No Association between Single Nucleotide Polymorphisms (SNPs) of the Interferon-Induced Transmembrane Protein 3 (IFITM3) Gene and the Susceptibility of Alzheimer’s Disease (AD)

Background and Objectives: Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) in the brain. A recent study reported that the interferon-induced transmembrane protein 3 (IFITM3) protein plays a pivotal role in Aβ processing by the γ-secretase complex. Since several single nucleotide polymorphisms (SNPs) of the IFITM3 gene are related to the function and expression levels of the IFITM3 gene, the relationship between genetic polymorphisms in the IFITM3 gene and susceptibility to AD needs to be investigated. Materials and Methods: We investigated the genotype and allele frequencies of IFITM3 polymorphisms in 177 AD patients and 233 matched healthy controls by amplicon sequencing. In addition, we compared the genotype, allele and haplotype frequencies between AD patients and matched controls and performed an association analysis. Results: There were no significant differences in the genotype, allele or haplotype frequency distributions of the IFITM3 polymorphisms between AD patients and matched controls. Conclusions: To the best of our knowledge, this is the first case-control association study of the IFITM3 gene in AD.

Allele Diversity, Haplotype Frequency and Diversity, and Forensic Genotyping of Fulanis and Yorubas Population in North Central Region of Nigeria

Nigeria is the most populous African nation, comprising over 250 ethnic groups. The Yoruba and Fulani are the second and fourth largest ethnic groups in Nigeria, respectively. Forensic genotyping of short tandem repeats (STRs) is used in computation of Combined DNA Index System databases of individuals and ethnic groups. We examined allele diversity, haplotype frequency, haplotype diversity, and forensic genotyping data of autosomal STRs in Fulani and Yoruba residents in Ilorin, Kwara State, North Central Nigeria, in-order to further provide forensic genotyping data of these ethnic groups. Samples of 25 Fulani males and 23 Yoruba males whose ethnicity was confirmed by three generations (paternal and maternal) were collected with informed consent using purposive sampling. All individuals in the samples were unrelated. The samples were amplified and then genotyped using the SureID® 21G PCR Amplification Kit containing Amelogenin and 20 autosomal STR loci. Statistical analyses of forensic genotyping parameters confirmed no deviation from expectation of Hardy-Weinberg Equilibrium and no dependence of alleles between loci. All tested loci were polymorphic. Expected Heterozygosity and gene diversity parameters showed lower genetic diversity amongst Fulanis compared to Yorubas. This is possibly due to the prevalent custom of marriage between cousins amongst Fulanis, which is forbidden in Yoruba customs.

Regulatory Single Nucleotide Polymorphism of the Bovine IFITM3 Gene Induces Differential Transcriptional Capacities of Hanwoo and Holstein Cattle

Interferon-induced transmembrane protein 3 (IFITM3), a crucial effector of the host’s innate immune system, prohibits an extensive range of viruses. Previous studies have reported that single nucleotide polymorphisms (SNPs) of the IFITM3 gene are associated with the expression level and length of the IFITM3 protein and can impact susceptibility to infectious viruses and the severity of infection with these viruses. However, there have been no studies on polymorphisms of the bovine IFITM3 gene. In the present study, we finely mapped the bovine IFITM3 gene and annotated the identified polymorphisms. We investigated polymorphisms of the bovine IFITM3 gene in 108 Hanwoo and 113 Holstein cattle using direct sequencing and analyzed genotype, allele, and haplotype frequencies and linkage disequilibrium (LD) between the IFITM3 genes of the two cattle breeds. In addition, we analyzed transcription factor-binding sites and transcriptional capacity using PROMO and luciferase assays, respectively. Furthermore, we analyzed the effect of a nonsynonymous SNP of the IFITM3 gene using PolyPhen-2, PANTHER, and PROVEAN. We identified 23 polymorphisms in the bovine IFITM3 gene and found significantly different genotype, allele, and haplotype frequency distributions and LD scores between polymorphisms of the bovine IFITM3 gene in Hanwoo and Holstein cattle. In addition, the ability to bind the transcription factor Nkx2-1 and transcriptional capacities were significantly different depending on the c.-193T > C allele. Furthermore, nonsynonymous SNP (F121L) was predicted to be benign. To the best of our knowledge, this is the first genetic study of bovine IFITM3 polymorphisms.

Spatiotemporal Dynamic of the RTS,S/AS01 Malaria Vaccine Target Antigens in Senegal

The RTS,S/AS01 malaria vaccine confers only moderate protection against malaria. Evidence suggests that the effectiveness of the RTS,S/AS01 vaccine depends upon the parasite population genetics, specifically regarding the circumsporozoite protein haplotypes in the population. We investigated Plasmodium falciparum circumsporozoite protein (PfCSP) gene sequences from two endemic sites in 2018 in Senegal. The PfCSP sequences were compared with those retrieved from the Pf3k genome database. In the central repeat region of PfCSP, the distribution of haplotypes differed significantly between the two study sites (Fisher’s exact test, P < 0.001). No 3D7 vaccine strain haplotype was observed in this locus. In the C-terminal region, there was no significant difference in haplotypes distribution between Kedougou and Diourbel (Fischer’s exact test, P = 0.122). The 3D7 haplotype frequency was 8.4% in early samples (2001–2011), but then it contracted in the subsequent years. The extensive plasticity of the P. falciparum genes coding the RTS,S/AS01 vaccine target antigens may influence the immune responses to circulating alleles. Monitoring the genetic diversity baseline and its dynamics over time and space would be instrumental in rationally improving the malaria RTS,S/AS01 vaccine and/or its implementation schedule.

Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching

The EuroTransplant Kidney Allocation System (ETKAS) aims at allocating organs to patients on the waiting list fairly whilst optimizing HLA match grades. ETKAS currently considers the number of HLA-A, -B, -DR mismatches. Evidently, epitope matching is biologically and clinically more relevant. We here executed ETKAS-based computer simulations to evaluate the impact of epitope matching on allocation and compared the strategies. A virtual population of 400,000 individuals was generated using the National Marrow Donor Program (NMDP) haplotype frequency dataset of 2011. Using this population, a waiting list of 10,400 patients was constructed and maintained during simulation, matching the 2015 Eurotransplant Annual Report characteristics. Unacceptable antigens were assigned randomly relative to their frequency using HLAMatchmaker. Over 22,600 kidneys were allocated in 10 years in triplicate using Markov Chain Monte Carlo simulations on 32-CPU-core cloud-computing instances. T-cell epitopes were calculated using the www.pirche.com portal. Waiting list effects were evaluated against ETKAS for five epitope matching scenarios. Baseline simulations of ETKAS slightly overestimated reported average HLA match grades. The best balanced scenario maintained prioritisation of HLA A-B-DR fully matched donors while replacing the HLA match grade by PIRCHE-II score and exchanging the HLA mismatch probability (MMP) by epitope MMP. This setup showed no considerable impact on kidney exchange rates and waiting time. PIRCHE-II scores improved, whereas the average HLA match grade diminishes slightly, yet leading to an improved estimated graft survival. We conclude that epitope-based matching in deceased donor kidney allocation is feasible while maintaining equal balances on the waiting list.

X-chromosomal STR based genetic polymorphisms and demographic history of Sri Lankan ethnicities and their relationship with global populations

A new 16 X-short tandem repeat (STR) multiplex PCR system has recently been developed for Sr Lankans, though its applicability in evolutionary genetics and forensic investigations has not been thoroughly assessed. In this study, 838 unrelated individuals covering all four major ethnic groups (Sinhalese, Sri Lankan Tamils, Indian Tamils and Moors) in Sri Lanka were successfully genotyped using this new multiplex system. The results indicated a high forensic efficiency for the tested loci in all four ethnicities confirming its suitability for forensic applications of Sri Lankans. Allele frequency distribution of Indian Tamils showed subtle but statistically significant differences from those of Sinhalese and Moors, in contrast to frequency distributions previously reported for autosomal STR alleles. This suggest a sex biased demographic history among Sri Lankans requiring a separate X-STR allele frequency database for Indian Tamils. Substantial differences observed in the patterns of LD among the four groups demand the use of a separate haplotype frequency databases for each individual ethnicity. When analysed together with other 14 world populations, all Sri Lankan ethnicities except Indian Tamils clustered closely with populations from Indian Bhil tribe, Bangladesh and Europe reflecting their shared Indo-Aryan ancestry.