Six Single Nucleotide Polymorphisms Research Articles

Phenotypic evidence of deltamethrin resistance and identification of selective sweeps in Anopheles mosquitoes on the Bijagós Archipelago, Guinea-Bissau

Vector control in the Bijagós Archipelago of Guinea-Bissau currently relies on pyrethroid insecticide-treated nets. However, data on insecticide resistance in Guinea-Bissau is limited. This study identified deltamethrin resistance in the Anopheles gambiae sensu lato complex on Bubaque island using WHO tube tests in November 2022. Whole genome sequencing of An. gambiae sensu stricto mosquitoes identified six single nucleotide polymorphisms (SNPs) previously associated with, or putatively associated with, insecticide resistance: T791M, L995F, N1570Y, A1746S and P1874L in the vgsc gene, and L119V in the gste2 gene. Twenty additional non-synonymous SNPs were identified in insecticide-resistance associated genes. Four of these SNPs were present at frequencies over 5% in the population: T154S, I126F and G26S in the vgsc gene and A65S in ace1. Genome wide selection scans using Garud’s H12 statistic identified two selective sweeps: one in chromosome X and one in chromosome 2R. Both selective sweeps overlap with metabolic genes previously associated with insecticide resistance, including cyp9k1 and the cyp6aa/cyp6p gene cluster. This study presents the first phenotypic testing for deltamethrin resistance and the first whole genome sequence data for Anophelesgambiae mosquitoes from the Bijagós, contributing data of significance for vector control policy in this region.

NR0B2 Is a Key Factor for Gastric Diseases: A GEO Database Analysis Combined with Drug-Target Mendelian Randomization.

Small Heterodimer Partner (SHP; NR0B2) is an orphan receptor that acts as a transcriptional regulator, controlling various metabolic processes, and is a potential therapeutic target for cancer. Examining the correlation between the expression of NR0B2 and the risk of gastric diseases could open a new path for treatment and drug development. The Gene Expression Omnibus (GEO) database was utilized to explore NR0B2 gene expression profiles in gastric diseases. Co-expressed genes were identified through Weighted Correlation Network Analysis (WGCNA), and GO enrichment was performed to identify potential pathways. The Xcell method was employed to analyze immune infiltration relationships. To determine the potential causal relationship between NR0B2 expression and gastric diseases, we identified six single-nucleotide polymorphisms (SNPs) as a proxy for NR0B2 expression located within 100 kilobases of NR0B2 and which are associated with triglyceride homeostasis and performed drug-target Mendelian randomization (MR). Bioinformatics analysis revealed that NR0B2 expression levels were reduced in gastric cancer and increased in gastritis. GO analysis and Gene Set Enrichment Analysis (GSEA) showed that NR0B2 is widely involved in oxidation-related processes. Immune infiltration analyses found that NR0B2 was associated with Treg. Prognostic analyses showed that a low expression of NR0B2 is a risk factor for the poor prognoses of gastric cancer. MR analyses revealed that NR0B2 expression is associated with a risk of gastric diseases (NR0B2 vs. gastric cancer, p = 0.006, OR: 0.073, 95%CI: 0.011-0.478; NR0B2 vs. gastric ulcer, p = 0.03, OR: 0.991, 95%CI: 0.984-0.999; NR0B2 vs. other gastritis, p = 0.006, OR:3.82, 95%CI: 1.468-9.942). Our study confirms the causal relationship between the expression of NR0B2 and the risk of gastric diseases, and highlights its role in the progression of gastric cancer. The present study opens new avenues for exploring the potential of drugs that either activate or inhibit the NR0B2 receptor in the treatment of gastric diseases.

Genetic variants associated with response to anti-CGRP monoclonal antibody therapy in a chronic migraine Han Chinese population

BackgroundAnti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine.MethodsWe conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database.ResultsSix single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10− 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10− 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure.ConclusionThe identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology.Trial registrationNot applicable.

The Impact of Cardiovascular Disease Gene Polymorphism and Interaction with Homocysteine on Deep Vein Thrombosis.

Deep vein thrombosis (DVT) affects vascular health and can even threaten life; however, its pathogenesis remains unclear. Cardiovascular disease (CVD) and DVT share common risk factors, such as dyslipidemia, aging, etc. We aimed to investigate the loci of published CVD susceptibility genes and their association with environmental factors that might be related to DVT. Genotyping by Kompetitive Allele Specific PCR (KASP), collection of lifestyle information, and determination of blood biochemical markers were performed in 165 DVT cases and 164 controls. The impact of six single nucleotide polymorphisms (SNPs) and additional potential variables on DVT morbidity was evaluated using unconditional logistic regression (ULR). To explore the high-order interactions related to genetics and the body's internal environment exposure that affect DVT, ULR, crossover analysis, and multifactor dimensionality reduction/generalized multifactor dimensionality reduction (MDR/GMDR) were employed. Sensitivity analyses were performed using the EpiR package. The polymorphisms of FGB rs1800790 and PLAT rs2020918 were significantly associated with DVT. The optimum GMDR interaction model for gene-gene (G × G) consisted of THBD rs1042579, PLAT rs2020918, and PON1 rs662. The PLAT rs2020918 and MTHFR rs1801133 polymorphisms together eliminated the maximum entropy by the MDR method. The optimum GMDR interaction model for gene-environment (G × E) consisted of MTHFR rs1801133, FGB rs1800790, PLAT rs2020918, PON1 rs662, and total homocysteine (tHcy). Those with high tHcy levels and three risk genotypes significantly increased the DVT risk. In conclusion, certain CVD-related SNPs and their interactions with tHcy may contribute to DVT. These have implications for investigating DVT etiology and developing preventive treatment plans.

Genome-Wide Association Analyses and Population Verification Highlight the Potential Genetic Basis of Horned Morphology during Polled Selection in Tibetan Sheep.

The types and morphology of sheep horns have been extensively researched, yet the genetic foundation underlying the emergence of diverse horn characteristics during the breeding of polled Tibetan sheep has remained elusive. Genome-wide association analysis (GWAS) was performed on 103 subtypes (normal large horn, scurs, and polled) differentiated from G2 (offspring (G2) of parent (G1) of polled) of the polled core herd. Six single nucleotide polymorphisms (SNPs) located on chromosome 10 of the relaxin family peptide receptor 2 (RXFP2) gene exhibited positive correlations with horn length, horn base circumference, and horn base interval. Furthermore, in genotyping 382 G2 individuals, significant variations were observed for each specific horn type. Three additional mutations were identified near the target SNP upstream of the amplification product. Finally, the RXFP2-specific haplotype associated with the horned trait effectively maintained horn length, horn base circumference, and horn base interval in Tibetan sheep, as confirmed by population validation of nine loci in a sample size of 1125 individuals. The present study offers novel insights into the genetic differentiation of the horned type during improvement breeding and evolution, thereby establishing a robust theoretical foundation for polled Tibetan sheep breeding and providing valuable guidance for practical production.

Preliminary investigation of potential links between pigmentation variants and opioid analgesic effectiveness in horses during cerebrospinal fluid centesis

BackgroundThe pleiotropic effects of the melanocortin system show promise in overcoming limitations associated with large variations in opioid analgesic effectiveness observed in equine practice. Of particular interest is variation in the melanocortin-1-receptor (MC1R) gene, which dictates pigment type expression through its epistatic interaction with the agouti signalling protein (ASIP) gene. MC1R has previously been implicated in opioid efficacy in other species; however, this relationship is yet to be explored in horses. In this study, analgesic effectiveness was scored (1-3) based on noted response to dura penetration during the performance of cerebrospinal fluid centisis after sedation and tested for association with known genetic regions responsible for pigmentation variation in horses.ResultsThe chestnut phenotype was statistically significant (P < 0.05) in lowering analgesic effectiveness when compared to the bay base coat colour. The 11bp indel in ASIP known to cause the black base coat colour was not significant (P>0.05); however, six single nucleotide polymorphisms (SNPs) within the genomic region encoding the ASIP gene and one within MC1R were identified as being nominally significant (P<0.05) in association with opioid analgesic effectiveness. This included the location of the known e MC1R variant resulting in the chestnut coat colour.ConclusionsThe current study provides promising evidence for important links between pigmentation genes and opioid effectiveness in horses. The application of an easily identifiable phenotype indicating variable sensitivity presents a promising opportunity for accessible precision medicine in the use of analgesics and warrants further investigation.

Genome-wide association study identifies host genetic variants influencing oral microbiota diversity and metabolic health

The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10–8). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10–9). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10–8). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.

Genetic Association of APOA5 and AKT3 Genes with Milk Production Traits in Chinese Holstein Cows

Genome selection (GS) technology is an important means to improve the genetic improvement of dairy cows, and the mining and application of functional genes and loci for important traits is one of the important bases for accelerating genetic improvement. Our previous study found that the apolipoprotein A5 (APOA5) and AKT serine/threonine kinase 3 (AKT3) genes were differentially expressed in the liver tissue of Chinese Holstein cows at different lactation stages and influenced milk component synthesis and metabolism, so we considered these two genes as the candidates affecting milk production traits. In this study, we found in total six single nucleotide polymorphisms (SNPs), three in APOA5 and three in AKT3. Subsequent association analysis showed that the six SNPs were significantly associated with milk yield, fat yield, protein yield, or fat percentage (p ≤ 0.05). Three SNPs in APOA5 formed a haplotype block, which was found to be significantly associated with milk yield, fat yield, and protein yield (p ≤ 0.05). In addition, four SNPs were proposed to be functional mutations affecting the milk production phenotype, of which three, 15:g.27446527C&gt;T and 15:g.27447741A&gt;G in APOA5 and 16:g.33367767T&gt;C in AKT3, might change the transcription factor binding sites (TFBSs), and one is a missense mutation, 15:g.27445825T&gt;C in APOA5, which could alter the secondary structure and stability of mRNA and protein. In summary, we demonstrated the genetic effects of APOA5 and AKT3 on milk production traits, and the valuable SNPs could be used as available genetic markers for dairy cattle’s GS.

PC Gene Affects Milk Production Traits in Dairy Cattle.

In previous work, we found that PC was differentially expressed in cows at different lactation stages. Thus, we deemed that PC may be a candidate gene affecting milk production traits in dairy cattle. In this study, we found the polymorphisms of PC by resequencing and verified their genetic associations with milk production traits by using an animal model in a cattle population. In total, we detected six single-nucleotide polymorphisms (SNPs) in PC. The single marker association analysis showed that all SNPs were significantly associated with the five milk production traits (p < 0.05). Additionally, we predicted that allele G of 29:g.44965658 in the 5' regulatory region created binding sites for TF GATA1 and verified that this allele inhibited the transcriptional activity of PC by the dual-luciferase reporter assay. In conclusion, we proved that PC had a prominent genetic effect on milk production traits, and six SNPs with prominent genetic effects could be used as markers for genomic selection (GS) in dairy cattle, which is beneficial for accelerating the improvement in milk yield and quality in Chinese Holstein cows.

Genetic Evidence for Causal Relationships between Plasma Eicosanoid Levels and Cardiovascular Disease.

Cardiovascular diseases are the most common causes of mortality and disability worldwide. Eicosanoids are a group of bioactive metabolites that are mainly oxidized by arachidonic acid. Eicosanoids play a diverse role in cardiovascular diseases, with some exerting beneficial effects while others have detrimental consequences. However, a causal relationship between eicosanoid levels and cardiovascular disease remains unclear. Six single nucleotide polymorphisms (SNPs) with strong associations with plasma eicosanoid levels were selected. Summary-level data for cardiovascular disease were obtained from publicly available genome-wide association studies. A two-sample MR analysis identified that plasma eicosanoid levels were inversely correlated with unstable angina pectoris (OR 1.06; 95% CI 1-1.12; p = 0.04), myocardial infarction (OR 1.05; 95% CI 1.02-1.09; p = 0.005), ischemia stroke (OR 1.05; 95% CI 1-1.11; p = 0.047), transient ischemic attack (OR 1.03; 95% CI 1-1.07; p = 0.042), heart failure (OR 1.03; 95% CI 1.01-1.05; p = 0.011), and pulmonary embolism (OR 1.08; 95% CI 1.02-1.14; p = 1.69 × 10-6). In conclusion, our data strongly suggest a genetic causal link between high plasma eicosanoid levels and an increased cardiovascular disease risk. This study provides genetic evidence for treating cardiovascular diseases.

To Investigate the Influence of Smoking Cessation Intention and Common Downstream Variants of HDAC9 Gene on Large Artery Atherosclerotic Cerebral Infarction.

To investigate the association of smoking cessation intention and single nucleotide polymorphism of HDAC9 gene with LAA-S in Han people in Hainan province. A case-control study was conducted. Six single nucleotide polymorphisms (SNPS) of HDAC9 gene were genotyped by SNPscan genotyping technique in 248 patients with LAA-S and 237 controls in Hainan Han population. SNP loci (rs10227612, rs12669496, rs1548577, rs2074633, rs2526626, and rs2717344) were genotyped, and the genotype and allele frequencies were compared between the case and control group. At the same time, the distribution of smoking between the case and control group was compared, and the 3-year and 7-year follow-up smoking cessation between the case and control group was compared, so as to find out the effects of smoking cessation intention and HDAC9 SNP on LAA-S. (1) The GT genotype at rs10227612, GG genotype at rs2717344, and GA genotype at rs1548577 in the case group were significantly higher than those in the control group, and the differences were statistically significant. (2) There were significant differences in the distribution of smoking between the case and control group (P < 0.05), and there were significant differences in the smoking cessation after 3 years and 7 years of follow-up between the case and control group (P < 0.05). The intention to quit smoking was positively correlated with the incidence of LAA-S. (1) The rs10227612, rs1548577, rs2074633, rs2717344 of HDAC9 gene may be significantly related to atherosclerotic cerebral infarction of great arteries in Hainan Han population, while rs12669496 and rs2526626 may not be related. (2) According to the statistics of smoking in the case and control group, smoking was related to large artery atherosclerotic cerebral infarction, and the intention to quit smoking was a very important factor affecting the success of smoking cessation.

Association between Genetic Polymorphism of SCN1A, GABRA1 and ABCB1 and Drug Responsiveness in Vietnamese Epileptic Children.

Background and Objectives: Drug resistant epilepsy (DRE) is a major hurdle in epilepsy, which hinders clinical care, patients' management and treatment outcomes. DRE may partially result from genetic variants that alter proteins responsible for drug targets and drug transporters in the brain. We aimed to examine the relationship between SCN1A, GABRA1 and ABCB1 polymorphism and drug response in epilepsy children in Vietnam. Materials and Methods: In total, 213 children diagnosed with epilepsy were recruited in this study (101 were drug responsive and 112 were drug resistant). Sanger sequencing had been performed in order to detect six single nucleotide polymorphisms (SNPs) belonging to SCN1A (rs2298771, rs3812718, rs10188577), GABRA1 (rs2279020) and ABCB1 (rs1128503, rs1045642) in study group. The link between SNPs and drug response status was examined by the Chi-squared test or the Fisher's exact test. Results: Among six investigated SNPs, two SNPs showed significant difference between the responsive and the resistant group. Among those, heterozygous genotype of SCN1A rs2298771 (AG) were at higher frequency in the resistant patients compared with responsive patients, playing as risk factor of refractory epilepsy. Conversely, the heterozygous genotype of SCN1A rs3812718 (CT) was significantly lower in the resistant compared with the responsive group. No significant association was found between the remaining four SNPs and drug response. Conclusions: Our study demonstrated a significant association between the SCN1A genetic polymorphism which increased risk of drug-resistant epilepsy in Vietnamese epileptic children. This important finding further supports the underlying molecular mechanisms of SCN1A genetic variants in the pathogenesis of drug-resistant epilepsy in children.

Association of rs4516035 Polymorphism with Osteoporosis in the Southeastern Iranian Population: A Case-Control Study.

Genetic polymorphisms are known to play a crucial role in the development of osteoporosis. Vitamin D3 regulates bone homeostasis through the vitamin D receptor (VDR). Reduced VDR activity increases osteoporosis risk. Study Design: A case-control study. This case-control study investigated the potential association between six single-nucleotide polymorphisms (SNPs) within the VDR gene (rs11568820, rs4516035, rs2228570, rs1544410, rs7975232, and rs731236) and the occurrence of osteoporosis in Kerman province. The genotypes of the SNPs were analyzed using polymerase chain reaction-restriction fragment length polymorphism, tetra primer amplification refractory mutation system-PCR, and sequencing in two groups of osteoporosis patients (n=40) and controls (n=42). Additionally, the levels of calcium and vitamin D3 in the serum of the patients were measured, and the in silico analysis of the VDR structure and interaction was performed using I-TASSER, ProSA, PROCHECK, GeneMANIA, GTEx, and GPS 6.0. None of the patients exhibited calcium or vitamin D3 deficiencies. Among the six SNPs, only the T allele in rs4516035, which leads to a shorter variant called VDRA, showed a significant association with susceptibility to osteoporosis (odds ratio=3.061, P=0.007). The in silico analysis demonstrated that the 3D structure, expression, and post-transcriptional modification of VDRA are distinct from those of the more extended variant, VDRB1. VDRB1 is upregulated in sun-exposed skin, and its interactions with its partners differ from those of VDRA. Despite adequate vitamin D levels, the VDRA variant, which has lower activity, could increase the predisposition to osteoporosis in the studied population. These findings clarify the importance of genetic screening for personalized medicine and the effectiveness of prevention and treatment strategies.

Galectin-3 and peripheral artery disease: a Mendelian randomization study.

Multiple clinical studies have found a significant correlation between elevated galectin-3 (Gal-3) in circulation and the diagnosis and severity of peripheral arterial disease (PAD). The current study used the Mendelian randomization (MR) technique to evaluate the possible causal relationship between Gal-3 and PAD. Genome-wide association study (GWAS) data of Gal-3 and PAD were obtained through the MR-Base platform. Then, using Gal-3 as the exposure and PAD as the outcome, a two-sample MR analysis was performed utilizing several regression techniques, including MR-Egger regression, inverse variance weighted (IVW), weighted median, and weighted mode. Six single-nucleotide polymorphisms (SNPs) were identified and designated as instrumental variables (IVs) that exhibited significant correlations with Gal-3 (linkage disequilibrium r2 < 0.001; P < 5 × 10-8). Various statistical methods showed that there was an absence of a significant link between Gal-3 and PAD (IVW: odds ratio (OR) = 0.9869, 95% confidence interval (CI) = 0.8792-1.1078, P = 0.8232). In addition, the presence of genetic pleiotropy did impact the putative causal relationship between PAD and Gal-3 (MR-Egger intercept = 0.0099, P = 0.659). There is no current evidence to establish a causal relationship between the level of Gal-3 in circulation and PAD.

Salmonella Saintpaul outbreak associated with cantaloupe consumption, the United Kingdom and Portugal, September to November 2023.

In September 2023, the UK Health Security Agency identified cases of Salmonella Saintpaul distributed across England, Scotland, and Wales, all with very low genetic diversity. Additional cases were identified in Portugal following an alert raised by the United Kingdom. Ninety-eight cases with a similar genetic sequence were identified, 93 in the United Kingdom and 5 in Portugal, of which 46% were aged under 10years. Cases formed a phylogenetic cluster with a maximum distance of six single nucleotide polymorphisms (SNPs) and average of less than one SNP between isolates. An outbreak investigation was undertaken, including a case-control study. Among the 25 UK cases included in this study, 13 reported blood in stool and 5 were hospitalized. One hundred controls were recruited via a market research panel using frequency matching for age. Multivariable logistic regression analysis of food exposures in cases and controls identified a strong association with cantaloupe consumption (adjusted odds ratio: 14.22; 95% confidence interval: 2.83-71.43; p-value: 0.001). This outbreak, together with other recent national and international incidents, points to an increase in identifications of large outbreaks of Salmonella linked to melon consumption. We recommend detailed questioning and triangulation of information sources to delineate consumption of specific fruit varieties during Salmonella outbreaks.

Molecular Characterization of Erythrocyte Glucose-6-Phosphate Dehydrogenase Deficiency in Different Ethnic Groups of Blood Donors in Mauritania.

Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is the most frequent enzymopathy worldwide; it is a genetic disorder that affects red blood cells and causes hemolysis. Here, we conducted a study on G6PD-deficient subjects in Mauritania to evaluate the molecular characteristics associated with a deficiency in this enzyme and the frequency of nucleotide polymorphisms in the glucose-6-phosphate dehydrogenase gene. A total of 943 blood samples were collected from blood donors (803 males and 140 females; 364 white Moors; 439 black Moors; 112 Pulaar; 18 Wolof; 10 Soninke). All blood samples were analyzed using a rapid screening test. G6PD status was analyzed quantitatively by the Randox G6PD test. Samples deficient in G6PD were extracted from the whole blood samples and subjected to DNA genotyping. The most frequent G6PD variants were determined by two molecular techniques: restriction fragment length polymorphism (RFLP) and multiplex PCR using the GENESPARK G6PD African kit. A total of six single nucleotide polymorphisms (SNPs) (G202A, A376G, A542T, G680T, C563T, and T968C) were identified. The prevalence of G6PD deficiency in this population sample was 8.1%. The most common mutation was A376G/202A and was characterized by the G6PD A-phenotype, which is more common in the G6PD-deficient black Moors population. The wilaya in Nouakchott was the most affected among the 13 wilayas studied. This study shows, for the first time, the presence of the G680T mutation.

Collagen Gene Variants and Anterior Cruciate Ligament Rupture in Italian Athletes: A Preliminary Report.

Several studies have investigated the role of genetics in anterior cruciate ligament (ACL) rupture, often returning conflicting results. The present pilot study aimed to analyze the association between six Single Nucleotide Polymorphisms (SNPs) (rs1800012; rs12722; rs13946; rs240736; rs970547; and rs4870723, located on the COL1A1, COL5A1, COL12A1, and COL14A1 genes), and ACL rupture, among Italian athletes. A hypothesis-driven association study was conducted. In total, 181 male and female athletes (n = 86 injured; n = 96 non-injured) were genotyped for the prioritized variants. All polymorphisms were genotyped using PCR RFLP, with the only exception being the rs1800012 on the COL1A1 gene, which was detected using MTPA PCR. The allele frequency distribution fell within the worldwide range. Despite the evident population variability, no selective pressure signals were recorded using PBS analysis. No significant difference was detected between the cases and controls for any of the SNPs (rs1800012; rs13946; rs240736; rs970547, and rs4870723) included in the analyses (p > 0.008, Bonferroni-adjusted for multiple comparisons). Moreover, no significant differences were found when males and females were assessed separately. Further investigations based on a larger sample size are needed, in order to draw solid conclusions for the influence between collagen genes and ACL rupture.

#3949 NPY GENE POLYMORPHISMS ARE STRONGLY LINKED TO CKD PROGRESSION: A MENDELIAN RANDOMIZATION STUDY

Abstract Background and Aims Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that regulates various physiological processes in both the central and peripheral nervous systems, including cardiovascular and metabolic control. We showed that high plasma NPY predicts CKD progression (NDT 2018;33:1805-1812) in a cohort of 735 patients with stage G2-5 CKD. Whether this association is causal in nature is undetermined. Method In the same cohort of the previous study, we tested the relationship between NPY gene variability, as assessed by six single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure which explained about 80% of gene variability, and the incidence rate of renal events (dialysis/transplantation/eGFR reduction &amp;gt;30%) over a median follow up of 36 months (inter-quartile range 35-37 months). Results Three variants [rs16131 (TT, n = 563; CT+CC, n = 172), rs16140 (CG+GG, n = 413; CC, n = 322), rs16148 (CT+CC, n = 456; TT, n = 279)] coherently associated to the incidence rate of renal events (HR ranging from 1.36 to 1.57, P≤0.029). A dose response relationship was found between the number of risk variants and renal events, the HR for this outcome being highest in patients with three risk genotypes (HR: 1.66, 95% 1.05-2.61). In a multivariate model adjusting for traditional risk factors (age, gender, smoking, diabetes, cholesterol, systolic BP and background cardiovascular comorbidities) and factors peculiar to CKD (haemoglobin, eGFR, albumin, phosphate, and C-reactive protein), the association remained highly significant (P for trend = 0.001). In a separate analysis including the three variants simultaneously, only the rs16131 variant maintained an independent association with the risk for renal events (HR: 1.58, 95% CI 1.11-2.24, P = 0.01). Conclusion This Mendelian randomization study based on three gene variants is fully in line with findings indicating that high plasma NPY predicts a high risk for renal events and lends support to the hypothesis that NPY is causally involved in CKD progression. Establishing the functional significance of the rs16131 variant is a clinical research priority. Drugs antagonizing circulating NPY or its receptors, indeed, might favourably impact on CKD progression.

Decoding the genetic relationship between Alzheimer's disease and type 2 diabetes: potential risk variants and future direction for North Africa.

Alzheimer's disease (AD) and Type 2 diabetes (T2D) are both age-associated diseases. Identification of shared genes could help develop early diagnosis and preventive strategies. Although genetic background plays a crucial role in these diseases, we noticed an underrepresentation tendency of North African populations in omics studies. First, we conducted a comprehensive review of genes and pathways shared between T2D and AD through PubMed. Then, the function of the identified genes and variants was investigated using annotation tools including PolyPhen2, RegulomeDB, and miRdSNP. Pathways enrichment analyses were performed with g:Profiler and EnrichmentMap. Next, we analyzed variant distributions in 16 worldwide populations using PLINK2, R, and STRUCTURE software. Finally, we performed an inter-ethnic comparison based on the minor allele frequency of T2D-AD common variants. A total of 59 eligible papers were included in our study. We found 231 variants and 363 genes shared between T2D and AD. Variant annotation revealed six single nucleotide polymorphisms (SNP) with a high pathogenic score, three SNPs with regulatory effects on the brain, and six SNPs with potential effects on miRNA-binding sites. The miRNAs affected were implicated in T2D, insulin signaling pathways, and AD. Moreover, replicated genes were significantly enriched in pathways related to plasma protein binding, positive regulation of amyloid fibril deposition, microglia activation, and cholesterol metabolism. Multidimensional screening performed based on the 363 shared genes showed that main North African populations are clustered together and are divergent from other worldwide populations. Interestingly, our results showed that 49 SNP associated with T2D and AD were present in North African populations. Among them, 11 variants located in DNM3, CFH, PPARG, ROHA, AGER, CLU, BDNF1, CST9, and PLCG1 genes display significant differences in risk allele frequencies between North African and other populations. Our study highlighted the complexity and the unique molecular architecture of North African populations regarding T2D-AD shared genes. In conclusion, we emphasize the importance of T2D-AD shared genes and ethnicity-specific investigation studies for a better understanding of the link behind these diseases and to develop accurate diagnoses using personalized genetic biomarkers.

Association of Polymorphisms in ZFHX1B and PAX6 With Anisometropia in Chinese Children: The Hong Kong Children Eye Genetics Study.

To identify gene variants associated with anisometropia development in children. This is a population-based, cross-sectional, and longitudinal genetic association study involving 1057 children aged 6 to 10 years with both baseline and 3-year follow-up data. Six single nucleotide polymorphisms (SNPs), ZC3H11B rs4373767, ZFHX1B rs13382811, KCNQ5 rs7744813, SNTB1 rs7839488, PAX6 rs644242, and GJD2 rs524952 were analyzed in all children. Anisometropia was defined by an interocular difference in SE of ≥1 diopter (D) (Aniso-SE) and an interocular difference in axial length (AL) of ≥0.3 mm (Aniso-AL), respectively. Genetic associations of individual SNPs and joint SNP effects were analyzed. ZFHX1B rs13382811 was associated nominally with Aniso-AL (odds ratio [OR], 1.66; P = 0.003) at baseline. At 3 years, rs13382811 was significantly associated with Aniso-AL (OR, 1.49; P = 0.001) and became nominally associated with Aniso-SE (OR, 1.40; P = 0.01). In addition, PAX6 rs644242 was significantly associated with Aniso-AL at 3 years (OR, 1.45; P = 0.002). At the 3-year follow-up, PAX6 rs644242 was associated significantly with Aniso-AL development (OR, 1.61; P = 0.0003) and nominally with Aniso-SE development (P = 0.03) in children who were not anisometropic at baseline, whereas ZFHX1B rs13382811 was associated nominally with Aniso-AL development (P = 0.02). An additive SNP analysis indicated children carrying the risk allele T of ZFHX1B rs13382811 and allele A of PAX6 rs644242 might have a 4.33- and 6.90-fold of increased risk of Aniso-SE and Aniso-AL development by 3 years, respectively. This study identified two susceptible gene variants, ZFHX1B rs13382811 and PAX6 rs644242, for anisometropia development in Hong Kong Chinese children, implicating their role in imbalanced refractive change and axial elongation between both eyes.