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12 pages, 728 KiB

Open AccessArticle

Association between Polymorphism rs61876744 in PNPLA2 Gene and Keratoconus in a Saudi Cohort

by Altaf A. Kondkar, Taif A. Azad, Tahira Sultan, Tanvir Khatlani, Abdulaziz A. Alshehri, Glenn P. Lobo, Hatem Kalantan, Saleh A. Al-Obeidan and Abdulrahman M. Al-Muammar

Genes 2023, 14(12), 2108; https://doi.org/10.3390/genes14122108 - 21 Nov 2023

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Abstract

The genetic etiology of Keratoconus (KC) in Middle Eastern Arabs of Saudi origin is still unclear. A recent genome-wide study identified two significant loci in the region of PNPLA2 (rs61876744) and CSNK1E (rs138380) for KC that may be associated with KC in the [...] Read more.

The genetic etiology of Keratoconus (KC) in Middle Eastern Arabs of Saudi origin is still unclear. A recent genome-wide study identified two significant loci in the region of PNPLA2 (rs61876744) and CSNK1E (rs138380) for KC that may be associated with KC in the Saudi population. In addition, polymorphisms in the apolipoprotein E (APOE) gene, namely, rs429358 and rs7412, responsible for APOE allelic variants ε2, ε3, and ε4, may influence KC via oxidative stress mechanism(s). Thus, we investigated the possible association of polymorphisms rs61876744, rs138380, rs429358, rs7412, and APOE genotypes in KC patients of the Saudi population. This study included 98 KC cases and 167 controls. Polymorphisms rs6187644 and rs138380 were genotyped using TaqMan assays, and rs429358 and rs7412 were genotyped via Sanger sequencing. Although the allele frequency of rs61876744(T) in PNPLA2 was a protective effect against KC (odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44–0.93), the p-value (p = 0.020) was not significant for multiple testing correction (p = 0.05/4 = 0.015). However, rs6187644 genotype showed a modestly significant protective effect in the dominant model (OR = 0.53, 95% CI = 0.32–0.88, p = 0.013). Polymorphisms rs138380, rs429358, and rs7412 showed no significant allelic or genotype association with KC. However, the ε2-carriers (ε2/ε2 and ε2/ε3 genotypes) exhibited a greater than 5-fold increased risk of KC, albeit non-significantly (p = 0.055). Regression analysis showed no significant effect of age, gender, and the four polymorphisms on KC. Our results suggest that polymorphism rs6187644 in PNPLA2 might be associated with KC in the Middle Eastern Arabs of Saudi origin but warrant a large-scale association analysis at this locus. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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21 pages, 6562 KiB

Open AccessArticle

Analysis of Epidemiological Factors and SNP rs3804100 of TLR2 for COVID-19 in a Cohort of Professionals Who Worked in the First Pandemic Wave in Belém-PA, Brazil

by Marcos Jessé Abrahão Silva, Caroliny Soares Silva, Rebecca Lobato Marinho, Jeanne Gonçalves Cabral, Ellen Polyana da Costa Gurrão, Pabllo Antonny Silva dos Santos, Samir Mansour Moraes Casseb, Karla Valéria Batista Lima and Luana Nepomuceno Gondim Costa Lima

Genes 2023, 14(10), 1907; https://doi.org/10.3390/genes14101907 - 05 Oct 2023

Cited by 2 | Viewed by 1261

Abstract

COVID-19 is an infectious disease caused by coronavirus 2 of the severe acute syndrome (SARS-CoV-2). Single nucleotide polymorphisms (SNPs) in genes, such as TLR2, responsible for an effective human immune response, can change the course of infection. The objective of this article [...] Read more.

COVID-19 is an infectious disease caused by coronavirus 2 of the severe acute syndrome (SARS-CoV-2). Single nucleotide polymorphisms (SNPs) in genes, such as TLR2, responsible for an effective human immune response, can change the course of infection. The objective of this article was to verify associations between epidemiological factors and TLR2 SNP rs3804100 (Thymine [T] > Cytosine [C]) in professionals from Health Institutions (HI) who worked during the first pandemic wave and COVID-19. A case-control study was conducted with Belém-PA HI workers (Northern Brazil), divided into symptomatology groups (Asymptomatic-AS; n = 91; and Symptomatic-SI; n = 123); and severity groups classified by Chest Computerized Tomography data (symptomatic with pulmonary involvement—SCP; n = 35; symptomatic without pulmonary involvement—SSP; n = 8). Genotyping was performed by Sanger sequencing, and Statistical Analysis was conducted through the SPSS program. Bioinformatics servers predicted the biological functions of the TLR2 SNP. There were associations between the presence of comorbidities and poor prognosis of COVID-19 (especially between symptomatology and severity of COVID-19 and overweight and obesity) and between the sickness in family members and kinship (related to blood relatives). The homozygous recessive (C/C) genotype was not found, and the frequency of the mutant allele (C) was less than 10% in the cohort. No significant associations were found for this SNP in this cohort. The presence of SNP was indicated to be benign and causes a decrease in the stability of the TLR2 protein. These data can help the scientific community and medicine find new forms of COVID-19 containment. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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17 pages, 1266 KiB

Open AccessArticle

Non-Random Enrichment of Single-Nucleotide Polymorphisms Associated with Clopidogrel Resistance within Risk Loci Linked to the Severity of Underlying Cardiovascular Diseases: The Role of Admixture

by Mariangeli Monero-Paredes, Roberto Feliu-Maldonado, Kelvin Carrasquillo-Carrion, Pablo Gonzalez, Igor B. Rogozin, Abiel Roche-Lima and Jorge Duconge

Genes 2023, 14(9), 1813; https://doi.org/10.3390/genes14091813 - 17 Sep 2023

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Abstract

Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, [...] Read more.

Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, the non-random enrichment of single-nucleotide polymorphisms (SNPs) associated with clopidogrel resistance within risk loci linked to underlying CVDs, and the role of admixture, have yet to be tested. This study aimed to assess the possible interaction between genetic biomarkers linked to CVDs and those associated with clopidogrel resistance among admixed Caribbean Hispanics. We identified 50 SNPs significantly associated with CVDs in previous genome-wide association studies (GWASs). These SNPs were combined with another ten SNPs related to clopidogrel resistance in Caribbean Hispanics. We developed Python scripts to determine whether SNPs related to CVDs are in close proximity to those associated with the clopidogrel response. The average and individual local ancestry (LAI) within each locus were inferred, and 60 random SNPs with their corresponding LAIs were generated for enrichment estimation purposes. Our results showed no CVD-linked SNPs in close proximity to those associated with the clopidogrel response among Caribbean Hispanics. Consequently, no genetic loci with a dual predictive role for the risk of CVD severity and clopidogrel resistance were found in this population. Native American ancestry was the most enriched within the risk loci linked to CVDs in this population. The non-random enrichment of disease susceptibility loci with drug-response SNPs is a new frontier in Precision Medicine that needs further attention. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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13 pages, 321 KiB

Open AccessArticle

Association of PCSK1 and PPARG1 Allelic Variants with Obesity and Metabolic Syndrome in Mexican Adults

by Jorge Velazquez-Roman, Uriel A. Angulo-Zamudio, Nidia Leon-Sicairos, Hector Flores-Villaseñor, Miriam Benitez-Baez, Ana Espinoza-Salomón, Alejandra Karam-León, Hugo Villamil-Ramírez, Samuel Canizales-Quinteros, Luis Macías-Kauffer, Jose Monroy-Higuera, Erika Acosta-Smith and Adrian Canizalez-Roman

Genes 2023, 14(9), 1775; https://doi.org/10.3390/genes14091775 - 08 Sep 2023

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Abstract

Metabolic diseases, including obesity, diabetes, and metabolic syndrome, are among the most important public health challenges worldwide. Metabolic diseases are classified as multifactorial diseases in which genetic variants such as single-nucleotide polymorphisms (SNPs) may play an important role. The present study aimed to [...] Read more.

Metabolic diseases, including obesity, diabetes, and metabolic syndrome, are among the most important public health challenges worldwide. Metabolic diseases are classified as multifactorial diseases in which genetic variants such as single-nucleotide polymorphisms (SNPs) may play an important role. The present study aimed to identify associations linking allelic variants of the PCSK1, TMEM18, GPX5, ZPR1, ZBTB16, and PPARG1 genes with anthropometric and biochemical traits and metabolic diseases (obesity or metabolic syndrome) in an adult population from northwestern Mexico. Methods: Blood samples were collected from 523 subjects, including 247 with normal weight, 276 with obesity, and 147 with metabolic syndrome. Anthropometric and biochemical characteristics were recorded, and single-nucleotide polymorphisms (SNPs) were genotyped by real-time PCR. Results: PCSK1 was significantly (p < 0.05) associated with BMI, weight, and waist-to-hip ratio; TMEM18 was significantly associated with systolic blood pressure and triglyceride levels; GPX5 was significantly associated with HDL cholesterol levels. In addition, PCSK1 was associated with obesity (p = 1.0 × 10⁻⁴) and metabolic syndrome (p = 3.0 × 10⁻³), whereas PPARG1 was associated with obesity (p = 0.044). Conclusions: The associations found in this study, mainly between allelic variants of PCSK1 and metabolic traits, obesity, and metabolic syndrome, may represent a risk for developing metabolic diseases in adult subjects from northwestern Mexico. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

13 pages, 10776 KiB

Open AccessArticle

Heterozygosity of ALG9 in Association with Autosomal Dominant Polycystic Liver Disease

by Melissa M. Boerrigter, Renée Duijzer, René H. M. te Morsche and Joost P. H. Drenth

Genes 2023, 14(9), 1755; https://doi.org/10.3390/genes14091755 - 02 Sep 2023

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Abstract

α-1,2-mannosyltransferase (ALG9) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) [...] Read more.

α-1,2-mannosyltransferase (ALG9) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) without kidney cysts and established the presence of a heterozygous missense variant (c.677G>C p.(Gly226Ala)) in ALG9. In silico pathogenicity prediction and 3D protein modeling determined this variant as pathogenic. Loss of heterozygosity is regularly seen in liver cyst walls. Immunohistochemistry indicated the absence of ALG9 in liver tissue from this patient. ALG9 expression was absent in cyst wall lining from ALG9- and PRKCSH-caused ADPLD patients but present in the liver cyst lining derived from an ADPKD patient with a PKD2 variant. Thus, heterozygous pathogenic variants in ALG9 are also associated with ADPLD. Somatic loss of heterozygosity of the ALG9 enzyme was seen in the ALG9 patient but also in ADPLD patients with a different genetic background. This expanded the phenotypic spectrum of ADPLD to ALG9. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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12 pages, 2006 KiB

Open AccessArticle

Association of the ACTN3 Gene’s Single-Nucleotide Variant Rs1815739 (R577X) with Sports Qualification and Competitive Distance in Caucasian Athletes of the Southern Urals

by Olga V. Balberova, Natalia A. Shnayder, Evgeny V. Bykov, Yuri E. Zakaryukin, Marina M. Petrova, Irina A. Soloveva, Ekaterina A. Narodova, Galina A. Chumakova, Mustafa Al-Zamil, Azat R. Asadullin, Elena E. Vaiman, Vera V. Trefilova and Regina F. Nasyrova

Genes 2023, 14(8), 1512; https://doi.org/10.3390/genes14081512 - 25 Jul 2023

Cited by 1 | Viewed by 1468

Abstract

An elite athlete’s status is associated with a multifactorial phenotype depending on many environmental and genetic factors. Of course, the peculiarities of the structure and function of skeletal muscles are among the most important characteristics in the context of athletic performance. Purpose: To [...] Read more.

An elite athlete’s status is associated with a multifactorial phenotype depending on many environmental and genetic factors. Of course, the peculiarities of the structure and function of skeletal muscles are among the most important characteristics in the context of athletic performance. Purpose: To study the associations of SNV rs1815739 (C577T or R577X) allelic variants and genotypes of the ACTN3 gene with qualification and competitive distance in Caucasian athletes of the Southern Urals. Methods: A total of 126 people of European origin who lived in the Southern Urals region took part in this study. The first group included 76 cyclical sports athletes (speed skating, running disciplines in track-and-field): SD (short distances) subgroup—40 sprinters (mean 22.1 ± 2.4 y.o.); LD (long distances) subgroup—36 stayer athletes (mean 22.6 ± 2.7 y.o.). The control group consisted of 50 healthy nonathletes (mean 21.4 ± 2.7 y.o.). We used the Step One Real-Time PCR System (Applied Biosystems, USA) device for real-time polymerase chain reaction. Results: The frequency of the major allele R was significantly higher in the SD subgroup compared to the control subgroup (80% vs. 64%; p-value = 0.04). However, we did not find any significant differences in the frequency of the R allele between the athletes of the SD subgroup and the LD subgroup (80% vs. 59.7%, respectively; p-value > 0.05). The frequency of the X allele was lower in the SD subgroup compared to the LD subgroup (20% vs. 40.3%; p-value = 0.03). The frequency of homozygous genotype RR was higher in the SD subgroup compared to the control group (60.0% vs. 34%; p-value = 0.04). The R allele was associated with competitive distance in the SD group athletes compared to those of the control group (OR = 2.45 (95% CI: 1.02–5.87)). The X allele was associated with competitive distance in the LD subgroup compared to the SD subgroup (OR = 2.7 (95% CI: 1.09–6.68)). Conclusions: Multiplicative and additive inheritance models demonstrated that high athletic performance for sprinters was associated with the homozygous dominant genotype 577RR in cyclical sports athletes of Caucasian origin in the Southern Urals. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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12 pages, 444 KiB

Open AccessArticle

Lack of Association of Polymorphism Located Upstream of ABCA1 (rs2472493), in FNDC3B (rs7636836), and Near ANKRD55–MAP3K1 Genes (rs61275591) in Primary Open-Angle Glaucoma Patients of Saudi Origin

by Altaf A. Kondkar, Tahira Sultan, Taif A. Azad, Essam A. Osman, Faisal A. Almobarak, Glenn P. Lobo and Saleh A. Al-Obeidan

Genes 2023, 14(3), 704; https://doi.org/10.3390/genes14030704 - 13 Mar 2023

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Abstract

Polymorphisms rs2472493 near ABCA1, rs7636836 in FNDC3B, and rs61275591 near the ANKRD55–MAP3K1 genes were previously reported to exhibit genome-wide significance in primary open-angle glaucoma (POAG). Since these polymorphisms have not been investigated in the Arab population of Saudi Arabia, we examined [...] Read more.

Polymorphisms rs2472493 near ABCA1, rs7636836 in FNDC3B, and rs61275591 near the ANKRD55–MAP3K1 genes were previously reported to exhibit genome-wide significance in primary open-angle glaucoma (POAG). Since these polymorphisms have not been investigated in the Arab population of Saudi Arabia, we examined their association with POAG in a Saudi cohort. Genotyping was performed in 152 POAG cases and 246 controls using Taqman real-time assays and their associations with POAG and clinical markers, such as intraocular pressure, cup/disc ratio, and the number of antiglaucoma medications, were tested by statistical methods. There was no association observed between POAG and the minor allele frequencies of rs2472493[G], rs7636836[T], or rs61275591[A]. None of the genetic models such as co-dominant, dominant, recessive, over-dominant, and log-additive demonstrated any genotype link. The Rs2472493 genotype showed a modest association (p = 0.044) with the number of antiglaucoma medications in the POAG group, but no significant genotype effect on post hoc analysis. In addition, a G-T allelic haplotype of rs2472493 (ABCA1) and rs7636836 (FNDC3B) did show an over two-fold increased risk of POAG (odds ratio = 2.18), albeit non-significantly (p = 0.092). Similarly, no other allelic haplotype of the three variants showed any significant association with POAG. Our study did not replicate the genetic association of rs2472493 (ABCA1), rs763683 (FNDC3B), and rs61275591 (ANKRD55–MAP3K1) in POAG and related clinical phenotypes, suggesting that these polymorphisms are not associated with POAG in a Saudi cohort of Arab ethnicity. However, large population-based multicenter studies are needed to validate these results. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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14 pages, 1255 KiB

Open AccessArticle

Association of APOE (rs429358 and rs7412) and PON1 (Q192R and L55M) Variants with Myocardial Infarction in the Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan

by Naveed Rahman, Zakiullah, Asif Jan, Muhammad Saeed, Muhammad Asghar Khan, Zahida Parveen, Javaid Iqbal, Sajid Ali, Waheed Ali Shah, Rani Akbar and Fazli Khuda

Genes 2023, 14(3), 687; https://doi.org/10.3390/genes14030687 - 10 Mar 2023

Cited by 1 | Viewed by 2744

Abstract

Coronary Artery Diseases (CAD) remains the top among Non-communicable Diseases (NCDs). Variations in Apolipoprotein E (APOE) and Paroxonase 1 (PON1) have been associated with Myocardial Infarction (MI) in several populations. However, despite the high prevalence of CAD, no such [...] Read more.

Coronary Artery Diseases (CAD) remains the top among Non-communicable Diseases (NCDs). Variations in Apolipoprotein E (APOE) and Paroxonase 1 (PON1) have been associated with Myocardial Infarction (MI) in several populations. However, despite the high prevalence of CAD, no such study has been reported in the Pashtun ethnic population of Pakistan. We have conducted a two-stage (i.e., screening and validation) case-control study in which 200 cases and 100 control subjects have been recruited. In the first stage, Whole Exome Sequencing (WES) was used to screen for pathogenic variants of Myocardial Infarction (MI). In the second stage, selected variants of both APOE and PON1 genes (rs7412, rs429358, rs854560, and rs662) were analyzed through MassARRAY genotyping. Risk Allele Frequencies (RAFs) distribution and association of the selected SNPs with MI were determined using the Chi-square test and logistic regression analysis. WES identified a total of 12 sequence variants in APOE and 16 in PON1. Genotyping results revealed that APOE variant rs429358 (ɛ4 allele and ɛ3/ɛ4 genotype) showed significant association in MI patients (OR = 2.11, p value = 0.03; 95% CI = 1.25–2.43); whereas no significant difference (p˃ 0.05) was observed for rs7412. Similarly, the R allele of PON1 Q192R (rs662) was significantly associated with cases (OR = 1.353, p value = 0.048; 95% CI = 0.959–1.91), with particular mention of RR genotype (OR = 1.523, p value = 0.006; 95% CI = 1.087–2.132). Multiple logistic regression analysis showed that rs429358 (C allele) and rs662 (R allele) have a significantly higher risk of MI after adjustment for the conventional risk factors. Our study findings suggested that the rs429358 variant of APOE and PON1 Q192R are associated with MI susceptibility in the Pashtun ethnic population of Pakistan. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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16 pages, 1139 KiB

Open AccessArticle

Missense Variants of von Willebrand Factor in the Background of COVID-19 Associated Coagulopathy

by Zsuzsanna Elek, Eszter Losoncz, Katalin Maricza, Zoltán Fülep, Zsófia Bánlaki, Réka Kovács-Nagy, Gergely Keszler and Zsolt Rónai

Genes 2023, 14(3), 617; https://doi.org/10.3390/genes14030617 - 28 Feb 2023

Cited by 1 | Viewed by 1371

Abstract

COVID-19 associated coagulopathy (CAC), characterized by endothelial dysfunction and hypercoagulability, evokes pulmonary immunothrombosis in advanced COVID-19 cases. Elevated von Willebrand factor (vWF) levels and reduced activities of the ADAMTS13 protease are common in CAC. Here, we aimed to determine whether common genetic variants [...] Read more.

COVID-19 associated coagulopathy (CAC), characterized by endothelial dysfunction and hypercoagulability, evokes pulmonary immunothrombosis in advanced COVID-19 cases. Elevated von Willebrand factor (vWF) levels and reduced activities of the ADAMTS13 protease are common in CAC. Here, we aimed to determine whether common genetic variants of these proteins might be associated with COVID-19 severity and hemostatic parameters. A set of single nucleotide polymorphisms (SNPs) in the vWF (rs216311, rs216321, rs1063856, rs1800378, rs1800383) and ADAMTS13 genes (rs2301612, rs28729234, rs34024143) were genotyped in 72 COVID-19 patients. Cross-sectional cohort analysis revealed no association of any polymorphism with disease severity. On the other hand, analysis of variance (ANOVA) uncovered associations with the following clinical parameters: (1) the rs216311 T allele with enhanced INR (international normalized ratio); (2) the rs1800383 C allele with elevated fibrinogen levels; and (3) the rs1063856 C allele with increased red blood cell count, hemoglobin, and creatinine levels. No association could be observed between the phenotypic data and the polymorphisms in the ADAMTS13 gene. Importantly, in silico protein conformational analysis predicted that these missense variants would display global conformational alterations, which might affect the stability and plasma levels of vWF. Our results imply that missense vWF variants might modulate the thrombotic risk in COVID-19. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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12 pages, 287 KiB

Open AccessArticle

Genetic Variants of HNF4A, WFS1, DUSP9, FTO, and ZFAND6 Genes Are Associated with Prediabetes Susceptibility and Inflammatory Markers in the Saudi Arabian Population

by Dalal N. Binjawhar, Mohammed G. A. Ansari, Shaun Sabico, Syed Danish Hussain, Amal M. Alenad, Majed S. Alokail, Abeer A. Al-Masri and Nasser M. Al-Daghri

Genes 2023, 14(3), 536; https://doi.org/10.3390/genes14030536 - 21 Feb 2023

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Abstract

Prediabetes is a reversible, intermediate stage of type 2 diabetes mellitus (T2DM). Lifestyle changes that include healthy diet and exercise can substantially reduce progression to T2DM. The present study explored the association of 37 T2DM- and obesity-linked single nucleotide polymorphisms (SNPs) with prediabetes [...] Read more.

Prediabetes is a reversible, intermediate stage of type 2 diabetes mellitus (T2DM). Lifestyle changes that include healthy diet and exercise can substantially reduce progression to T2DM. The present study explored the association of 37 T2DM- and obesity-linked single nucleotide polymorphisms (SNPs) with prediabetes risk in a homogenous Saudi Arabian population. A total of 1129 Saudi adults [332 with prediabetes (29%) and 797 normoglycemic controls] were randomly selected and genotyped using the KASPar SNP genotyping method. Anthropometric and various serological parameters were measured following standard procedures. Heterozygous GA of HNF4A-rs4812829 (0.64; 95% CI 0.47–0.86; p < 0.01), heterozygous TC of WFS1-rs1801214 (0.60; 95% confidence interval (CI) 0.44–0.80; p < 0.01), heterozygous GA of DUSP9-rs5945326 (0.60; 95% CI 0.39–0.92; p = 0.01), heterozygous GA of ZFAND6-rs11634397 (0.75; 95% CI 0.56–1.01; p = 0.05), and homozygous AA of FTO-rs11642841 (1.50; 95% CI 0.8–1.45; p = 0.03) were significantly associated with prediabetes, independent of age and body mass index (BMI). Additionally, C-reactive protein (CRP) levels in rs11634397 (AA) with a median of 5389.0 (2767.4–7412.8) were significantly higher than in the heterozygous GA genotype with a median of 1736.3 (1024.4–4452.0) (p < 0.01). In conclusion, only five of the 37 genetic variants previously linked to T2DM and obesity in the Saudi Arabian population [HNF4A-rs4812829, WFS1-rs1801214, DUSP9-rs5945326, ZFAND6-rs11634397, FTO-rs11642841] were associated with prediabetes susceptibility. Prospective studies are needed to confirm the potential clinical value of the studied genetic variants of interest. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

15 pages, 987 KiB

Open AccessArticle

Association of Single-Nucleotide Polymorphisms Rs2779249 (chr17:26128581 C>A) and Rs rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 Gene with Tension-Type Headache and Arterial Hypertension Overlap Syndrome in Eastern Siberia

by Polina V. Alyabyeva, Marina M. Petrova, Diana V. Dmitrenko, Natalia P. Garganeeva, Galina A. Chumakova, Mustafa Al-Zamil, Vera V. Trefilova, Regina F. Nasyrova and Natalia A. Shnayder

Genes 2023, 14(2), 513; https://doi.org/10.3390/genes14020513 - 17 Feb 2023

Cited by 2 | Viewed by 1540

Abstract

Inducible nitric oxide (NO) synthase (iNOS), encoded by the NOS2 gene, promotes the generation of high levels of NO to combat harmful environmental influences in a wide range of cells. iNOS can cause adverse effects, such as falling blood pressure, if overexpressed. Thus, [...] Read more.

Inducible nitric oxide (NO) synthase (iNOS), encoded by the NOS2 gene, promotes the generation of high levels of NO to combat harmful environmental influences in a wide range of cells. iNOS can cause adverse effects, such as falling blood pressure, if overexpressed. Thus, according to some data, this enzyme is an important precursor of arterial hypertension (AH) and tension-type headache (TTH), which are the most common multifactorial diseases in adults. The purpose of this study was to investigate the association of rs2779249 (chr17:26128581 C>A) and rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 gene with TTH and AH overlap syndrome (OS) in Caucasians in Eastern Siberia. The sample size was 91 participants: the first group—30 patients with OS; the second group—30 patients AH; and the third group—31 healthy volunteers. RT-PCR was used for the determination of alleles and genotypes of the SNPs rs2779249 and rs2297518 of the NOS2 gene in all groups of participants. We showed that the frequency of allele A was significantly higher among patients with AH compared with healthy volunteers (p-value < 0.05). The frequency of the heterozygous genotype CA of rs2779249 was higher in the first group vs. the control (p-value = 0.03), and in the second group vs. the control (p-value = 0.045). The frequency of the heterozygous genotype GA of rs2297518 was higher in the first group vs. the control (p-value = 0.035), and in the second group vs. the control (p-value = 0.001). The allele A of rs2779249 was associated with OS (OR = 3.17 [95% CI: 1.31–7.67], p-value = 0.009) and AH (OR = 2.94 [95% CI: 1.21–7.15], p-value = 0.015) risks compared with the control. The minor allele A of rs2297518 was associated with OS (OR = 4.0 [95% CI: 0.96–16.61], p-value = 0.035) and AH (OR = 8.17 [95% CI: 2.03–32.79], p-value = 0.001) risks compared with the control. Therefore, our pilot study demonstrated that the SNPs rs2779249 and rs229718 of the NOS2 gene could be promising genetic biomarkers for this OS risk in Caucasians from Eastern Siberia. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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10 pages, 1224 KiB

Open AccessArticle

Role of miR-143 and miR-146 in Risk Evaluation of Coronary Artery Diseases in Autopsied Samples

by Jian Tie, Hiroki Takanari, Koya Ota and Takahisa Okuda

Genes 2023, 14(2), 471; https://doi.org/10.3390/genes14020471 - 12 Feb 2023

Cited by 1 | Viewed by 1367

Abstract

Coronary artery disease (CAD) is a common and fatal cardiovascular disease. Among known CAD risk factors, miRNA polymorphisms, such as Has-miR-143 (rs41291957 C>G) and Has-miR-146a (rs2910164 G>A), have emerged as important genetic markers of CAD. Despite many genetic association [...] Read more.

Coronary artery disease (CAD) is a common and fatal cardiovascular disease. Among known CAD risk factors, miRNA polymorphisms, such as Has-miR-143 (rs41291957 C>G) and Has-miR-146a (rs2910164 G>A), have emerged as important genetic markers of CAD. Despite many genetic association studies in multiple populations, no study assessing the association between CAD risk and SNPs of miR-143 and miR-146 was documented in the Japanese people. Therefore, using the TaqMan SNP assay, we investigated two SNP genotypes in 151 subjects with forensic autopsy-proven CAD. After pathological observation, we used ImageJ software to assess the degree of coronary artery atresia. Moreover, the genotypes and miRNA content of the two groups of samples with atresia <10% and >10% were analyzed. The results showed that the CC genotype of rs2910164 was more frequent in patients with CAD than in controls, which was associated with the risk of CAD in the study population. However, Has-miR-143 rs41291957 genotype did not show a clear correlation with the risk of CAD. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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11 pages, 281 KiB

Open AccessArticle

ABCA1 C69T Gene Polymorphism Association with Dysglycemia in Saudi Prediabetic Adults

by Ghada M. A. Ajabnoor, Suhad M. Bahijri, Wafa Alrashidi, Sumia Mohammad Enani, Aliaa A. Alamoudi, Lubna Al Sheikh and Basmah Eldakhakhny

Genes 2022, 13(12), 2277; https://doi.org/10.3390/genes13122277 - 02 Dec 2022

Viewed by 1384

Abstract

Studies suggest that ATP-binding cassette transporter A1 (ABCA1 C69T) polymorphism is associated with a decreased incidence of type 2 diabetes mellitus (T2DM) and that there is an association between ABCA1 C69T polymorphism and the risk of dyslipidemia in diabetic individuals. However, other [...] Read more.

Studies suggest that ATP-binding cassette transporter A1 (ABCA1 C69T) polymorphism is associated with a decreased incidence of type 2 diabetes mellitus (T2DM) and that there is an association between ABCA1 C69T polymorphism and the risk of dyslipidemia in diabetic individuals. However, other studies contradict these suggestions. Therefore, we aimed to investigate the prevalence of ABCA1 C69T (rs1800977) gene polymorphism in a representative sample of the Saudi population not previously diagnosed with diabetes and its possible association with dyslipidemia and dysglycemia. A cross-sectional design was used to recruit nondiabetic adults of both genders from the Saudi population in Jeddah by employing a stratified, two-stage cluster sampling method. A total of 650 people (337 men and 313 women) were recruited. Demographic, dietary, and lifestyle variables, as well as medical history and family history of chronic diseases, were collected using a predesigned questionnaire. Fasting blood samples were taken for the determination of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and lipids profile, which were followed by a 1-h oral glucose tolerance test (OGTT). Real-time PCR technology was used to determine the ABCA1 C69T gene SNP (rs1800977). The T allele of ABCA1 C69T (rs1800977) was very frequent (TT in 44.9% and CT in 43.7%). There was a trend toward significance for a higher dysglycemia percentage in people with CT and TT genotypes (25.7%, and 23.3%, respectively) compared with CC genotypes (16.2%). In addition, FPG and 1-h plasma glucose were significantly higher in people with both TT and CT genotypes compared to CC genotypes. However, T allele was not associated with any dysregulation of lipid parameters. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

12 pages, 1486 KiB

Open AccessArticle

9p21 Locus Polymorphism Is A Strong Predictor of Metabolic Syndrome and Cardiometabolic Risk Phenotypes Regardless of Coronary Heart Disease

by Muhammad Mobeen Zafar, Muhammad Saqlain, Asad Mehmood Raja, Pakeeza Arzoo Shaiq, Muhammad Javaid Asad, Muhammad Kausar Nawaz Shah, Farah Fatima, Hadi Valadi, Muhammad Nawaz and Ghazala Kaukab Raja

Genes 2022, 13(12), 2226; https://doi.org/10.3390/genes13122226 - 27 Nov 2022

Cited by 1 | Viewed by 1708

Abstract

The world population is genetically predisposed to metabolic syndrome (MetS) and its components, also known as cardiometabolic risk phenotypes, which can cause severe health complications including coronary heart disease (CHD). Genetic variants in the 9p21 locus have been associated with CHD in a [...] Read more.

The world population is genetically predisposed to metabolic syndrome (MetS) and its components, also known as cardiometabolic risk phenotypes, which can cause severe health complications including coronary heart disease (CHD). Genetic variants in the 9p21 locus have been associated with CHD in a number of populations including Pakistan. However, the role of the 9p21 locus in MetS and cardiometabolic risk phenotypes (such as obesity, hypertension, hyperglycemia, and dyslipidemia) in populations with CHD or no established CHD has not been explored. Therefore, the present study was designed to explore the association of the minor/risk allele (C) of 9p21 locus SNP rs1333049 with MetS or its risk phenotypes regardless of an established CHD, in Pakistani subjects. Genotyping of rs1333049 (G/C) was performed on subjects under a case-control study design; healthy controls and cases, MetS with CHD (MetS-CHD⁺) and MetS with no CHD (MetS-CHD⁻), respectively. Genotype and allele frequencies were calculated in all study groups. Anthropometric and clinical variables (Means ± SD) were compared among study groups (i.e., controls, MetS + CHD and MetS-CHD) and minor/risk C allele carriers (GC + CC) vs. non-carriers (Normal GG genotype). Associations of the risk allele of rs1333049 SNP with disease and individual metabolic risk components were explored using adjusted multivariate logistic regression models (OR at 95% CI) with a threshold p-value of ≤0.05. Our results have shown that the minor allele frequency (MAF) was significantly high in the MAF cases (combined = 0.63, MetS-CHD⁺ = 0.57 and MetS-CHD⁻ = 0.57) compared with controls (MAF = 0.39). The rs1333049 SNP significantly increased the risk of MetS, irrespective of CHD (MetS-CHD⁺ OR = 2.36, p < 0.05 and MetS-CHD⁻ OR = 4.04, p < 0.05), and cardiometabolic risk phenotypes; general obesity, central obesity, hypertension, and dyslipidemia (OR = 1.56–3.25, p < 0.05) except hyperglycemia, which lacked any significant association (OR = 0.19, p = 0.29) in the present study group. The 9p21 genetic locus/rs1333049 SNP is strongly associated with, and can be a genetic predictor of, MetS and cardiometabolic risks, irrespective of cardiovascular diseases in the Pakistani population. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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12 pages, 392 KiB

Open AccessArticle

Association of Polymorphisms in the Long Non-Coding RNA HOTAIR with Recurrent Pregnancy Loss in a Korean Population

by Hyeon Woo Park, Young Ran Kim, Jeong Yong Lee, Eun Ju Ko, Min Jung Kwon, Ji Hyang Kim and Nam Keun Kim

Genes 2022, 13(11), 2138; https://doi.org/10.3390/genes13112138 - 17 Nov 2022

Cited by 3 | Viewed by 1565

Abstract

Recurrent pregnancy loss (RPL) affects 1% to 5% of women, with devastating effects on both reproductive health and psychological well-being. Homeobox (HOX) transcript antisense RNA (HOTAIR) is a long non-coding RNA (lncRNA) produced by HOXC; it plays a [...] Read more.

Recurrent pregnancy loss (RPL) affects 1% to 5% of women, with devastating effects on both reproductive health and psychological well-being. Homeobox (HOX) transcript antisense RNA (HOTAIR) is a long non-coding RNA (lncRNA) produced by HOXC; it plays a major role in invasion and development of ovarian and other cancers. The aim of the present study was to analyze effects of HOTAIR polymorphisms (rs4759314 A>G, rs920778 T>C, rs1899663 G>T, and rs7958904 G>C) on RPL in Korean women. A total of 403 women with RPL and 383 healthy women were selected for this study. Genotyping analysis was performed with the polymerase chain reaction, restriction fragment length polymorphism, and the TaqMan genotyping assay. Clinical characteristics were compared using Student’s unpaired t-test and the chi-square test for categorical variables. Logistic regression was performed to evaluate associations between single nucleotide polymorphisms and RPL incidence. In all assays, p < 0.05 was considered significant. HOTAIR polymorphisms rs4759314A>G and rs920778T>C were highly associated with increased risk of RPL, specifically the haplotypes rs4759314A>G/rs1899663G>T (G-T) and rs4759314A>G/rs920778 T>C (G-C). These associations were maintained in haplotypes that contained three polymorphisms (rs4759314 A>G, rs920778 T>C, and rs1899663 G>T) A-C-G, G-T-G, and G-T-T, further indicating that the HOTAIR rs4759314 and rs920778 polymorphisms play significant roles in idiopathic RPL in Korean women. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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10 pages, 273 KiB

Open AccessArticle

Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients

by Dana Dlouha, Jevgenija Vymetalova, Sarka Novakova, Pavlina Huckova, Vera Lanska and Jaroslav Alois Hubacek

Genes 2022, 13(10), 1855; https://doi.org/10.3390/genes13101855 - 14 Oct 2022

Viewed by 1047

Abstract

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart [...] Read more.

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

17 pages, 1665 KiB

Open AccessArticle

A Single Nucleotide Polymorphism (rs3811792) Affecting Human SCD5 Promoter Activity Is Associated with Diabetes Mellitus

by Veronika Zámbó, Gabriella Orosz, Luca Szabó, Kinga Tibori, Szabolcs Sipeki, Krisztina Molnár, Miklós Csala and Éva Kereszturi

Genes 2022, 13(10), 1784; https://doi.org/10.3390/genes13101784 - 03 Oct 2022

Cited by 3 | Viewed by 1719

Abstract

The combined prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus is 10.5% worldwide and this is constantly increasing. The pathophysiology of the diseases include disturbances of the lipid metabolism, in which acyl-CoA desaturases play a central role as they synthesize [...] Read more.

The combined prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus is 10.5% worldwide and this is constantly increasing. The pathophysiology of the diseases include disturbances of the lipid metabolism, in which acyl-CoA desaturases play a central role as they synthesize unsaturated fatty acids, thereby providing protection against lipotoxicity. The stearoyl-CoA desaturase-5 (SCD5) isoform has received little scientific attention. We aimed to investigate the SCD5 promoter and its polymorphisms in vitro, in silico and in a case-control study. The SCD5 promoter region was determined by a luciferase reporter system in HepG2, HEK293T and SK-N-FI cells and it was proved to be cell type-specific, but it was insensitive to different fatty acids. The effect of the SCD5 promoter polymorphisms rs6841081 and rs3811792 was tested in the transfected cells. The T allele of rs3811792 single nucleotide polymorphism (SNP) significantly reduced the activity of the SCD5 promoter in vitro and modified several transcription factor binding sites in silico. A statistically significant association of rs3811792 SNP with T1DM and T2DM was also found, thus supporting the medical relevance of this variation and the complexity of the molecular mechanisms in the development of metabolic disorders. In conclusion, the minor allele of rs3811792 polymorphism might contribute to the development of diabetes by influencing the SCD5 promoter activity. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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13 pages, 1920 KiB

Open AccessArticle

Relationships between Uncoupling Protein Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia

by Alena A. Nikanorova, Nikolay A. Barashkov, Vera G. Pshennikova, Nyurgun N. Gotovtsev, Georgii P. Romanov, Aisen V. Solovyev, Sargylana S. Kuzmina, Nikolay N. Sazonov and Sardana A. Fedorova

Genes 2022, 13(9), 1612; https://doi.org/10.3390/genes13091612 - 08 Sep 2022

Cited by 2 | Viewed by 2153

Abstract

Currently, it is known that irisin can participate in the processes of thermoregulation and browning of adipose tissue, and, therefore, it is possible that it is involved in the microevolutionary mechanisms of adaptation to a cold. The aim of this study is to [...] Read more.

Currently, it is known that irisin can participate in the processes of thermoregulation and browning of adipose tissue, and, therefore, it is possible that it is involved in the microevolutionary mechanisms of adaptation to a cold. The aim of this study is to investigate the relationship between the uncoupling protein genes (UCP1, UCP2, UCP3) and the irisin levels in the residents of the coldest region of Siberia. The sample consisted of 279 Yakut people (185 females, 94 males, average age 19.8 ± 2.03 years). The females plasma irisin concentration was 8.33 ± 2.74 mcg/mL and the males was 7.76 ± 1.86 mcg/mL. Comparative analysis of irisin levels with the genotypes of six studied SNP-markers in females revealed a significant association of irisin with rs1800849-UCP3. The TT genotype of rs1800849 was associated with elevated levels of irisin (p = 0.01). It was also found that this TT genotype in females was associated with reduced weight and height (p = 0.03). We searched for natural selection signals for the T-allele rs1800849-UCP3; as a result of which, it was found that this allele has a significantly high frequency of distribution in northern (45%, CI: 0.42–0.484) compared with southern Asian populations (28%, CI: 0.244–0.316) (p = 0.01). The results obtained indicate the probable involvement of irisin and the UCP3 gene in thermoregulation, and the spread of its allelic variants is probably related to adaptation to a cold climate. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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11 pages, 671 KiB

Open AccessArticle

Investigation of Klotho G395A and C1818T Polymorphisms and Their Association with Serum Glucose Level and Risk of Type 2 Diabetes Mellitus

by Muhammad Sadiq Aziz, Aziz-ul-Hasan Aamir, Ajab Khan, Zahid Khan, Syed Qaiser Shah, Sher Zaman Safi, Kalaivani Batumalaie, Hussah M. Alobaid, Abid Ali and Muhammad Imran

Genes 2022, 13(9), 1532; https://doi.org/10.3390/genes13091532 - 26 Aug 2022

Cited by 6 | Viewed by 1526

Abstract

Objective: The objective was to study the association of Klotho gene G395A and C1818T single nucleotide polymorphisms with glycemia, serum, glycosylated hemoglobin (HbA1c) level and the risk of type 2 diabetes mellitus (T2DM) in the Pashtun population of Pakistan. Methods: In this study, [...] Read more.

Objective: The objective was to study the association of Klotho gene G395A and C1818T single nucleotide polymorphisms with glycemia, serum, glycosylated hemoglobin (HbA1c) level and the risk of type 2 diabetes mellitus (T2DM) in the Pashtun population of Pakistan. Methods: In this study, 195 normal individuals and 217 T2DM patients were enrolled. All subjects were divided into three groups, namely overall subjects (control + T2DM patients), control individuals and T2DM patients, and their fasting glucose, HbA1c level, lipid profile and C1818T and G395A polymorphisms were determined. Results: The allele frequencies of G395A in overall subjects were 0.568 for A and 0.432 for G. Similarly, allele frequencies for G395A in overall subjects were 0.597 and 0.403 for C and T alleles, respectively. The AA genotype of G395A was observed to be a risk factor for T2DM. In normal individuals, no significant (p > 0.05) association was observed between klotho C1818T and G395A polymorphisms and hyperglycemia. In overall subjects, the C1818T polymorphism was associated (p < 0.05) with high fasting glucose and HbA1c levels in female subjects only. In T2DM patients, both C1818T and G395A polymorphisms were found to be significantly (p < 0.05) associated with high fasting glucose and HbA1c levels both in males and females. Conclusion: The G395A polymorphism was observed to increase the risk of T2DM. Both C1818T and G395 were associated with high fasting glucose and HbA1c levels in T2DM patients. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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11 pages, 577 KiB

Open AccessArticle

Risk Association, Linkage Disequilibrium, and Haplotype Analyses of β-Like Globin Gene Polymorphisms with Malaria Risk in the Sabah Population of Malaysian Borneo

by Eric Tzyy Jiann Chong, Lucky Poh Wah Goh, Ho Jin Yap, Eric Wei Choong Yong and Ping-Chin Lee

Genes 2022, 13(7), 1229; https://doi.org/10.3390/genes13071229 - 11 Jul 2022

Viewed by 1602

Abstract

Single nucleotide polymorphisms (SNPs) in the β-like globin gene of the human hosts to the risk of malaria are unclear. Therefore, this study investigates these associations in the Sabah population, with a high incidence of malaria cases. In brief, DNA was extracted from [...] Read more.

Single nucleotide polymorphisms (SNPs) in the β-like globin gene of the human hosts to the risk of malaria are unclear. Therefore, this study investigates these associations in the Sabah population, with a high incidence of malaria cases. In brief, DNA was extracted from 188 post-diagnostic blood samples infected with Plasmodium parasites and 170 healthy controls without a history of malaria. Genotyping of the β-like globin C-158T, G79A, C16G, and C-551T SNPs was performed using a polymerase chain reaction-restriction fragment length polymorphism approach. Risk association, linkage disequilibrium (LD), and haplotype analyses of these SNPs were assessed. This study found that the variant allele in the C-158T and C16G SNPs were protective against malaria infections by 0.5-fold, while the variant allele in the G79A SNP had a 6-fold increased risk of malaria infection. No SNP combination was in perfect LD, but several haplotypes (CGCC, CGCT, and CGGC) were identified to link with different correlation levels of malaria risk in the population. In conclusion, the C-158T, G79A, and C16G SNPs in the β-like globin gene are associated with the risk of malaria. The haplotypes (CGCC, CGCT, and CGGC) identified in this study could serve as biomarkers to estimate malaria risk in the population. This study provides essential data for the design of malaria control and management strategies. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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Review

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20 pages, 1569 KiB

Open AccessReview

Genetic Predictors of Antipsychotic Efflux Impairment via Blood-Brain Barrier: Role of Transport Proteins

by Regina F. Nasyrova, Natalia A. Shnayder, Sofia M. Osipova, Aiperi K. Khasanova, Ilya S. Efremov, Mustafa Al-Zamil, Marina M. Petrova, Ekaterina A. Narodova, Natalia P. Garganeeva and German A. Shipulin

Genes 2023, 14(5), 1085; https://doi.org/10.3390/genes14051085 - 15 May 2023

Viewed by 1785

Abstract

Antipsychotic (AP)—induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms [...] Read more.

Antipsychotic (AP)—induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms for the development of AP-induced ADRs is a genetically-determined impairment of AP efflux across the blood-brain barrier (BBB). We present a narrative review of publications in databases (PubMed, Springer, Scopus, Web of Science E-Library) and online resources: The Human Protein Atlas; GeneCards: The Human Gene Database; US National Library of Medicine; SNPedia; OMIM Online Mendelian Inheritance in Man; The PharmGKB. The role of 15 transport proteins involved in the efflux of drugs and other xenobiotics across cell membranes (P-gp, TAP1, TAP2, MDR3, BSEP, MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, MRP9, BCRP) was analyzed. The important role of three transporter proteins (P-gp, BCRP, MRP1) in the efflux of APs through the BBB was shown, as well as the association of the functional activity and expression of these transport proteins with low-functional and non-functional single nucleotide variants (SNVs)/polymorphisms of the ABCB1, ABCG2, ABCC1 genes, encoding these transport proteins, respectively, in patients with schizophrenia spectrum disorders (SSDs). The authors propose a new pharmacogenetic panel “Transporter protein (PT)—Antipsychotic (AP) Pharmacogenetic test (PGx)” (PTAP-PGx), which allows the evaluation of the cumulative contribution of the studied genetic biomarkers of the impairment of AP efflux through the BBB. The authors also propose a riskometer for PTAP-PGx and a decision-making algorithm for psychiatrists. Conclusions: Understanding the role of the transportation of impaired APs across the BBB and the use of genetic biomarkers for its disruption may make it possible to reduce the frequency and severity of AP-induced ADRs, since this risk can be partially modified by the personalized selection of APs and their dosing rates, taking into account the genetic predisposition of the patient with SSD. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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