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Macrolide resistance and genotypic characterization of Streptococcus pneumoniae in Asian countries: a study of the Asian Network for Surveillance of Resistant Pathogens (ANSORP)

Song JH, Chang HH, Suh JY, Ko KS, Jung SI, Oh WS, et al.

J Antimicrob Chemother, 2004 Mar;53(3):457-63.
PMID: 14963068

To characterize mechanisms of macrolide resistance among Streptococcus pneumoniae from 10 Asian countries during 1998-2001.

Matched MeSH terms: Alleles
Molecular and morphological approaches in discrimination of endangered Probarbus jullieni of Malaysia and Thailand stocks

Bhassu S, Abd Rashid Z

Genetika, 2009 Sep;45(9):1244-9.
PMID: 19824545

The population structure of Probarbus jullieni from Malaysia and Thailand stocks was based on seven microsatellite primers and truss network measurements. Truss morphometric measurements were made on Temoleh, Probarbus jullieni to demonstrate the degree of speciation that can be induced by both biotic and abiotic conditions and contribute to the definition of different stocks of Probarbus sp. At the momment no relevant information on stock definition has been produced recently concerning Probarbus spp., which is now in IUCN threatened red list. We also summarize the possible discriminant morphological characteristics that shows differentiation between Malaysia and Thailand stocks. We also compare the levels of morphology and genetic differences for Malaysian stocks throughout one year of sampling to determine whether sampling season and possible sexual dimorphism can be detected in this fishes. A total of 25 different alleles were found across the two populations by the seven microsatellites, of which 21 and 19 alleles were detected in Pahang, Malaysia and Thailand, respectively At the population level, the mean number of alleles of Pahang (3.4991) per locus was higher than that (3.1665) of Thailand. From both molecular and morphometric measurements showed that there were two distinct populations. However the differences between these two populations showed that they belong to the same species with least degree of separation

Matched MeSH terms: Alleles*
Genetic diversity analysis among collected purslane (Portulaca oleracea L.) accessions using ISSR markers

Alam MA, Juraimi AS, Rafii MY, Hamid AA, Arolu IW, Abdul Latif M

C. R. Biol., 2015 Jan;338(1):1-11.
PMID: 25468001 DOI: 10.1016/j.crvi.2014.10.007

Genetic diversity and relationships among 45 collected purslane accessions were evaluated using ISSR markers. The 28 primers gave a total of 167 bands, among which 163 were polymorphic (97.6%). The genetic diversity as estimated by Shannon's information index was 0.513, revealing a quite high level of genetic diversity in the germplasm. The average number of observed allele, effective allele, expected heterozygosity, polymorphic information content (PIC) and Nei's index were 5.96, 1.59, 0.43, 0.35 and 0.35, respectively. The UPGMA dendrogram based on Nei's genetic distance grouped the whole germplasm into 7 distinct clusters. The analysis of molecular variance (AMOVA) revealed that 89% of total variation occurred within population, while 11% were found among populations. Based on the constructed dendrogram using ISSR markers those accessions that are far from each other by virtue of genetic origin and diversity index (like Ac1 and Ac42; Ac19 and Ac45; Ac9 and Ac23; Ac18 and A25; Ac24 and Ac18) are strongly recommended to select as parent for future breeding program to develop high yielding and stress tolerant purslane variety in contribution to global food security.

Matched MeSH terms: Alleles
Fulltext A Novel Occulta-Type Spina Bifida Mediated by Murine Double Heterozygotes EphA2 and EphA4 Receptor Tyrosine Kinases

Abdullah NL, Mohd-Zin SW, Ahmad-Annuar A, Abdul-Aziz NM

Front Cell Dev Biol, 2017;5:105.
PMID: 29312933 DOI: 10.3389/fcell.2017.00105

Members of the Eph receptor tyrosine kinase have previously been implicated in cranial neural tube development. Failure of neural tube closure leads to the devastating conditions known as anencephaly and spina bifida. EphA2 and EphA4 are expressed at the tips of the closing spinal neural folds prior and during neural tube closure. We investigated the possible role of murine EphA2 and EphA4 during the last step of primary neural tube closure, which is adhesion and fusion. The individual mouse knockouts of EphA2 and EphA4 per se do not exhibit neural tube defects (NTDs). The embryos generated by the crossing of double heterozygotes Epha2tm1Jrui/+Epha4rb-2J/+ displayed NTDs with a wide degree of severity including close exencephaly and close spina bifida (spina bifida occulta). Interestingly, mutants displaying NTDs had skin covering the underlying lesion. The tissue sections revealed the elevated neural folds had not adhered and fused. The phenotypes seen in Epha2tm1Jrui/+Epha4rb-2J/+ double heterozygous embryos suggest both genes play a compensatory role with each other in the adhesion and fusion of the neural tube. In this study, there exists a >50% penetrance of NTDs in the mouse mutants, which genetically have a single allele each of EphA2 and EphA4 absent.

Matched MeSH terms: Alleles
Identification of the genomic mutation in Epha4(rb-2J/rb-2J) mice

Mohd-Zin SW, Abdullah NL, Abdullah A, Greene ND, Cheah PS, Ling KH, et al.

Genome, 2016 Jul;59(7):439-48.
PMID: 27373307 DOI: 10.1139/gen-2015-0142

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4(rb-2J/rb-2J), is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or "hopping gait" phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4(rb-2J) corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4(rb-2J) allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein-protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.

Matched MeSH terms: Alleles
Nematode control failure due to anthelmintic resistance in a sheep farm in Malaysia: First identification of the F200Y mutation in the isotype 1 β-tubulin gene

Khadijah S, Wahaf ANS, Syahmi MI, Tan TK, Low VL, Azrul LM, et al.

Trop Biomed, 2018 Dec 01;35(4):999-1006.
PMID: 33601847

This paper reports total nematode anthelmintic resistance towards albendazole, fenbendazole, levamisole and ivermectin in a commercial sheep farm located in Terengganu, Malaysia. Faecal Egg Count Reduction Test (FECRT) was conducted on 25 sheep, where five sheep in each group were treated with the respective four anthelmintics based on live bodyweight. The balance of five sheep placed in the control group were not treated with any anthelmintics. At day 13 post-treatment, faecal egg count was conducted and nematode worm egg count reduction percentage was calculated to determine the resistance status towards the respective anthelmintics tested. Results showed that nematodes were resistant to all the anthelmintics tested, namely albendazole, fenbendazole, levamisole and ivermectin with reduction percentage of 87%, 46%, 94% and 68%, respectively. Subsequently, the third stage larvae of Haemonchus contortus and Trichostrongylus colubriformis recovered from post-treatment faecal cultures were subjected to allele-specific polymerase chain reaction (AS-PCR) assay to determine the presence of the benzimidazole resistance gene. This study reports the occurrence of the classical F200Y mutation in the isotype 1 βtubulin gene, for the first time in Malaysia.

Matched MeSH terms: Alleles
Malignant glioma: the involvement of loss of allelic heterozygosity and PTEN mutations in a group of Malay patients

Zainuddin N, Jaafar H, Isa MN, Abdullah JM

Southeast Asian J. Trop. Med. Public Health, 2005 May;36(3):748-56.
PMID: 16124450

Frequent loss of heterozygosity (LOH) and mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) have been found in sporadic gliomas. The most documented regions of allelic losses include 9p21, 10q23-25 and 17p1 3 whereas PTEN aberrations are preferentially found in glioblastoma multiformes. This research aimed to detect the incidence of allelic losses on chromosomes 10q, 9p, 17p and 13q and mutations on exons 5, 6 and 8 of PTEN in malignant gliomas. Malignant glioma specimens obtained were classified histopathologically according to the WHO criteria. Each tumor was then subjected to polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis. Twelve of 23 (52%) malignant glioma cases showed allelic losses whereas 7 of 23 (30%) samples showed aberrant band patterns and mutations of PTEN. Four of these cases showed LOH in 10q23 and mutations of PTEN. The data on LOH indicated the involvement of different genes in the genesis of glioma whereas mutations of PTEN indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.

Matched MeSH terms: Alleles
Fulltext Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

Joyce-Tan SM, Zain SM, Abdul Sattar MZ, Abdullah NA

J Diabetes Res, 2016;2016:2161376.
PMID: 26682227 DOI: 10.1155/2016/2161376

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Matched MeSH terms: Alleles
Fulltext Genetic Diversity of Plasmodium falciparum Populations in Malaria Declining Areas of Sabah, East Malaysia

Mohd Abd Razak MR, Sastu UR, Norahmad NA, Abdul-Karim A, Muhammad A, Muniandy PK, et al.

PLoS One, 2016;11(3):e0152415.
PMID: 27023787 DOI: 10.1371/journal.pone.0152415

Malaysia has a national goal to eliminate malaria by 2020. Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets. This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah. Malaria active case detection was conducted in Kalabakan and Kota Marudu. All individuals in the study sites were screened for malaria infection by rapid diagnostic test. Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction. Genotyping was performed using merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2), glutamate rich protein (GLURP) and 10 neutral microsatellite loci markers. The size of alleles, multiplicity of infection (MOI), mean number of alleles (Na), expected heterozygosity (He), linkage disequilibrium (LD) and genetic differentiation (FST) were determined. In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively. The GLURP genotype VI (751-800 bp) was predominant. The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively. The Na per microsatellite locus was 1.70. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively. In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively. The GLURP genotype IV (651-700 bp) was predominant. The MOI for both MSP-1 and MSP-2 was 1.05. The Na per microsatellite locus was 3.60. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively. A significant LD was observed in Kalabakan (0.495, p<0.01) and Kota Marudu P. falciparum populations (0.601, p<0.01). High genetic differentiation between Kalabakan and Kota Marudu P. falciparum populations was observed (FST = 0.532). The genetic data from the present study highlighted the limited diversity and contrasting genetic pattern of P. falciparum populations in the malaria declining areas of Sabah.

Matched MeSH terms: Alleles
Detection of β-globin Gene Mutations Among β-thalassaemia Carriers and Patients in Malaysia: Application of Multiplex Amplification Refractory Mutation System-Polymerase Chain Reaction

Hassan S, Ahmad R, Zakaria Z, Zulkafli Z, Abdullah WZ

Malays J Med Sci, 2013 Jan;20(1):13-20.
PMID: 23613656

β-thalassaemia is one of the most common single-gene disorders worldwide. Each ethnic population has its own common mutations, accounting for the majority of cases, with a small number of mutations for the rarer alleles. Due to the heterogeneity of β-thalassaemia and the multi-ethnicity of Malaysians, molecular diagnostics may be expensive and time consuming.

Matched MeSH terms: Alleles
Fulltext Lack of Association between the Serotonin Transporter (5-HTT) and Serotonin Receptor (5-HT2A) Gene Polymorphisms with Smoking Behavior among Malaysian Malays

Rozak NI, Ahmad I, Gan SH, Abu Bakar R

Sci Pharm, 2014 07 18;82(3):631-42.
PMID: 25853073 DOI: 10.3797/scipharm.1406-01

An insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and a polymorphism (rs6313) in the serotonin 2A receptor gene (5-HT2A) have previously been linked to smoking behavior. The objective of this study was to determine the possible association of the 5-HTTLPR and 5-HT2A gene polymorphisms with smoking behavior within a population of Malaysian male smokers (n=248) and non-smokers (n=248). The 5-HTTLPR genotypes were determined using the polymerase chain reaction (PCR) and were classified as short (S) alleles or long (L) alleles. The 5HT2A genotypes were determined using PCR-restriction fragment length polymorphisms (PCR-RFLP). No significant differences in the distribution frequencies of the alleles were found between the smokers and the non-smokers for the 5-HTTLPR polymorphism (x(2) = 0.72, P>0.05) or the 5HT2A polymorphism (x(2) = 0.73, P>0.05). This is the first study conducted on Malaysian Malay males regarding the association of 5-HTTLPR and 5HT2A polymorphisms and smoking behavior. However, the genes were not found to be associated with smoking behavior in our population.

Matched MeSH terms: Alleles
Fulltext High producing tumor necrosis factor alpha gene alleles in protection against severe manifestations of dengue

Sam SS, Teoh BT, Chinna K, AbuBakar S

Int J Med Sci, 2015;12(2):177-86.
PMID: 25589894 DOI: 10.7150/ijms.8988

Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-α gene polymorphisms and dengue severity was investigated.
METHODS: A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-α genes were genotyped using PCR-RFLP and PCR-sequencing methods.
RESULTS: A protective association of TNF-α -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-α -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-α -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3'UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study.
CONCLUSION: The overall findings of the study support the correlation of high-producer TNF-α genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.
KEYWORDS: Infectious disease; cytokine; dengue; genetics; polymorphism.; tropical

Matched MeSH terms: Alleles
Fulltext The angiotensin converting enzyme (ACE) I/D gene polymorphism in Malaysian well trained athletes

Hazwani Ahmad Yusof, Rabinderjeet Singh, Zainuddin Zafarina, Kieron Rooney, Ahmad Munir Che Muhamed

Jurnal Sains Sukan & Pendidikan Jasmani, 2014;3(1):20-33.
MyJurnal

The purpose of this study was to examine the effect of the ACE I/D gene polymorphism on athletic status and physical performance of well-trained Malaysian athletes. The distribution of ACE I/D gene polymorphism among 180 well trained athletes was compared with 180 sedentary controls. 20 meter Yo-Yo intermittent recovery and leg strength tests were used to measure maximal oxygen consumption (VO2max) and leg strength value of athletes with different ACE I/D genotype, respectively. Chi-Square and one way ANOVA tests were used for data analysis. The II and DD genotype were more prevalent among the endurance athletes and the strength/ power athletes compared to the other groups, respectively (p=0.00). The VO2max was not significantly associated with ACE genotype in athlete (p=0.828). However, athletes with the DD genotype had recorded a greater result for leg strength (113.8 ± 36.2) than those with the II (96.2 ± 28.0) and the ID (112.2 ± 33.5) genotype (p=0.047). This study supports the notion that ACE I/D gene polymorphism might be a genetic factor associated with athletic status and strength performance among the Malaysian population. Future studies with more representation of endurance athletes might able to detect the association between I allele and endurance performance.

Matched MeSH terms: Alleles
Fulltext A brief review on ACE I/D gene polymorphism and blood pressure response to exercise training

Hazwani Ahmad Yusof, Abdul Rashid Aziz, Nor Farah Mohamad Fauzi, Ahmad Munir Che Muhamed

Malaysian Journal of Medicine and Health Sciences, 2018;14(201):179-189.
MyJurnal

Exercise has been suggested as the best and the most affordable way for managing blood pressure. The insertion/ deletion of angiotensin I-converting enzyme (ACE) I/D gene polymorphism had been reported to be linked with sev- eral diseases such as hypertension and diabetic nephropathy. Several studies showed that blood pressure response to exercise training for health management also vary among individuals with different genotypes of ACE I/D gene poly- morphism. A study of 9 months of endurance exercise training at 75 to 85 % of VO2max showed that the decrease of resting blood pressure in I allele carriers wass greater than D allele carriers. In contrast, other study discovered that adult women with D allele had greater reduction in resting blood pressure than those with I allele, following a 12-week combined aerobic and resistance exercise training. Despite the inconsistencies of some findings, it has remained unknown if the ACE I/D gene polymorphism would also influence blood pressure response to isometric handgrip training that had been found to be superior to the dynamic resistance exercise training in controlling and preventing high blood pressure. Thus, this article was to review the literature on ACE I/D gene polymorphism and blood pressure response to exercise training that could serve as the basis for future research to identify individuals who will lower resting blood pressure the most with exercise training program for health management.

Matched MeSH terms: Alleles
Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Tey S, Shahrizaila N, Drew AP, Samulong S, Goh KJ, Battaloglu E, et al.

Neurogenetics, 2019 08;20(3):117-127.
PMID: 31011849 DOI: 10.1007/s10048-019-00576-3

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.

Matched MeSH terms: Alleles
P450 (Cytochrome) Oxidoreductase Gene (POR) Common Variant (POR*28) Significantly Alters CYP2C9 Activity in Swedish, But Not in Korean Healthy Subjects

Hatta FH, Aklillu E

OMICS, 2015 Dec;19(12):777-81.
PMID: 26669712 DOI: 10.1089/omi.2015.0159

CYP2C9 enzyme contributes to the metabolism of several pharmaceuticals and xenobiotics and yet displays large person-to-person and interethnic variation. Understanding the mechanisms of CYP2C9 variation is thus of immense importance for personalized medicine and rational therapeutics. A genetic variant of P450 (cytochrome) oxidoreductase (POR), a CYP450 redox partner, is reported to influence CYP2C9 metabolic activity in vitro. We investigated the impact of a common variant, POR*28, on CYP2C9 metabolic activity in humans. 148 healthy Swedish and 146 healthy Korean volunteers were genotyped for known CYP2C9 defective variant alleles (CYP2C9*2, *3). The CYP2C9 phenotype was determined using a single oral dose of 50 mg losartan. Excluding oral contraceptive (OC) users and carriers of 2C9*2 and *3 alleles, 117 Korean and 65 Swedish were genotyped for POR*5, *13 and *28 using Taqman assays. The urinary losartan to its metabolite E-3174 metabolic ratio (MR) was used as an index of CYP2C9 metabolic activity. The allele frequency of the POR*28 variant allele in Swedes and Koreans was 29% and 44%, respectively. POR*5 and *13 were absent in both study populations. Considering the CYP2C9*1/*1 genotypes only, the CYP2C9 metabolic activity was 1.40-fold higher in carriers of POR*28 allele than non-carriers among Swedes (p = 0.02). By contrast, no influence of the POR*28 on CYP2C9 activity was found in Koreans (p = 0.68). The multivariate analysis showed that ethnicity, POR genotype, and smoking were strong predictors of CYP2C9 MR (p < 0.05). This is the first report to implicate the importance of POR*28 genetic variation for CYP2C9 metabolic activity in humans. These findings contribute to current efforts for global personalized medicine and using medicines by taking into account pharmacogenetic and phenotypic variations.

Matched MeSH terms: Alleles
Fulltext Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children

Dashti M, Nizam R, Jacob S, Al-Kandari H, Al Ozairi E, Thanaraj TA, et al.

Front Immunol, 2023;14:1238269.
PMID: 37638053 DOI: 10.3389/fimmu.2023.1238269

Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB1*03:01:01, DQA1*05:01:01, and DQB1*02:01:01, which conferred high risk, and DRB1*11:04:01, DQA1*05:05:01, and DQB1*03:01:01, which were protective. The DRB1*03:01:01~DQA1*05:01:01~DQB1*02:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB1*11:04-DQA1*05:05-DQB1*03:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.

Matched MeSH terms: Alleles
Fulltext GWAS signals revisited using human knockouts

Maddirevula S, AlZahrani F, Anazi S, Almureikhi M, Ben-Omran T, Abdel-Salam GMH, et al.

Genet Med, 2018 01;20(1):64-68.
PMID: 28640246 DOI: 10.1038/gim.2017.78

PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.

Matched MeSH terms: Alleles
Fulltext Expanding the phenome and variome of skeletal dysplasia

Maddirevula S, Alsahli S, Alhabeeb L, Patel N, Alzahrani F, Shamseldin HE, et al.

Genet Med, 2018 12;20(12):1609-1616.
PMID: 29620724 DOI: 10.1038/gim.2018.50

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.
METHODS: Detailed phenotyping and next-generation sequencing (panel and exome).
RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.
CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Matched MeSH terms: Alleles
Fulltext HLA-DRB1*04 as a Risk Allele to Systemic Lupus Erythematosus and Lupus Nephritis in the Malay Population of Malaysia

Selvaraja M, Chin VK, Abdullah M, Arip M, Amin-Nordin S

Front Med (Lausanne), 2020;7:598665.
PMID: 33644084 DOI: 10.3389/fmed.2020.598665

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease afflicting multiple organs. Lupus nephritis (LN) is a serious complication of SLE and remains a major cause of mortality and morbidity. Curative therapy remains unavailable as etiology from genetic and environmental factors is still unclear. The present study was conducted to elucidate the link between HLA-DRB1 gene polymorphisms with SLE and LN through clinical and laboratory/biological presentations in a population of Malaysian Malay females with SLE. A total of 100 Malay female SLE patients inclusive of 70 SLE patients without LN and 30 patients with LN were included in this study. HLA-DRB1 allele examination in SLE patients was performed using PCR-SSO, and the alleles' frequencies were compared with 951 publicly available datasets representing Malay healthy controls in Malaysia. Cytokines and free radical levels were detected by ELISA and bead-based multiplexed Luminex assays. The association between HLA-DRB1 alleles with clinical and serological manifestations and immune mediators was analyzed using different statistical approaches whenever applicable. Our study showed that HLA-DRB1*0405, HLA-DRB1*1502, and HLA-DRB1*1602 were associated with the increased risk of SLE while HLA-DRB1*1201 and HLADRB1*1202 alleles were associated with a lower risk of SLE development. Furthermore, HLA-DRB1*04 showed significant association to LN and arthritis while HLA-DRB1*15 was significantly associated with oral ulcer in Malay SLE patients. Association analysis of HLA-DRB1*04 with clinical and biological factors revealed that HLA-DRB1*04 was significantly associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-nuclear antibody (ANA), C-reactive protein (CRP) in the blood, and total protein in the urine. SLE carriers with the HLA-DRB1*04 allele were significantly correlated to the increased levels of cytokines (IFN-y, GM-CSF, IL-17F, IL-18, IL-21, and VEGF) and were significantly showing negative correlation to IL-5 and free radicals (LPO and catalase enzyme) levels compared to SLE carriers without HLA-DRB1*04 allele. The results suggested that disease severity in SLE may be determined by HLA-DRB1 alleles. The risk of HLA-DRB1*04 allele with LN was supported by the demonstration of an intense inflammatory response in Malay SLE patients in Malaysia. More studies inclusive of a larger and multiple SLE cohorts in the future are warranted to validate these findings.

Matched MeSH terms: Alleles

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