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Global Disparities in Breast Cancer Genetics Testing, Counselling and Management

Yip CH, Evans DG, Agarwal G, Buccimazza I, Kwong A, Morant R, et al.

World J Surg, 2019 05;43(5):1264-1270.
PMID: 30610270 DOI: 10.1007/s00268-018-04897-6

Hereditary breast cancers, mainly due to BRCA1 and BRCA2 mutations, account for only 5-10% of this disease. The threshold for genetic testing is a 10% likelihood of detecting a mutation, as determined by validated models such as BOADICEA and Manchester Scoring System. A 90-95% reduction in breast cancer risk can be achieved with bilateral risk-reducing mastectomy in unaffected BRCA mutation carriers. In patients with BRCA-associated breast cancer, there is a 40% risk of contralateral breast cancer and hence risk-reducing contralateral mastectomy is recommended, which can be performed simultaneously with surgery for unilateral breast cancer. Other options for risk management include surveillance by mammogram and breast magnetic resonance imaging, and chemoprevention with hormonal agents. With the advent of next-generation sequencing and development of multigene panel testing, the cost and time taken for genetic testing have reduced, making it possible for treatment-focused genetic testing. There are also drugs such as the PARP inhibitors that specifically target the BRCA mutation. Risk management multidisciplinary clinics are designed to quantify risk, and offer advice on preventative strategies. However, such services are only possible in high-income settings. In low-resource settings, the prohibitive cost of testing and the lack of genetic counsellors are major barriers to setting up a breast cancer genetics service. Family history is often not well documented because of the stigma associated with cancer. Breast cancer genetics services remain an unmet need in low- and middle-income countries, where the priority is to optimise access to quality treatment.

Matched MeSH terms: Genes, BRCA1; Genes, BRCA2
Gene symbol: APC. Disease: colorectal cancer

Tan LP, Ng BK, Balraj P, Poh BH, Lim PK, Peh SC

Hum Genet, 2005 Dec;118(3-4):539-40.
PMID: 16521263
Matched MeSH terms: Genes, APC*
The nearly complete mitogenome of the Southeast Asian firefly Pteroptyx tener (Coleoptera: Lampyridae)

Cheng S, Mat-Isa MN, Sapian IS, Ishak SF

Mol Biol Rep, 2021 Feb;48(2):1281-1290.
PMID: 33582950 DOI: 10.1007/s11033-021-06189-0

The estuarine firefly, Pteroptyx tener, aggregates in the thousands in mangrove trees lining tidal rivers in Southeast Asia where they engage one another in a nocturnal, pre-mating ritual of synchronised courtship flashes. Unfortunately, populations of the species by virtue of being restricted to isolated estuarine rivers systems in the region, are at risk of genetic isolation. Because of this concern we undertook the task of sequencing and characterising the mitochondrial DNA genome of P. tener, as the first step towards helping us to characterise and better understand their genetic diversity. We sequenced and assembled the mitochondrial DNA genome of P. tener from two male and female specimens from the district of Kuala Selangor in Peninsular Malaysia and announce the molecules in this publication. We also reconstructed the phylogenetic trees of all available lampyrids mitogenomes and suggest the need to re-examine our current understanding of their classification which have largely been based on morphological data and the cox1 gene. Separately, our analysis of codon usage patterns among lampyrid mitogenomes showed that the codon usage in a majority of the protein-coding genes were non-neutral. Codon usage patterns between mitogenome sequences of P. tener were, however, largely neutral. Our findings demonstrate the usefulness of mitochondrial genes/mitogenomes for analysing both inter- and intra- specific variation in the Lampyridae to aid in species discovery in this highly variable genus; and elucidate the phylogenetic relationships of Pteroptyx spp. from the region.

Matched MeSH terms: Genes, Mitochondrial/genetics
Progress in gene therapy treatments for prostate cancer

Xue J, Chen K, Hu H, Gopinath SCB

Biotechnol Appl Biochem, 2021 May 14.
PMID: 33988271 DOI: 10.1002/bab.2193

Prostate cancer is one of the predominant cancers affecting men and has been widely reported. In the past, various therapies and drugs have been proposed to treat prostate cancer. Among these treatments, gene therapy has been considered to be an optimal and widely applicable treatment. Furthermore, due to the increased specificity of gene sequence complementation, the targeted delivery of complementary gene sequences may represent a useful treatment in certain instances. Various gene therapies, including tumor-suppressor gene therapy, suicide gene therapy, immunomodulation gene therapy and anti-oncogene therapies, have been established to treat a wide range of diseases, such as cardiac disease, cystic fibrosis, HIV/AIDS, diabetes, hemophilia, and cancers. To this end, several gene therapy clinical trials at various phases are underway. This overview describes the developments and progress in gene therapy, with a special focus being placed on prostate cancer.

Matched MeSH terms: Genes, Tumor Suppressor; Genes, Suppressor
Fulltext Co-application of a biosolids product and biochar to two coarse-textured pasture soils influenced microbial N cycling genes and potential for N leaching

Shanmugam S, Jenkins SN, Mickan BS, Jaafar NM, Mathes F, Solaiman ZM, et al.

Sci Rep, 2021 01 13;11(1):955.
PMID: 33441591 DOI: 10.1038/s41598-020-78843-9

Co-application of biochar and biosolids to soil has potential to mitigate N leaching due to physical and chemical properties of biochar. Changes in N cycling pathways in soil induced by co-application of biological amendments could further mitigate N loss, but this is largely unexplored. The aim of this study was to determine whether co-application of a biochar and a modified biosolids product to three pasture soils differing in texture could alter the relative abundance of N cycling genes in soil sown with subterranean clover. The biosolids product contained lime and clay and increased subterranean clover shoot biomass in parallel with increases in soil pH and soil nitrate. Its co-application with biochar similarly increased plant growth and soil pH with a marked reduction in nitrate in two coarse textured soils but not in a clayey soil. While application of the biosolids product altered in silico predicted N cycling functional genes, there was no additional change when applied to soil in combination with biochar. This supports the conclusion that co-application of the biochar and biosolids product used here has potential to mitigate loss of N in coarse textured soils due to N adsoption by the biochar and independently of microbial N pathways.

Matched MeSH terms: Genes, Microbial/genetics*
Integrative meta-analysis for the identification of hub genes in chemoresistant colorectal cancer

Abu N, Othman N, W Hon K, Nazarie WF, Jamal R

Biomark Med, 2020 05;14(7):525-537.
PMID: 32462912 DOI: 10.2217/bmm-2019-0241

Background: Finding a new target or a new drug to overcome chemoresistance is difficult due to the heterogenous nature of cancer. Meta-analysis was performed to combine the analysis of different microarray studies to get a robust discovery. Materials & methods: Herein, we analyzed three microarray datasets on combination of folinic acid, fluorouracil, and oxaliplatin drugs (FOLFOX) resistance that fit our inclusion/exclusion criteria and performed a meta-analysis using the OmiCC system. Results: We identified several deregulated genes and we discovered HNF4A as a hub gene. We performed functional validation and observed that by targeting HNF4A, HCT116 cells were more sensitive toward both oxaliplatin and 5-fluorouracil significantly. Conclusion: Our findings show that HNF4A could be a potential target in overcoming FOLFOX chemoresistance in colorectal cancer.

Matched MeSH terms: Genes, Neoplasm/genetics*
Fulltext Quantitative analysis of the expression of p53 gene in colorectal carcinoma by using real-time PCR

Bong I, Lim P, Balraj P, Sim Ui Hang E, Zakaria Z

Trop Biomed, 2006 Jun;23(1):53-9.
PMID: 17041552 MyJurnal

Colorectal carcinoma ranks third among ten leading causes of cancer in Malaysia. The colorectal carcinoma tumourigenesis involves the inactivation of tumour suppressor genes, and activation of proto-oncogenes. The p53 is one of the tumour suppressor genes that is involved in the colorectal carcinogenesis. The p53 gene is located on human chromosome 17p13.1 and comprises of 11 exons. Deficiencies in the p53 gene can cause the cancerous cells to spread to distant organs such as liver, lungs, lymph nodes, spine and bone. The most common p53 abnormalities that can lead to the metastasis of colorectal tumours are mutation and deregulation of the gene. In this study, nine colorectal carcinoma samples were used to establish a simple and sensitive strategy in the study on in vivo p53 expression by using realtime LightCycler SYBR Green I technology.

Matched MeSH terms: Genes, p53*
Fulltext Geographic origin and individual assignment of Shorea platyclados (Dipterocarpaceae) for forensic identification

Ng CH, Lee SL, Tnah LH, Ng KKS, Lee CT, Diway B, et al.

PLoS One, 2017;12(4):e0176158.
PMID: 28430826 DOI: 10.1371/journal.pone.0176158

The development of timber tracking methods based on genetic markers can provide scientific evidence to verify the origin of timber products and fulfill the growing requirement for sustainable forestry practices. In this study, the origin of an important Dark Red Meranti wood, Shorea platyclados, was studied by using the combination of seven chloroplast DNA and 15 short tandem repeats (STRs) markers. A total of 27 natural populations of S. platyclados were sampled throughout Malaysia to establish population level and individual level identification databases. A haplotype map was generated from chloroplast DNA sequencing for population identification, resulting in 29 multilocus haplotypes, based on 39 informative intraspecific variable sites. Subsequently, a DNA profiling database was developed from 15 STRs allowing for individual identification in Malaysia. Cluster analysis divided the 27 populations into two genetic clusters, corresponding to the region of Eastern and Western Malaysia. The conservativeness tests showed that the Malaysia database is conservative after removal of bias from population subdivision and sampling effects. Independent self-assignment tests correctly assigned individuals to the database in an overall 60.60-94.95% of cases for identified populations, and in 98.99-99.23% of cases for identified regions. Both the chloroplast DNA database and the STRs appear to be useful for tracking timber originating in Malaysia. Hence, this DNA-based method could serve as an effective addition tool to the existing forensic timber identification system for ensuring the sustainably management of this species into the future.

Matched MeSH terms: Genes, Plant*
Genetic analysis and identification of SSR markers associated with rice blast disease in a BC2F1 backcross population

Hasan N, Rafii MY, Abdul Rahim H, Nusaibah SA, Mazlan N, Abdullah S

Genet. Mol. Res., 2017 Jan 23;16(1).
PMID: 28128411 DOI: 10.4238/gmr16019280

Rice (Oryza sativa L.) blast disease is one of the most destructive rice diseases in the world. The fungal pathogen, Magnaporthe oryzae, is the causal agent of rice blast disease. Development of resistant cultivars is the most preferred method to achieve sustainable rice production. However, the effectiveness of resistant cultivars is hindered by the genetic plasticity of the pathogen genome. Therefore, information on genetic resistance and virulence stability are vital to increase our understanding of the molecular basis of blast disease resistance. The present study set out to elucidate the resistance pattern and identify potential simple sequence repeat markers linked with rice blast disease. A backcross population (BC2F1), derived from crossing MR264 and Pongsu Seribu 2 (PS2), was developed using marker-assisted backcross breeding. Twelve microsatellite markers carrying the blast resistance gene clearly demonstrated a polymorphic pattern between both parental lines. Among these, two markers, RM206 and RM5961, located on chromosome 11 exhibited the expected 1:1 testcross ratio in the BC2F1 population. The 195 BC2F1 plants inoculated against M. oryzae pathotype P7.2 showed a significantly different distribution in the backcrossed generation and followed Mendelian segregation based on a single-gene model. This indicates that blast resistance in PS2 is governed by a single dominant gene, which is linked to RM206 and RM5961 on chromosome 11. The findings presented in this study could be useful for future blast resistance studies in rice breeding programs.

Matched MeSH terms: Genes, Plant*
Comparison between Pork and wild Boar meat (Sus Scrofa ) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)

Sahilah Abu Mutalib, Wan Sakeenah Wan Nazari, Safiyyah Shahimi, Norhayati Yaakob, Norrakiah Abdullah Sani, Aminah Abdullah, et al.

Sains Malaysiana, 2012;41:199-204.

A method of PCR-restriction fragment length polymorphism (RFLP) has been utilized to differentiate the mitochondrial genes of pork and wild boar meat (Sus scrofa). The amplification PCR products of 359 bp and 531 bp were successfully amplified from the cyt b gene of these two meats. The amplification product of pork and wild boar using mt-12S rRNA gene successfully produced a single band with molecular size of 456 bp. Three restriction endonucleases (AluI, HindIII and BsaJI) were used to restrict the amplification products of the mitochondrial genes. The restriction enzymes of AluI and BsaJI were identified as potential restriction endonucleases to differentiate those meats. HindIII enzyme was unable to restrict the PCR product of both meats. The genetic differences within the cyt b gene among the two meats were successfully confirmed by PCR-RFLP analysis.

Matched MeSH terms: Genes, rRNA; Genes, Mitochondrial
Phylogeny of sea cucumber (Echinodermata: Holothuroidea) as inferred from 16S mitochondrial rRNa gene sequences

Kamarul Rahim Kamarudin, Ridzwan Hashim, Usup G

Sains Malaysiana, 2010;39:209-218.

This study aimed to determine phylogenetic relationship between and among selected species of sea cucumbers (Echinodermata: Holothuroidea) using 16S mitochondrial ribosomal RNA (rRNA) gene. Phylogenetic analyses of 37 partial sequences of 16S mitochondrial rRNA gene using three main methods namely neighbour joining (NJ), maximum parsimony (MP) and maximum likelihood (ML) showed the presence of five main genera of sea cucumbers: Molpadia from order Molpadiida and four genera of order Aspidochirotida namely Holothuria, Stichopus, Bohadschia and Actinopyga. All of the 17 species obtained from Malaysia distributed among the main genera except within Actinopyga. Interestingly, Holothuria excellens was out of Holothuria group causing Holothuria to be paraphyletic. High bootstrap value and consistent clustering made Molpadia, Stichopus, Bohadschia and Actinopyga monophyletic. The relationship of Actinopyga with the other genera was unclarified and Stichopus was sister to Molpadia. The latter finding caused the resolution at order level unclear. The pairwise genetic distance calculated using Kimura 2-parameter model further supported and verified findings from the phylogenetic trees. Further studies with more samples and different mitochondrial DNA genes need to be done to get a better view and verification on the molecular phylogeny of sea cucumbers.

Matched MeSH terms: Genes, rRNA; Genes, Mitochondrial
Fulltext MHC class I characterization of Indonesian cynomolgus macaques

Pendley CJ, Becker EA, Karl JA, Blasky AJ, Wiseman RW, Hughes AL, et al.

Immunogenetics, 2008 Jul;60(7):339-51.
PMID: 18504574 DOI: 10.1007/s00251-008-0292-4

Cynomolgus macaques (Macaca fascicularis) are quickly becoming a useful model for infectious disease and transplantation research. Even though cynomolgus macaques from different geographic regions are used for these studies, there has been limited characterization of full-length major histocompatibility complex (MHC) class I immunogenetics of distinct geographic populations. Here, we identified 48 MHC class I cDNA nucleotide sequences in eleven Indonesian cynomolgus macaques, including 41 novel Mafa-A and Mafa-B sequences. We found seven MHC class I sequences in Indonesian macaques that were identical to MHC class I sequences identified in Malaysian or Mauritian macaques. Sharing of nucleotide sequences between these geographically distinct populations is also consistent with the hypothesis that Indonesia was a source of the Mauritian macaque population. In addition, we found that the Indonesian cDNA sequence Mafa-B7601 is identical throughout its peptide binding domain to Mamu-B03, an allele that has been associated with control of Simian immunodeficiency virus (SIV) viremia in Indian rhesus macaques. Overall, a better understanding of the MHC class I alleles present in Indonesian cynomolgus macaques improves their value as a model for disease research, and it better defines the biogeography of cynomolgus macaques throughout Southeast Asia.

Matched MeSH terms: Genes, MHC Class I*
Mitogenome of gymnothorax minor and phylogenetic relationship with its congeners and related genera (anguilliformes: muraenidae)

Sze-Looi Song, Kar-Hoe Loh, Phaik-Eem Lim, Amy Yee-Hui Then, Hoi-Sen Yong, Praphathip Eamsobhana

Sains Malaysiana, 2018;47:2519-2531.

Gymnothorax minor is a moray eel of the family Muraenidae found in the Western Pacific Ocean. We report here
its complete mitogenome as determined by Illumina next-generation sequencing and the phylogenetic relationship
with its congeners and other taxa of the family Muraenidae. The whole mitogenome of G. minor had a total length
of 16,574 bp, comprising 37 genes - 13 protein-coding genes (PCGs), two ribosomal ribonucleic acid (rRNA) and 22
transfer ribonucleic acid (tRNA) genes - and a control region. Excepting cox1 with GTG, the other 12 PCGs had ATG
start codon. Seven of its PCGs had incomplete stop codon - five (nad2; cox1; cox2; nad3 and nad4) with T and two
(atp6 and cox3) with TA. Molecular phylogeny based on 13 PCGs was concordant with 15 mitochondrial genes (13 PCGs
and 2 rRNA genes). The subfamily Muraeninae as well as the subfamily Uropterygiinae were monophyletic. However,
the genus Gymnothorax was paraphyletic, with G. minor forming a sister group with Rhinomuraena quaesita in the
lineage containing also G. kidako and G. formosus forming a sister group with Enchelynassa canina. The phylogenetic
relationship of the genus Gymnothorax and related taxa of the family Muraenidae, based on the mitochondrial cob
gene, was in general similar to that based on 15 mt-genes. The mitogenome is useful for future studies on phylogenetics
and systematics of eels of the family Muraenidae and other taxa of the order Anguilliformes.

Matched MeSH terms: Genes, rRNA; Genes, Mitochondrial
Homeobox genes and tooth development: Understanding the biological pathways and applications in regenerative dental science

Ramanathan A, Srijaya TC, Sukumaran P, Zain RB, Abu Kasim NH

Arch Oral Biol, 2018 Jan;85:23-39.
PMID: 29031235 DOI: 10.1016/j.archoralbio.2017.09.033

OBJECTIVES: Homeobox genes are a group of conserved class of transcription factors that function as key regulators during the embryonic developmental processes. They act as master regulator for developmental genes, which involves coordinated actions of various auto and cross-regulatory mechanisms. In this review, we summarize the expression pattern of homeobox genes in relation to the tooth development and various signaling pathways or molecules contributing to the specific actions of these genes in the regulation of odontogenesis.
MATERIALS AND METHODS: An electronic search was undertaken using combination of keywords e.g. Homeobox genes, tooth development, dental diseases, stem cells, induced pluripotent stem cells, gene control region was used as search terms in PubMed and Web of Science and relevant full text articles and abstract were retrieved that were written in English. A manual hand search in text books were also carried out. Articles related to homeobox genes in dentistry and tissue engineering and regenerative medicine of odontogenesis were selected.
RESULTS: The possible perspective of stem cells technology in odontogenesis and subsequent analysis of gene correction pertaining to dental disorders through the possibility of induced pluripotent stem cells technology is also inferred.
CONCLUSIONS: We demonstrate the promising role of tissue engineering and regenerative medicine on odontogenesis, which can generate a new ray of hope in the field of dental science.

Matched MeSH terms: Genes, Homeobox/physiology*
Stability and expression of K-ras mimotopes in freeze-dried recombinant Lactococcus lactis NZ3900-fermented milk powder during storage in vacuum packaging

How YH, Teo MYM, In LLA, Yeo SK, Bhandari B, Yusof YA, et al.

J Appl Microbiol, 2024 Jul 02;135(7).
PMID: 38955370 DOI: 10.1093/jambio/lxae162

AIMS: This study aims to evaluate the storage stability of the freeze-dried recombinant Lactococcus lactis NZ3900-fermented milk powder expressing K-ras (Kristen rat sarcoma viral oncogene homolog) mimotopes targeting colorectal cancer in vacuum packaging.
METHODS AND RESULTS: The freeze-dried L. lactis-fermented milk powder stored in 4-ply retortable polypropylene (RCPP)-polyamide (PA)-aluminium (AL)-polyethylene terephthalate (PET) and aluminium polyethylene (ALPE) was evaluated throughout 49 days of accelerated storage (38°C and 90% relative humidity). The fermented milk powder stored in 4-ply packaging remained above 6 log10 CFU g-1 viability, displayed lower moisture content (6.1%), higher flowability (43° angle of repose), water solubility (62%), and survivability of L. lactis after simulated gastric and intestinal digestion (>82%) than ALPE packaging after 42 days of accelerated storage. K-ras mimotope expression was detected intracellularly and extracellularly in the freeze-dried L. lactis-fermented milk powder upon storage.
CONCLUSIONS: This suggests that fermented milk powder is a suitable food carrier for this live oral vaccine.

Matched MeSH terms: Genes, ras/genetics
Safety of Pregnancy After Breast Cancer in BRCA Mutation Carriers

Newman LA, Shippee Rockefeller E, Yip CH

JAMA Surg, 2024 May 01;159(5):482-483.
PMID: 38536201 DOI: 10.1001/jamasurg.2024.0005
Matched MeSH terms: Genes, BRCA1; Genes, BRCA2
Fulltext An integration of phenotypic and transcriptomic data analysis reveals yield-related hub genes in Jatropha curcas inflorescence

Govender N, Senan S, Sage EE, Mohamed-Hussein ZA, Mackeen MM, Wickneswari R

PLoS One, 2018;13(9):e0203441.
PMID: 30240391 DOI: 10.1371/journal.pone.0203441

Jatropha curcas is an oil-rich seed crop with huge potentials for bioenergy production. The inflorescence carries a number of processes that are likely to affect the overall yield potentials; floral development, male-to-female flower ratio, floral abscission and fruit set. In this study, a weighted gene co-expression network analysis which integrates the transcriptome, physical and simple sugar data of J. curcas inflorescence was performed and nine modules were identified by means of hierarchical clustering. Among them, four modules (green4, antiquewhite2, brown2 and lightskyblue4) showed significant correlation to yield factors at p≤0.01. The four modules are categorized into two clusters; cluster 1 of green4 and antiquewhite2 modules correspond to number of flowers/inflorescence, total seed weight/plant, number of seeds/plant, and number of fruits/plant, whereas cluster 2 of brown2 and lightskyblue4 modules correspond to glucose and fructose. Descriptive characterizations of cluster 1 show putative involvement in gibberellin signaling and responses, whereas cluster 2 may have been involved in sugar signaling, signal transductions and regulation of flowerings. Our findings present a list of hub genes for J. curcas yield improvement and reproductive biology enhancement strategies.

Matched MeSH terms: Genes, Plant/physiology*
Specific detection of the Old World screwworm fly, Chrysomya bezziana, in bulk fly trap catches using real-time PCR

Jarrett S, Morgan JA, Wlodek BM, Brown GW, Urech R, Green PE, et al.

Med Vet Entomol, 2010 Sep;24(3):227-35.
PMID: 20497318 DOI: 10.1111/j.1365-2915.2010.00867.x

The Old World screwworm fly (OWS), Chrysomya bezziana Villeneuve (Diptera: Calliphoridae), is a myiasis-causing blowfly of major concern for both animals and humans. Surveillance traps are used in several countries for early detection of incursions and to monitor control strategies. Examination of surveillance trap catches is time-consuming and is complicated by the presence of morphologically similar flies that are difficult to differentiate from Ch. bezziana, especially when the condition of specimens is poor. A molecular-based method to confirm or refute the presence of Ch. bezziana in trap catches would greatly simplify monitoring programmes. A species-specific real-time polymerase chain reaction (PCR) assay was designed to target the ribosomal DNA internal transcribed spacer 1 (rDNA ITS1) of Ch. bezziana. The assay uses both species-specific primers and an OWS-specific Taqman((R)) MGB probe. Specificity was confirmed against morphologically similar and related Chrysomya and Cochliomyia species. An optimal extraction protocol was developed to process trap catches of up to 1000 flies and the assay is sensitive enough to detect one Ch. bezziana in a sample of 1000 non-target species. Blind testing of 29 trap catches from Australia and Malaysia detected Ch. bezziana with 100% accuracy. The probability of detecting OWS in a trap catch of 50 000 flies when the OWS population prevalence is low (one in 1000 flies) is 63.6% for one extraction. For three extractions (3000 flies), the probability of detection increases to 95.5%. The real-time PCR assay, used in conjunction with morphology, will greatly increase screening capabilities in surveillance areas where OWS prevalence is low.

Matched MeSH terms: Genes, Insect/genetics
Possible polyphyletic origin of major histocompatibility complex class I chain-related gene A (MICA) alleles

Choy MK, Phipps ME

J Mol Evol, 2003 Jul;57(1):38-43.
PMID: 12962304

Phylogenetic relationships among 23 nonhuman primate (NHP) major histocompatibility complex class I chain-related gene (MIC) sequences, 54 confirmed human MICA alleles, and 16 human MICE alleles were constructed with methods of sequence analysis. Topology of the phylogenetic tree showed separation between NHP MICs and human MICs. For human MICs, the topology indicated monophyly for the MICB alleles, while MICA alleles were separated into two lineages, LI and LII. Of these, LI MICA alleles shared a common ancestry with gorilla (Ggo) MIC. One conservative amino acid difference and two nonconservative amino acid differences in the alpha3 domain were found between the MICA lineages. The nonconservative amino acid differences might imply structural and functional differences. Transmembrane (TM) trinucleotide-repeat variants were found to be specific to the MICA lineages such as A4, A9, and A10 to LI and A5 to LII. Variants such as A5.1 and A6 were commonly found in both MICA lineages. Based on these analyses, we postulate a polyphyletic origin for MICA alleles and their division into two lineages, LI and LII. As such, there would be 30 alleles in LI and 24 alleles in LII, thereby reducing the current level of polymorphism that exists, based on a presumed monophyletic origin. The lower degree of polymorphism in MICA would then be in line with the rest of the human major histocompatibility complex nonclassical class I genes.

Matched MeSH terms: Genes, MHC Class I*
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: Genes, MHC Class II*

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