Background: Metformin as an anti-hyperglycaemic drug is commonly used for the treatment of type 2 diabetes mellitus (T2DM). The metformin response is variable due to the interindividual variation of pharmacokinetics which is based on strong genetic background. MATE1 and MATE2 proteins are significantly implicated in the pharmacokinetics of metformin. Missense SNPs with high risk of pathogenicity are expected to affect response to metformin via pharmacokinetics. Therefore, the aim of the current study is to determine the effects of missense SNPs in the SLC47A1 and SLC47A2 genes. The structural and functional consequences of all known SLC47A1 and SLC47A2 missense SNPs of the human MATE1 and MATE2 proteins were identified by various bioinformatics methods (SIFT, PhD-SNP, PolyPhen-2, PROVEAN, PMut, MUpro, I-Mutant 3.0, COACH, RaptorX Binding, ConSurf, STRING). Results: The SLC47A1 variants P186T, L116P and the SLC47A2 variants I158N, L112P, V118G exhibited ΔΔG values less than − 1 kcal/mol, and these variants are considered to disrupt the structure and function of MATE1 and MATE2 proteins. SLC47A1 R118Q and SLC47A2 Y273C, V118G may significantly disturb protein function and transporting activities according to the analysis of ligand-binding regions. Conclusion: It is suggested that high-risk deleterious missense SNPs may mediate the pharmacokinetics of metformin and may be associated with altered tissue distribution, renal clearance and metformin toxicity. We suppose that our results might serve as potential targets for the studies composed of the development of potential diagnostic and therapeutic strategies based on the relationship between mutations and metformin response.

Alzheimer's disease is one of the most common causes of dementia and is a neurodegenerative disease that occurs with memory loss, loss of language, thinking and problem-solving skills. In this study, it was aimed to reveal the relationship between Alzheimer's disease and the variable number tandem repeat (VNTR) polymorphism in the aggrecan (ACAN) gene. Thus, it is thought that it will contribute to enlightenment about disease by contributing to the pathophysiology of Alzheimer's disease. A total of 203 people, including 102 patients diagnosed with Alzheimer's and 101 healthy individuals, were included in the study. Deoxyribonucleic acid (DNA) extraction was performed from the blood samples taken. The variable number tandem repeat (VNTR) polymorphism of the ACAN gene was determined using the Polymerase Chain Reaction (PCR) method. In our study, the 30 R, 31 R and 33 R alleles were the most repetitive alleles in patients and controls. 30 R, 31 R and shorter alleles were more common in patients than in the control group and were found to be statistically significant (p = 0.042). According to our results, 30 R and 31 R alleles of the VNTR polymorphism in the ACAN gene may be associated with Alzheimer's disease. In addition, having less than 30 repeat alleles increases the risk of the disease by 2,202 times. Our study is the first to investigate the relationship between ACAN gene VNTR polymorphism and Alzheimer's disease. Further studies are needed to definitively relate it.

Alzheimer's Disease (AD) is a multifactorial neurodegenerative disease and there is still no definitive treatment today. Early diagnosis of the disease is important, but there are almost no biomarkers that can be used in early diagnosis. The cerebrospinal fluid used in the diagnosis of the disease is not sufficient and is very difficult to obtain. Therefore, blood biomarkers that are less costly, less invasive, easily accessible, and can be used in long-term studies would be a better alternative. The aim of this study is to determine the relationship between Alzheimer's Disease and P301L MAPT gene mutation, homocysteine, folate and uric acid. 101 Alzheimer's patients and 101 healthy individuals were included in this study. Mutation analysis was performed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method with blood samples taken from the subjects. There was no significant difference between the patient and control groups in terms of homocysteine (p = 0.771), folate (p = 0.366) and uric acid (p = 0.860). When the genotypes were compared between the patient and control groups in terms of MAPT gene mutation (P301L), no statistically significant difference was detected (p = 0.081). There are very few studies in the literature investigating the relationship between Alzheimer's disease and P301L MAPT gene mutation. Additionally, there is no study investigating the relationship between Alzheimer's disease and homocysteine, folate, uric acid and P301L MAPT mutation in the Turkish population. We believe that this study has shed light on future studies.

Genetic variations in the human CYP2C9 and CYP2D6 genes may affect drug metabolism and lead to alterations in phenotypes. Genetic variations are associated

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease and pathologically characterized by the presence of neurofibrillary tangles (tau aggregation) and amyloid plaques (amyloid-beta (A𝛽) aggregation). PSEN1 protein with 9 transmembrane helices acts as aspartyl protease and is one of the catalytic components of γ secretase complex, that cleaves amyloid precursor protein (APP). Furthermore, PSEN1 protein plays a significant role in the process of APP and in the generation of amyloid beta (Aβ). In the present study, it was aimed to estimate the probable deleterious effects of missense SNPs in PSEN1 gene that is associated with AD on protein stability and structure by using bioinformatics tools. SIFT, PolyPhen-2, PROVEAN, PhD-SNP, and PANTHER PSEP software were used to estimate the deleterious SNPs, whereas I-Mutant 3.0 and MUpro web tools were used to determine the effects of amino acid substitution on protein stability. Additionally, the effects of wild type and mutant amino acids on protein three-dimensional structure via modeling were predicted by Project HOPE webserver. The phylogenetic conservation of amino acid residues of PSEN1 protein was analyzed by ConSurf. In total, 386 missense SNPs were found in the human PSEN1 gene from the National Center for Biotechnology Information Single Nucleotide Polymorphism (NCBI dbSNP) database and 65 SNPs of which were determined to be deleterious or damaging. In the present study, 8 significant missense SNPs- rs63749891 (R278T), rs63750301 (P264L), rs63750353 (N135D), rs63750524 (R278S), rs63750772 (E273A), rs63751229 (P267S), rs121917807 (G266S), and rs201617677 (R157S)- were determined as high-risk pathogenic. Some differences between wild-type amino acids and mutant amino acids such as hydrophobicity, charge, size, and folding properties were determined according to the modeling findings. Our study demonstrates that high-risk pathogenic missense SNPs have the potential to alter the catalytic activity of the γ secretase complex and subsequently the amount of Aβ40 and Aβ42. Therefore, these missense SNPs may contribute to AD pathogenesis studies. Alzheimer Hastalığı (AH), progresif nörodejeneratif hastalıktır ve patolojik olarak nörofibriler yumaklar (tau agregasyonu) ve amiloid plakların (amiloid beta (A𝛽) agregasyonu) varlığı ile karakterize edilir. 9 transmembran heliks içeren PSEN1 proteini, aspartil proteaz olarak işlev görmektedir ve amiloid öncü proteini (APP) parçalayan γ sekretaz kompleksinin katalitik bileşenlerinden biridir. Ayrıca, PSEN1 proteini APP sürecinde ve amiloid beta (A𝛽) oluşumunda önemli rol oynamaktadır. Bu çalışmada, AH ile ilişkili PSEN1 genindeki missense (yanlış anlamlı) SNP’lerin protein stabilitesi ve yapısı üzerindeki olası zararlı etkilerinin biyoinformatik araçlar kullanılarak tahmin edilmesi amaçlanmıştır. Zararlı SNP’lerin tahmin edilmesinde SIFT, PolyPhen-2, PROVEAN, PhD-SNP ve PANTHER PSEP yazılımları kullanılırken, amino asit değişiminin protein stabilitesi üzerindeki etkilerini belirlemek için I-Mutant 3.0 ve MUpro web araçları kullanıldı. Ek olarak, yabanıl tip ve mutant amino asitlerin proteinin üç boyutlu yapısı üzerindeki etkileri ise modelleme yoluyla Project HOPE programı ile tahmin edilmiştir. PSEN1 proteininin amino asit kalıntılarının filogenetik korunumu ConSurf ile analiz edildi. NCBI dbSNP veritabanında insan PSEN1 geninde toplam 386 missense SNP bulunduğu ve 65 SNP’nin ise zararlı veya zarar verici olduğu belirlendi. Bu çalışmada, 8 önemli missense SNP- rs63749891 (R278T), rs63750301 (P264L), rs63750353 (N135D), rs63750524 (R278S), rs63750772 (E273A), rs63751229 (P267S), rs121917807 (G266S), ve rs201617677 (R157S)- yüksekli riskli patojenik olarak belirlendi. Yabanıl tip ve mutant amino asitler arasındaki hidrofobiklik, yük, boyut ve katlanma özellikleri gibi bazı farklılıklar modelleme bulgularına göre belirlenmiştir. Çalışmamız, yüksek riskli patojenik missense SNP’lerin γ sekretaz kompleksinin katalitik aktivitesini ve akabinde Aβ40 ve Aβ42 miktarını değiştirme potansiyelinin olduğunu göstermektedir. Bu nedenle, bu missense SNP'ler, AH patogenez çalışmalarına katkı sağlayabilir.

Worldwide, approximately 10–15% of couples is affected by infertility and infertility is associated with disturbances in female and/or male reproductive systems. The aim of the current study is to ...