020 and 14th October 2020, respectively. This new B.1.524(G) group was not the direct descendant of any of the previously detected lineages. The new B.1.524(G) carried a set of genetic variations, including A701V (position variant frequency = 0.0007) in Spike protein and a novel G114T mutation at the 5'UTR. The biological importance of the specific mutations remained unknown. The sequential appearance of the mutations, however, suggests that the spread of the new B.1.524(G) lineages likely begun in Sabah and then spread to Selangor. The findings presented here support the importance of SARS-CoV-2 full genome sequencing as a tool to establish an epidemiological link between cases or clusters of COVID-19 worldwide.

Matched MeSH terms: Genetic Variation
Shedding and Genetic Diversity of Leptospira spp. From Urban Stray Dogs in Klang Valley, Malaysia

Goh SH, Khor KH, Radzi R, Lau SF, Khairani-Bejo S, Abdul Rahman MS, et al.

Top Companion Anim Med, 2021 Nov;45:100562.
PMID: 34271178 DOI: 10.1016/j.tcam.2021.100562

Leptospirosis is an endemic zoonoses of global proportions. Stray dogs have been postulated to play a role in disease transmission; however, supporting information are still limited. Roaming behavior may not only predispose the dogs to infection, but could also contribute to disease spread. In this study, the susceptibility of urban stray dogs in shedding Leptospira spp. was determined. Blood, urine, and tissue samples of kidney and liver were collected from 100 dogs from 2 animal control facilities. Serological testing using microscopic agglutination test (MAT) were performed on blood against 20 leptospiral serovars with a cut-off titre of ≥ 1:100. Samples were cultured onto semi-solid Ellinghausen and McCullough modified by Johnson and Harris (EMJH) media. Isolates were identified using molecular polymerase chain reaction (PCR) using 2 primers (16s rRNA and LipL32) and hyperimmune serum (HIS) MAT. The seroprevalence for the dogs positive for leptospirosis was 32% (n=32/100) with the following detected serovars: Javanica (n=13), Bataviae (n=10), Icterohaemorrhagiae (n=3), Autumnalis (n=2), Canicola (n=1), Pyrogenes (n=1), Copenhageni (n=1), and Australis (n=1). Six Leptospira spp. isolated were procured from urine (n=2), kidney (n=2) and liver (n=2). All 6 isolates belonged to L. interrogans, a pathogenic variant of Leptospira spp. Serotyping and phylogenetic analysis suggested serovar Bataviae (n=5) and serovar Canicola (n=1). Presence of vaccinal serovars (Icterohaemorrhagiae and Canicola) suggested potential post-vaccination antibodies but the predominance of non-vaccinal serovars (Javanica and Bataviae) indicate the possibility of current infection or post-exposure. Isolation of Leptospira spp. directly from urine sample not only suggested an active infection but highlighted the potential shedding capability among these stray dogs. These findings further strengthen speculations that urban stray dogs could play a role in transmission and dissemination of leptospirosis through their constant movement. The urine of infected dogs may contaminate the environment, posing a major public health threat.

Matched MeSH terms: Genetic Variation
Fulltext The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies

Kountouris P, Stephanou C, Archer N, Bonifazi F, Giannuzzi V, Kuo KHM, et al.

Am J Hematol, 2021 Nov 01;96(11):E416-E420.
PMID: 34406671 DOI: 10.1002/ajh.26323
Matched MeSH terms: Genetic Variation
HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study

Md Pauzi SH, Masir N, Yahaya A, Mohammed F, Tizen Laim NMS, Mustangin M, et al.

Indian J Pathol Microbiol, 2021 10 22;64(4):677-682.
PMID: 34673585 DOI: 10.4103/IJPM.IJPM_983_20

Background: Human epidermal growth factor receptor 2 (HER2) over-expression in breast cancer is associated with aggressive tumor behavior and predicts response to targeted therapy. Accurate HER2 result is paramount for optimal patient management. However, routine HER2 immunohistochemistry (IHC) testing are subjected to intra- and inter-laboratory variability.
Objective: This study aims to determine inter-laboratory variation in HER2 IHC testing through a slide-exchange program between five main reference laboratories.
Method: A total of 20 breast carcinoma cases with different known HER2 expression and gene status were selected by the central laboratory in five testing rounds. Three unstained tissue sections from each case were sent to participating laboratories, which immunostained and interpreted the HER2 immunohistochemistry result. One of the stained slides was sent to one designated participating laboratory for evaluation. Results were analyzed by the central laboratory.
Results: A complete concordance was achieved in six IHC-positive and six IHC-negative cases, its gene status of which was confirmed by in-situ-hybridization (ISH) study. The discordant results were observed in six equivocal cases, one negative case and one positive case with a concordance rate of 50-88.3%. Interestingly, the negative discordant case actually displays tumor heterogeneity. Good inter-observer agreement was achieved for all participating laboratories (k = 0.713-1.0).
Conclusion: Standardization of HER2 testing method is important to achieve optimum inter-laboratory concordance. Discordant results were seen mainly in equivocal cases. Intra-tumoral heterogeneity may impact the final HER2 IHC scoring. The continuous quality evaluation is therefore paramount to achieve reliable HER2 results.

Matched MeSH terms: Genetic Variation
Fulltext High proportion of norovirus infection and predominance of GII.3 [P12] genotype among the children younger than 5 in Sabah, Malaysian Borneo

John JL, Mori D, Amit LN, Mosiun AK, Chin AZ, Ahmed K

J Clin Virol, 2021 10;143:104968.
PMID: 34509928 DOI: 10.1016/j.jcv.2021.104968

Globally, norovirus (NoV) has become one of the important causes of acute gastroenteritis (AGE) in children. It is responsible for death of children younger than 5 years in developing countries. Although there is limited information and the rate of child mortality caused by diarrhea is low in Malaysia, the burden of diarrhea is high, especially in Sabah. NoV GI, GII and GIV genogroups are known to infect humans, and GII.4 is the predominant genotype distributed worldwide. Better understanding of the etiology of NoV will help to inform policies for prevention and control. The aim of this study was to determine the burden and genotype distribution of NoV in children younger than 5 years with AGE who attended health-care facilities in Sabah, Malaysia. Diarrhea stool samples were collected from 299 children with AGE and NoV was detected by amplifying the capsid and RNA-dependent RNA polymerase gene and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Nucleotide sequencing of the amplicons was used for genotypes and phylogenetic analyses . NoV-positive stool samples were found in 17.7% (53/299) among which 13/53 (24.5%), 38/53 (71.7%), and 2/53 (3.8%) identified as NoV GI, GII and combination of GI and GII, respectively. The most common genotypes were GII.3 [P12] (80%) followed by GII.6 [P7] (13.3%), and GII.17 [P17] (6.7%). In the phylogenetic tree, all Sabahan NoV samples were shown to share ancestry with their respective genotype from predominantly East Asian countries and to some extent Australia and Europe. However, the Sabahan strains formed independent clusters with significant bootstrap values, indicating a clonal spread after the strains had entered Sabah.

Matched MeSH terms: Genetic Variation
Fulltext X-treme loss of sequence diversity linked to neo-X chromosomes in filarial nematodes

Mattick J, Libro S, Bromley R, Chaicumpa W, Chung M, Cook D, et al.

PLoS Negl Trop Dis, 2021 Oct;15(10):e0009838.
PMID: 34705823 DOI: 10.1371/journal.pntd.0009838

The sequence diversity of natural and laboratory populations of Brugia pahangi and Brugia malayi was assessed with Illumina resequencing followed by mapping in order to identify single nucleotide variants and insertions/deletions. In natural and laboratory Brugia populations, there is a lack of sequence diversity on chromosome X relative to the autosomes (πX/πA = 0.2), which is lower than the expected (πX/πA = 0.75). A reduction in diversity is also observed in other filarial nematodes with neo-X chromosome fusions in the genera Onchocerca and Wuchereria, but not those without neo-X chromosome fusions in the genera Loa and Dirofilaria. In the species with neo-X chromosome fusions, chromosome X is abnormally large, containing a third of the genetic material such that a sizable portion of the genome is lacking sequence diversity. Such profound differences in genetic diversity can be consequential, having been associated with drug resistance and adaptability, with the potential to affect filarial eradication.

Matched MeSH terms: Genetic Variation*
Fulltext Brown banded bamboo shark (Chiloscyllium punctatum) shows high genetic diversity and differentiation in Malaysian waters

Lim KC, Then AY, Wee AKS, Sade A, Rumpet R, Loh KH

Sci Rep, 2021 Jul 21;11(1):14874.
PMID: 34290296 DOI: 10.1038/s41598-021-94257-7

The demersal brown banded bamboo shark Chiloscyllium punctatum is a major component of sharks landed in Malaysia. However, little is known about their population structure and the effect of high fishing pressure on these weak swimming sharks. Both mitochondrial DNA control region (1072 bp) and NADH dehydrogenase subunit 2 (1044 bp) were used to elucidate the genetic structure and connectivity of C. punctatum among five major areas within the Sundaland region. Our findings revealed (i) strong genetic structure with little present day mixing between the major areas, (ii) high intra-population genetic diversity with unique haplotypes, (iii) significant correlation between genetic differentiation and geographical distance coupled with detectable presence of fine scale geographical barriers (i.e. the South China Sea), (iv) historical directional gene flow from the east coast of Peninsular Malaysia towards the west coast and Borneo, and (v) no detectable genetic differentiation along the coastline of east Peninsular Malaysia. Genetic patterns inferred from the mitochondrial DNA loci were consistent with the strong coastal shelf association in this species, the presence of contemporary barriers shaped by benthic features, and limited current-driven egg dispersal. Fine scale population structure of C. punctatum highlights the need to improve genetic understanding for fishery management and conservation of other small-sized sharks.

Matched MeSH terms: Genetic Variation/genetics*
Fulltext DNA fingerprinting, fixation-index (Fst), and admixture mapping of selected Bambara groundnut (Vigna subterranea [L.] Verdc.) accessions using ISSR markers system

Khan MMH, Rafii MY, Ramlee SI, Jusoh M, Al Mamun M, Halidu J

Sci Rep, 2021 Jul 15;11(1):14527.
PMID: 34267249 DOI: 10.1038/s41598-021-93867-5

As a new crop in Malaysia, forty-four Bambara groundnut (Vigna subterranea L. verdc.) genotypes were sampled from eleven distinct populations of different origins to explore the genetic structure, genetic inconsistency, and fixation index. The Bambara groundnut, an African underutilized legume, has the capacity to boost food and nutrition security while simultaneously addressing environmental sustainability, food availability, and economic inequalities. A set of 32 ISSRs were screened out of 96 primers based on very sharp, clear, and reproducible bands which detected a total of 510 loci with an average of 97.64% polymorphism. The average calculated value of PIC = 0.243, RP = 5.30, H = 0.285, and MI = 0.675 representing the efficiency of primer set for genetic differentiation among the genotypes. The ISSR primers revealed the number of alleles (Na = 1.97), the effective number of alleles (Ne = 1.38), Nei's genetic diversity (h = 0.248), and a moderate level of gene flow (Nm = 2.26) across the genotypes studied. The estimated Shannon's information index (I = 0.395) indicates a high level of genetic variation exists among the accessions. Based on Nei's genetic dissimilarity a UPMGA phylogenetic tree was constructed and grouped the entire genotypes into 3 major clusters and 6 subclusters. PCA analysis revealed that first principal component extracted maximum variation (PC1 = 13.92%) than second principal component (PC2 = 12.59%). Bayesian model-based STRUCTURE analysis assembled the genotypes into 3 (best ΔK = 3) genetic groups. The fixation-index (Fst) analysis narrated a very great genetic diversity (Fst = 0.19 to 0.40) exists within the accessions of these 3 clusters. This investigation specifies the effectiveness of the ISSR primers system for the molecular portrayal of V. subterranea genotypes that could be used for genetic diversity valuation, detection, and tagging of potential genotypes with quick, precise, and authentic measures for this crop improvement through effective breeding schemes.

Matched MeSH terms: Genetic Variation
Diversity and natural selection of Merozoite surface Protein-1 in three species of human malaria parasites: Contribution from South-East Asian isolates

Goh XT, Lim YAL, Lee PC, Nissapatorn V, Chua KH

Mol Biochem Parasitol, 2021 07;244:111390.
PMID: 34087264 DOI: 10.1016/j.molbiopara.2021.111390

The present study aimed to examine the genetic diversity of human malaria parasites (i.e., P. falciparum, P. vivax and P. knowlesi) in Malaysia and southern Thailand targeting the 19-kDa C-terminal region of Merozoite Surface Protein-1 (MSP-119). This region is essential for the recognition and invasion of erythrocytes and it is considered one of the leading candidates for asexual blood stage vaccines. However, the genetic data of MSP-119 among human malaria parasites in Malaysia is limited and there is also a need to update the current sequence diversity of this gene region among the Thailand isolates. In this study, genomic DNA was extracted from 384 microscopy-positive blood samples collected from patients who attended the hospitals or clinics in Malaysia and malaria clinics in Thailand from the year 2008 to 2016. The MSP-119 was amplified using PCR followed by bidirectional sequencing. DNA sequences identified in the present study were subjected to Median-joining network analysis with sequences of MSP-119 obtained from GenBank. DNA sequence analysis revealed that PfMSP-119 of Malaysian and Thailand isolates was not genetically conserved as high number of haplotypes were detected and positive selection was prevalent in PfMSP-119, hence questioning its suitability to be used as a vaccine candidate. A novel haplotype (Q/TNG/L) was also detected in Thailand P. falciparum isolate. In contrast, PvMSP-119 was highly conserved, however for the first time, a non-synonymous substitution (A1657S) was reported among Malaysian isolates. As for PkMSP-119, the presence of purifying selection and low nucleotide diversity indicated that it might be a potential vaccine target for P. knowlesi.

Matched MeSH terms: Genetic Variation
Fulltext Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Ting YW, Kong AS, Zain SM, Chan WK, Tan HL, Mohamed Z, et al.

Clin Mol Hepatol, 2021 Jul;27(3):486-498.
PMID: 33618508 DOI: 10.3350/cmh.2020.0162

BACKGROUND/AIMS: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.
METHODS: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.
RESULTS: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00-0.64; P=0.033 and HR, 0.01; 95% CI, 0.00-0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.
CONCLUSION: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

Matched MeSH terms: Genetic Variation
Fulltext Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R, et al.

Am J Hum Genet, 2021 Jul 01;108(7):1190-1203.
PMID: 34146516 DOI: 10.1016/j.ajhg.2021.05.013

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

Matched MeSH terms: Genetic Variation
Genetic diversity of the full length apical membrane antigen-1 of Plasmodium knowlesi clinical isolates from Peninsular Malaysia

Ng YL, Fong MY, Lau YL

Trop Biomed, 2021 Jun 01;38(2):159-164.
PMID: 34172705 DOI: 10.47665/tb.38.2.052

The Plasmodium knowlesi apical membrane antigen-1 (PkAMA-1) plays an important role in the invasion of the parasite into its host erythrocyte, and it has been regarded as a potential vaccine candidate against human knowlesi malaria. This study investigates genetic diversity and natural selection of the full length PkAMA-1 of P. knowlesi clinical isolates from Peninsular Malaysia. Blood samples were collected from P. knowlesi malaria patients from Peninsular Malaysia. The PkAMA-1 gene was amplified from DNA samples using PCR, cloned into a plasmid vector and sequenced. Results showed that nucleotide diversity of the full length PkAMA-1 from Peninsular Malaysia isolates (π: 0.006) was almost similar to that of Sarawak (π: 0.005) and Sabah (π: 0.004) isolates reported in other studies. Deeper analysis revealed Domain I (π: 0.007) in the PkAMA-1 had the highest diversity as compared to Domain II (π: 0.004) and Domain III (π: 0.003). Z-test indicated negative (purifying) selection of the gene. Combined alignment analysis at the amino acid level for the Peninsular Malaysia and Sarawak PkAMA-1 sequences revealed 34 polymorphic sites. Thirty-one of these sites were dimorphic, and 3 were trimorphic. The amino acid sequences could be categorised into 31 haplotypes. In the haplotype network, PkAMA-1 from Peninsular Malaysia and Sarawak were separated into two groups.

Matched MeSH terms: Genetic Variation*
Fulltext Genetic diversity of Coxsackievirus A21 associated with sporadic cases of acute respiratory infections in Malaysia

Supian NI, Ng KT, Chook JB, Takebe Y, Chan KG, Tee KK

BMC Infect Dis, 2021 May 17;21(1):446.
PMID: 34001016 DOI: 10.1186/s12879-021-06148-x

BACKGROUND: Coxsackievirus A21 (CVA21), a member of Enterovirus C from the Picornaviridae family, has been associated with respiratory illnesses in humans.
METHODS: A molecular epidemiological investigation of CVA21 was conducted among patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014 in Kuala Lumpur, Malaysia.
RESULTS: Epidemiological surveillance of acute respiratory infections (n = 3935) showed low-level detection of CVA21 (0.08%, 1.4 cases/year) in Kuala Lumpur, with no clear seasonal distribution. Phylogenetic analysis of the new complete genomes showed close relationship with CVA21 strains from China and the United States. Spatio-temporal mapping of the VP1 gene determined 2 major clusters circulating worldwide, with inter-country lineage migration and strain replacement occurring over time.
CONCLUSIONS: The study highlights the emerging role of CVA21 in causing sporadic acute respiratory outbreaks.

Matched MeSH terms: Genetic Variation*
Human tuberculosis and Mycobacterium tuberculosis complex: A review on genetic diversity, pathogenesis and omics approaches in host biomarkers discovery

Kanabalan RD, Lee LJ, Lee TY, Chong PP, Hassan L, Ismail R, et al.

Microbiol Res, 2021 May;246:126674.
PMID: 33549960 DOI: 10.1016/j.micres.2020.126674

Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. "Multi-omics" approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of "omics" approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of "omics" approaches in host biomarkers innovation and clinical implementation.

Matched MeSH terms: Genetic Variation
International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Lindgren AG, Braun RG, Juhl Majersik J, Clatworthy P, Mainali S, Derdeyn CP, et al.

Int J Stroke, 2021 Apr 26.
PMID: 33739214 DOI: 10.1177/17474930211007288

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Matched MeSH terms: Genetic Variation

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