Genetic Variants Research Articles

Screening and Site Adaptability Evaluation of Qi-Nan Clones (Aquilaria sinensis) in Southern China

In recent years, plantations of Aquilaria sinensis in China have been dominated by Qi-nan, yet there remains limited research on the growth evaluation and breeding of these clones. In this study, a multi-point joint variance analysis, an additive main effect and multiplicative interaction (AMMI) model, a weighted average of absolute scores (WAASB) stability index, and a genotype main effect plus a genotype-by-environment interaction (GGE) biplot were used to comprehensively analyze the yield, stability, and suitable environment of 25 3-year-old Qi-Nan clones from five sites in southern China. The results showed that all the growth traits exhibited significant differences in the clones, test sites, and interactions between the clones and test sites. The phenotypic variation coefficient (PCV) and genetic variation coefficient (GCV) of the clones’ growth traits at the different sites ranged from 16.56% to 32.09% and 5.24% to 27.06%, respectively, showing moderate variation. The medium–high repeatability (R) of tree height and ground diameter ranged from 0.50 to 0.96 and 0.69 to 0.98, respectively. Among the clones, Clones G04, G05, G10, G11 and G13 showed good growth performance and could be good candidates for breeding. Environmental effects were found to be the primary source of variation, with temperature and light primarily affecting growth, while rainfall influenced survival and preservation rates. Yangjiang (YJ) was found to be the most suitable experimental site for screening high-yield and stable clones across the different sites, whereas the tree height and ground diameter at the Chengmai (CM) site were significantly higher than at the other sites, and the Pingxiang (PX) and Zhangzhou (ZZ) sites showed poor growth performance. The findings suggest that Qi-nan clones are suitable for planting in southern China. There were also abundant genetic variations in germplasm resources for the Qi-nan clones. The five selected clones could be suitable for extensive planting. Therefore, large-scale testing is necessary for determining genetic improvements in Qi-nan clones, which will be conducive to the precise localization of their promotion areas.

7694 Characterizing NF1 Germline Pathogenic Variants In A Cohort Of Patients With Pheochromocytomas And Neurofibromatosis Type 1

Abstract Disclosure: T. Hristova: None. S. Parisien-La Salle: None. S. Lapointe: None. D. Tremblay: None. N. Dumas: None. M. Labidi: None. Z. El Haffaf: None. I. Bourdeau: None. Introduction: Pheochromocytomas and paragangliomas (PPGLs) are the tumors with the highest heritability in adult patients, with identification of a germline mutation in more than 30% of cases. Up to 20 susceptibility genes for PPGLs are known, including NF1. Neurofibromatosis type 1 (NF1) is an inherited disease affecting approximately 1 in 3000 people that predisposes to the development of tumors, such as pheochromocytomas (PHEO). Up to recently, the diagnosis of NF1 was mainly based on clinical manifestations and NF1 genetic characterization was not systematically performed. Objectives: To characterize germline pathogenic variants in the NF1 gene in patients with NF1 developing and PHEO. Methods: We reviewed the charts of patients with a pathology-proven diagnosis of PHEOs that were investigated at Centre hospitalier de l’Université de Montréal (CHUM) between 2000 and May 2023. Genetic analysis included gene sequencing by Sanger method or multigene sequencing by NGS with a panel (Invitae, CA) Results: In our cohort of 220 PHEOs, 15 patients (6.8%) (Males: 6, Females: 9) had a diagnosis of NF1. Mean age at diagnosis of PHEO in NF1 patients was 48 ± 13.6 years, contrasting to the mean age of 38,7 ± 15.2 years in patients carrying germline mutations in non-NF1 genes, most likely reflecting lack of systematic biochemically screening of PHEO in NF1. Urinary metanephrines were elevated in 9/15 patients. 2/15 (15.4%) NF1 patients had bilateral PHEO and 1/15 (7,7%) metastatic disease. Mean tumour diameter was 4.64cm (min-max 1.5 – 12.5 cm). Eight out of 15 NF1 patients underwent NF1 genetic analysis. Heterozygous NF1 germline pathogenic variants were found in all of them: 3 deletions (c.7379delG, c.5844_5845delAA and one encompassing the entire gene), 3 premature stop codons leading to truncated proteins or loss of function (c.7549C>T, c.3916C>T, c.1246C>T), and 2 splicing defects (c.4269+1 G>A, c.1885G>A). Conclusions: We report a large cohort of patients with NF1 and PHEO. The older age at diagnosis of PHEO in NF1 is expected based on lack of systematic biochemical screening for PHEO in NF1 clinical guidelines. We report 8 germline NF1 mutations associated with PHEOs. Further studies are required to fully understand the impact of genetic pathogenic variants in this population and to unravel a possible genotype-phenotype correlation. Presentation: 6/2/2024

6560 Atypical Diabetes Mellitus in a Mother-Son Pair with Multiple Autoimmune Conditions & Pathogenic Variant in BCL11B Inherited from the Mother

Abstract Disclosure: R. Elrajabi: None. N. Gurtunca: None. The etiology of diabetes can be challenging to determine at times and misdiagnosis is common in all age groups. To provide the right treatment and enhance glycemic control, which results in better outcomes and fewer comorbidities, an accurate diagnosis is crucial. We describe a mother-son pair who share a pathogenic variant in BCL11B gene with multiple autoimmune conditions including atypical autoimmune DM. A 13 year old young boy with a history of 33-week prematurity, developmental delay, autoimmune hypothyroidism, and vitiligo presented with concerns for DM given mother’s recent diagnosis of DM treated with Metformin and GLP-1 receptor agonist with poor control of her DM. His mother has a learning disability, hypothyroidism, alopecia totalis, vitiligo and hypertension. Interestingly, he and his mother share a genetic variant in BCL11B gene detected on whole exome sequencing sent as part of the workup of developmental delay. His weight and height were in the 13.5% and 13.9% centiles, respectively. He has vitiligo, but other than that, the physical examination was unremarkable. He is prepubertal. HbA1c was high, 6.4% despite the presence of anemia. An oral glucose tolerance test (OGTT) was consistent with DM as was his repeat HbA1c of 7.1%. He had elevated IA 2, zinc transporter 8, and GAD 65 antibodies, all consistent with autoimmune DM. He was admitted to the hospital and started on both long-acting and short acting insulin via multiple daily injections. BCL11B is a transcription factor that is expressed in all T cells and regulates important processes involved in T cell growth, survival, and function, including Treg cells and Foxp3 activity. Autoimmune diseases have been linked to abnormal Treg activity and Foxp3 deficiency. BCL11B functions as a checkpoint required for T cell lineage commitment while minimizing natural killer cell potential. Impaired BCL11B activity at a young age result in severe whole-body autoimmunity, defined by a fully stimulated immune system similar to animals lacking functioning Treg cells. DM associated with BCL11B variant has not previously been reported. If we follow the theory that autoimmunity affects beta cell function or mass, this patient's and his mother's DM and autoimmune disorders are most likely connected to the BCL11B variation they share. Presentation: 6/2/2024

8481 A 32 Year Old Male With Recurrent Acute Pancreatits and Severe Hypertriglyceridemia: Importance of Considering Genetic Variants

Abstract Disclosure: M.F. Salazar Zelaya: None. J.D. Sibaja Jiménez: None. Background : Hypertriglyceridemia is a common medical scenario in daily practice, causing a variety of symptoms including recurrent episodes of acute pancreatits, which can be severe. Multiple genetic variants can lead to different spectrums of the disease. CLINICAL CASE: A 32 year old male police officer presented to our Endocrinology Outpatient Clinic with a history of long standing hypertriglyceridemia and six previous episodes of acute pancreatits, two in the last twelve months. Familiy history was negative for lipid disorders. The patient had adecuate adherence to diet and exercise as well to prescribed medications, which included Fenofibrate 250 mgs/day and Rosuvastatin 40 mgs/day. The patient denied consumption of alcoholic beverages. Recent abdominal ultrasound was reported without abnormalities. His lipid panel reported elevated triglycerides at 5831 mg/dl (n<150 mg/dl), Total Cholesterol normal at 147 (n<200 mg/dl), low HDL levels at 12 mg/dl (range 12-92 mg/dl) and direct LDL Cholesterol at 120 mg/dl. His TSH value was normal at 1.02 uUI/mL (range 0.55-4.78 uUI/mL). Creatinine level was normal at 0.81 mg/dl (range 0.7-1.3 mg/dl). Liver function tests were normal with AST level at 25 IU/L (range 13-39 IU/L) ALT levels at 22 IU/L (range 7-52 IU/L) and alcaline phosphatase at 62 IU/L (range 34-104 IU/L).His fasting glucose level were normal at 82 mg/dl (n<100 mg/dl). Due to a high Familial Chylomicronemia Syndrome clinical score (13 points) we proceeded with genetic analysis of this patient. Next Generation Sequencing for genes related with chylomicronemia (APOA5, APOC2, GPIHBP1,LMFI, LPL) was performed to determine gene sequence plus copy number variation.Two heterocigote variants were reported, both in the LPL gene. The first one: LPL (NM 000237.3) c.644>A;p.Gly215Glu heterozygous is a missense variant already reported in the literature, registered in ClinVar (ID 1522) and the Leiden Open Variation Database. This variant is classified as pathogenic according to criteria PS3, PM1, PP3, PP5 of the American College of Medical Genetics and Genomics. The second one: LPL (nm 000237.3): c.383C>A;p.Thr128Asn;heterozygous is also a missense variant which to the extent of our knowledge has previously been reported only once in the literature: ClinVar (ID 1520537). This variant is classified currently as of unknown clinical significance according to PM2 criteria. There is however and entry reported (PMID: 8778602) of another variant affecting the same codon (p.Thr128AIa) that is associated to chylomicronemia syndrome. Conclusion: In cases of severe hypertriglyceridemia, suspicion and determination of gene variants are of great importance nowadays as they could eventually guide treatment, given the availability in some countries (and currently pending FDA approval) of new pharmacological therapies such as apo C-III inhibitors. Presentation: 6/2/2024

8721 A Case of Congenital Hyperinsulinism Manifesting as Transient Hypoglycemia During Illness Due to Mosaic Variant of Unknown Significance in ABCC8

Abstract Disclosure: E.E. Bell-Sambataro: None. L. Mamilly: None. Background: Congenital hyperinsulinism (CHI) is characterized by inappropriate secretion of insulin during periods of low blood glucose. CHI can lead to significant complications such as seizures, developmental delays and neurologic damage. CHI can be caused by multiple genetic variants. The most common genetic etiologies are loss of function mutations in the genes ABCC8 and KCNJ11 encoding the pancreatic Beta (β)-cell ATP-sensitive potassium channel causing over secretion of insulin from the β-cells. We report a challenging pediatric case with a clinical presentation of CHI in an infant with a de novo mosaic ABCC8 gene variant of unknown significance manifesting only during times of illness. Clinical Case: A male infant born at 36 weeks gestational age was transferred to a tertiary center NICU secondary to seizure activity and hypoglycemia after the 24 hours of life with glucose levels as low as 32 mg/dL. His birth weight was normal and there was not maternal history of diabetes mellitus. The hypoglycemia persisted throughout the first week of life and required a glucose infusion rate of 11 mg/kg/min, without success in obtaining a critical sample. He had multiple seizures and MRI brain showed signs of hypoglycemic encephalopathy. Subsequently, he was weaned off IV dextrose and completed a 6 hour safety fast prior to discharge. Rapid genome testing resulted in a de novo, mosaic variant of unknown significance in ABCC8 (C.3622G>A resulting in amino acid substitution p.Glu1208Lys). His family reported significant but transient hypoglycemia during times of illness. At the age of 11 months, he was hospitalized for significant hypoglycemia during an episode of acute gastroenteritis and was treated with dextrose-containing fluids for 36 hours. A subsequent diagnostic fasting study resulted in hypoglycemia within 5.5 hours with capillary glucose of 49 mg/dL. At the time of hypoglycemia, beta hydroxybutyrate was inappropriately low at 0.78 mm, insulin level was suppressed <2 mcIU/mL. Glucagon (30 mcg/Kg) was administered after the initial sample was drawn with a significant increase in glucose from 49 mg/dL to 103 mg/dL. Based on the positive glucagon response and low serum ketone, the clinical diagnosis of CHI was made and diazoxide was initiated while awaiting other results. After the second dose of diazoxide, all glucose levels remained above 80 mg/dL. He was sent home on a continuous glucose monitor and diazoxide. Conclusion: CHI can occur due to autosomal recessive or autosomal dominant ABCC8 loss-of-function mutations of which more than half are not responsive to diazoxide. In this case report, we describe the diagnosis of hyperinsulinemic hypoglycemia in an infant with an ABCC8 variant classified with unknown significance. We describe a good initial response to diazoxide in normalizing blood glucose levels in this infant. Presentation: 6/2/2024

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

6483 Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma: A Rare Skeletal Dysplasia/Sarcoma Syndrome

Abstract Disclosure: A. Grover: None. C.R. Ferreira: None. R.I. Gafni: None. S. Jumani: None. M.T. Collins: None. K.L. Roszko: None. I.R. Hartley: None. Introduction: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is a rare autosomal dominant syndrome associated with pathologic fractures, myopathy, premature hair graying, and aggressive osteosarcomas. DMS-MFH has been linked to genetic variants in the methylthioadenosine phosphorylase (MTAP) gene, which encodes an enzyme in the methionine salvage and polyamine synthesis pathway. This pathway is implicated in other skeletal fragility disorders, such as Snyder-Robinson syndrome, suggesting a still undefined role of this pathway in bone biology. We describe a kindred with DMS-MFH and identify diagnostic challenges. Case: A 53-year-old perimenopausal woman presented with four fragility fractures over one year. Relevant history included premature hair graying, esophageal strictures, and nephrolithiasis. The patient’s bone formation markers were slightly elevated; bone resorption markers were within reference range. Her only osteoporosis risk factor was perimenopausal status. Bone series showed a diffuse heterogeneous appearance of the long bones with a mixed lytic/sclerotic appearance. DEXA scan revealed osteopenia. Family history was significant for 2 sons with aggressive osteosarcomas diagnosed in their late teens; one died at age 20. The other son is currently 39-years-old with recurrent osteosarcomas in three different limbs. The family also has a multigenerational history of severe bone fragility, muscle weakness, and premature hair graying. The patient, her living son, and his father underwent genome sequencing that identified a variant in MTAP (c.885A>G; p.(R295=)) in the patient and son. This variant was previously reported in three other families with DMS-MFH and has been shown to alter splicing. Notably, commercial genetic testing did not report this as a relevant variant, and diagnosis required independent analysis of the raw sequence data. Based on these findings, the patient and her son were diagnosed with DMS-MFH. Given the bone fragility with elevated bone turnover markers we treated the patient with yearly zoledronic acid infusions with no subsequent fractures. Surveillance for osteosarcoma is also being performed with annual whole-body MRI. Conclusion: DMS-MFH has been reported in only five families to date. The sixth family described here has clinical characteristics similar to the other kindreds. Due to high risk of aggressive osteosarcoma, timely diagnosis is imperative to decrease morbidity and mortality. Commercial genome sequencing may miss this diagnosis, so targeted genetic testing should be pursued. As more cases are identified, characterization of affected families may enhance our understanding of the natural history of the disease and guide surveillance and treatment strategies. Presentation: 6/2/2024

8294 Association between gene mutations and DNA methylation of CYP11B2 in aldosterone-producing adenoma

Abstract Disclosure: M. Kometani: None. R. Mizoguchi: None. M. Demura: None. K. Aiga: None. S. Konishi: None. D. Aono: None. S. Karashima: None. Y. Takeda: None. T. Yoneda: None. Context: Primary aldosteronism (PA) causes hypertension and cardiovascular complications. Recently, in aldosterone producing adenomas (APA), various genetic mutations have been identified. In addition, epigenetic mechanisms, such as DNA methylation, are also involved in excessive aldosterone production. Several studies have shown that aldosterone synthase (CYP11B2) is hypomethylated in APA. On the other hand, the relationship between specific genetic variants identified in APA and DNA methylation has not been fully clarified. Objective: To investigate the relationship between specific genetic mutations in APA and DNA methylation of CYP11B2. Methods: We analyzed 48 patients (female 23 cases) diagnosed with APA and treated between 2001 and 2022. First, Gene mutation analysis using next-generation sequencing was performed. KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CACNA1H, which are known mutations in PA, and PRKACA, PRKA1A, GNAS, CTNNB1, and ARMC5, which are known mutations in Cushing’s syndrome, were evaluated. Next, DNA methylation analysis of the CYP11B2 promoter using pyrosequencing were performed using APA. We targeted three CpG regions near the transcription start site of CYP11B2. Results: The respective mean values for all patients were: age 52 years, systolic blood pressure 138 mmHg, diastolic blood pressure 87 mmHg, ARR 1,326, serum potassium level 3.4 mEq/L, and tumor diameter 15 mm. Genetic mutation analysis revealed KCNJ5 gene mutations in 33 of the 48 patients. Among the other cases, mutations in the CTNNB1 gene were found in three cases, mutations in the ATP1A1 gene in two cases, mutations in the CACNA1D gene in one case, and PRKACA gene mutations in one case. The remaining seven patients had no mutations in any of the analyzed genes. When DNA methylation of the promoter region of CYP11B2 was analyzed in APAs with and without mutations in KCNJ5, we found that in all three CpG regions, DNA methylation rate was significantly reduced in APAs with mutations in KCNJ5 gene (CpG1 22% vs. 30%, CpG2 42% vs. 73%, CpG3 47% vs. 75%, respectively). Conclusions: The most common genetic mutation in APA was the KCNJ5 mutation; APA with the KCNJ5 mutation had significantly lower methylation rates than CYP11B2. This suggests that genetic mutations in APA affect DNA methylation and result in hormone overproduction. Presentation: 6/3/2024

7397 Characterization of Sperm-Carried IGF2 Transcript Variants

Abstract Disclosure: R. Cannarella: None. M. Suryavanshi: None. A. Miller: None. S.D. Lundy: None. A.E. Calogero: None. Background: We have previously identified the expression of the highly-conserved paternally-imprinted insulin-like growth factor 2 (IGF2) gene in human spermatozoa and suggested its role in early embryo development. Although there are 5 different variants of the IGF2, there is no evidence of the variants expressed in human spermatozoa. Objective: The present basic research study was undertaken to characterize the IGF2 transcript variant(s) expressed in human spermatozoa and to develop a sensitive method that can distinguish variants based on quantitative polymerase chain reaction (qPCR). Methods: Two post-gradient sperm samples from healthy, fertile men with proven paternity were used. Granulosa cells (GCs) obtained after the oocyte retrieval procedure and subsequently isolated and purified from follicular fluid were used as controls. Each sample underwent RNA extraction, cDNA synthesis, and PCR. The PCR product was ligated with the pCR4-TOPO vector and used to transform TOPO10 one-shot electro-competent cells of E. coli DH-10α. For each sample, 32 white colonies (true positive clones selected by blue-white screening method) were grown per sample (total in 96). All 96 clones were fully characterized by Sanger sequencing and single nucleotide polymorphism (SNP) were detected. Variations in products from single IGF2 gene primers pair were recorded on Sybr green-based qPCR, such as variations in melting temperatures (Tm), product size, and number of copies. Results: We successfully isolated and identified 96 true positive colonies, which were confirmed as IGF2 cDNA clones. This comprehensive analysis revealed 11 distinct genetic variants within the cDNA clones. Specifically, these variants comprised 6 SNPs and 5 deletions, highlighting the diversity in the sequences. These findings were particularly significant in relation to the IGF2 primer employed in the study, as they indicated the presence of 11 different sequence variants. By Sybr green qPCR, clones derived from GCs and sperm samples predominantly showed an IGF2 transcript variant with Tms of 89.01°C, 88.86°C, and 88.71°C. In a surprising observation, the sperm samples exhibited three sperm-specific variants with a range of a Tm ranging from 89.01°C to 88.26°C. Furthermore, the deletions were characterized by a significantly lower Tm, ranging between 78.86°C and 71.11°C. Conclusion: The IGF2 transcript is intrinsically present in sperm samples, albeit with notable variations. The detected variants likely arise from SNPs within the transcripts and the deletions could be attributed to splicing activity during maturation or post-transcriptional modifications. To our knowledge, this is the first study targeting the IGF2 transcript variants in spermatozoa from fertile men. Basic research is needed to understand the implications of different sperm-specific IGF2 transcript variants on early embryo development. Presentation: 6/2/2024

The goat pan-genome reveals patterns of gene loss during domestication

BackgroundUnveiling genetic diversity features and understanding the genetic mechanisms of diverse goat phenotypes are pivotal in facilitating the preservation and utilization of these genetic resources. However, the total genetic diversity within a species can’t be captured by the reference genome of a single individual. The pan-genome is a collection of all the DNA sequences that occur in a species, and it is expected to capture the total genomic diversity of the specific species.ResultsWe constructed a goat pan-genome using map-to-pan assemble based on 813 individuals, including 723 domestic goats and 90 samples from their wild relatives, which presented a broad regional and global representation. In total, 146 Mb sequences and 974 genes were identified as absent from the reference genome (ARS1.2; GCF_001704415.2). We identified 3,190 novel single nucleotide polymorphisms (SNPs) using the pan-genome analysis. These novel SNPs could properly reveal the population structure of domestic goats and their wild relatives. Presence/absence variation (PAV) analysis revealed gene loss and intense negative selection during domestication and improvement.ConclusionsOur research highlights the importance of the goat pan-genome in capturing the missing genetic variations. It reveals the changes in genomic architecture during goat domestication and improvement, such as gene loss. This improves our understanding of the evolutionary and breeding history of goats.

Infection Frequency and Allelic Variants of Toxoplasma gondii in Wildlife from the Panama Canal Zone

Panama has a large number of wild animal species, which could host a highly diverse amount of genetic variants of Toxoplasma gondii (T. gondii). In this context, we highlight the importance of understanding the population structure of T. gondii in Panamanian wildlife and the genetic variants that can be rapidly transferred to domestic environments. This study analyzed the infection frequency and allelic composition of T. gondii in different tissue samples from wild animals. The infection frequency was measured by the PCR technique using the B1 gene as a molecular marker. The results showed a high frequency (65.6%) of infection in tissue samples collected from 221 wild animals. Stratified analyses for bird and mammal samples showed positivity rates of 67.2% and 70.12%, respectively, with no statistically significant differences. Infection frequency was also measured in five types of organs (brain, liver, heart, lung, and skeletal muscle), which showed homogeneous frequencies. The genetic diversity of the T. gondii population contained in the tissues of wild animals was analyzed by the Multilocus Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique, using five genes called SAG1, SAG2, SAG3, GRA6, and Apico. This analysis revealed the presence of alleles of these genes corresponding to T. gondii lineages I, II, and III. Allele III was only identified with the Apico gene in a single reptile individual analyzed. Our findings indicated diverse allelic distribution at the analyzed loci, suggesting that the tissues were probably infected by non-archetypal individuals of T. gondii.

Investigating the Genetic Association of 40 Biochemical Indicators with Parkinson's Disease.

The mechanisms of Parkinson's disease (PD) are not fully understood, which hinders the development of effective therapies. Research indicates that lower levels of biochemical indicators like bilirubin, vitamin D, and cholesterol may elevate the risk of PD. However, clinical studies on abnormal levels of biochemical indicators in PD patients' circulation are inconsistent, leading to ongoing debate about their association with PD. Here, we investigate the genetic correlation between 40 biochemical indicators and PD using a bidirectional two-sample Mendelian randomization (MR) approach to uncover potential causal relationships. Data from genome-wide association studies (GWAS) were utilized, with genetic variations from specific lineages serving as instrumental variables (IVs). The methodology followed the STROBE-MR checklist and adhered to the three principal assumptions of MR. Statistical analyses employed methods including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Biochemical indicators including albumin, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) showed significant associations with PD risk. Elevated levels of albumin (OR = 1.246, 95% CI 1.006-1.542, P = 0.043) and SHBG (OR = 1.239, 95% CI 1.065-1.439, P = 0.005) were linked to higher PD risk. Conversely, increased CRP levels (OR = 0.663, 95% CI 0.517-0.851; P = 0.001) could potentially lower PD risk. The robustness of the results was confirmed through various MR analysis techniques, including assessments of directional pleiotropy and heterogeneity using MR-Egger intercept and MR-PRESSO methods. This study systematically reveals, for the first time at the genetic level, the relationship between 40 biochemical indicators and PD risk. Our research verifies the role of inflammation in PD and provides new genetic evidence, further advancing the understanding of PD pathogenesis. The study shows a positive correlation between albumin and SHBG with PD risk and a negative correlation between CRP and PD risk. This study identifies for the first time that SHBG may be involved in the onset of PD and potentially worsen disease progression.

Uric acid levels and cardiovascular and cerebrovascular diseases: a Mendelian randomization study.

The relationship between uric acid (UA) levels and cardiovascular and cerebrovascular diseases (CCVD) is controversial. A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects of UA levels on CCVD. Genetic variants strongly associated with UA levels were selected as instrumental variables from the Genome-Wide Association Study (GWAS) dataset. The GWAS data, sourced from the Global Urate Genetics Consortium (GUGC), comprised a sample size of 110,347 individuals. The selected CCVD outcomes included stroke, coronary artery disease (CAD), as well as atrial fibrillation and flutter. The primary analytical approach employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median as complementary methods. Sensitivity analysis was performed to test heterogeneity and pleiotropy. The MR analysis results indicated a causal association between UA levels and stroke (OR: 1.002; 95% CI: 1.000-1.003; p = 0.036), CAD (OR: 1.118; 95% CI: 1.044-1.197; p = 0.001), as well as atrial fibrillation and flutter (OR: 1.141; 95% CI: 1.037- 1.256; p = 0.007). The results of MR-Egger and weighted median methods confirmed the direction of the IVW results, enhancing the robustness of the findings. No significant anomalies were detected in the sensitivity analysis. The MR study suggests that UA levels exert causal effects on stroke, CAD, as well as atrial fibrillation and flutter.

Association of genetic ancestry with pre-eclampsia in multi-ethnic cohorts of pregnant women

ObjectivesMaternal self-reported ethnicity is recognised as a risk factor for pre-eclampsia in clinical screening tools and models. This study investigated whether ethnicity is acting as a proxy for genetic variants in this context. Study designA total of 436 women from multi-ethnic backgrounds recruited to two UK observational pregnancy hypertension cohort studies were genotyped. Genetically-computed individual ancestry estimates were calculated for each individual through comparison to the multi-ethnic 1000 Genomes reference panel genotypes. Regression models for pre-eclampsia using clinical risk factors including self-reported ethnicity with and without ancestry estimates were built and compared using Likelihood Ratio Tests (LRT). Main outcome measuresPre-eclampsia (early- and late-onset). ResultsIn these multi-ethnic cohorts (mean age 34.9 years; 41.3 % White, 34.2 % Black, 13.1 % Asian ethnic backgrounds; 82.6 % chronic hypertension), discrepancies between self-reported ethnicity and genetically-computed individual ancestry estimates were present in all ethnic groups, particularly minority groups. Genetically-computed pan-African ancestry percentage was associated with early-onset (< 34 weeks) pre-eclampsia in adjusted models (aOR 100 % vs 0 % African ancestry: 3.81, 95 % CI 1.04–14.14, p-value 0.044) independently of self-reported ethnicity and established clinical risk factors. Addition of genetically-computed African ancestry to a clinical risk factor model including self-reported ethnicity, improved model fit (Likelihood ratio test p-value 0.023). ConclusionsSelf-reported maternal ethnicity is an imperfect proxy for genetically-computed individual ancestry estimates, particularly in ethnic minority groups. Genetically-computed African ancestry percentage was associated with early-onset pre-eclampsia independently of self-reported maternal ethnicity. Well-powered studies in multi-ethnic cohorts are required to delineate the genetic contribution to pre-eclampsia.

Advances in Factors Affecting ALDH2 Activity and its Mechanisms.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme primarily involved in the detoxification of alcohol-derived aldehyde and endogenous toxic aldehydes. It exhibits widespread expression across various organs and exerts a broad and significant impact on diverse acute cardiovascular diseases, including acute coronary syndrome, acute aortic dissection, hypoxic pulmonary hypertension, and heart failure. The ALDH2 rs671 variant represents the most prevalent genetic variant in East Asian populations, with carriage rates ranging from 30 to 50% among the Chinese population. Given its widespread presence in the body, the wide range of diseases it affects, and its high rate of variation, it can serve as a crucial tool for the precise prevention and treatment of acute cardiovascular diseases, while offering individualized medication guidance. This review aims to provide a comprehensive overview of the latest advancements in factors affecting ALDH2 activity, encompassing post-transcriptional modifications, modulators of ALDH2, and relevant clinical drugs.

Genome-wide association study of cassava brown streak disease resistance in cassava germplasm conserved in South America

Cassava (Manihot esculenta Crantz) is a vital carbohydrate source for over 800 million people globally, yet its production in East Africa is severely affected by cassava brown streak disease (CBSD). Genebanks, through ex-situ conservation, play a pivotal role in preserving crop diversity, providing crucial resources for breeding resilient and disease-resistant crops. This study genotyped 234 South American cassava accessions conserved at the CIAT genebank, previously phenotyped for CBSD resistance by an independent group, to perform a genome-wide association analysis (GWAS) to identify genetic variants associated with CBSD resistance. Our GWAS identified 35 single nucleotide polymorphism (SNP) markers distributed across various chromosomes, associated with disease severity or the presence/absence of viral infection. Markers were annotated within or near genes previously identified with functions related to pathogen recognition and immune response activation. Using the SNP candidates, we screened the world’s largest cassava collection for accessions with a higher frequency of favorable genotypes, proposing 35 accessions with potential resistance to CBSD. Our results provide insights into the genetics of CBSD resistance and highlight the importance of genetic resources to equip breeders with the raw materials needed to develop new crop varieties resistant to pests and diseases.

A Mendelian analysis of the causality between inflammatory cytokines and digestive tract cancers.

In this study, we performed a two-sample Mendelian randomization (MR) analysis to assess the causality between inflammatory cytokines and the risk of digestive tract cancers (DTCs). Furthermore, we conducted a molecular docking study to predict the therapeutic mechanisms of traditional Chinese medicine (TCM) compounds in the treatment of DTCs. In our MR analysis, genetic variations associated with eight types of DTCs were utilized, which were sourced from a large publicly available genome-wide association study dataset (7929 cases and 1 742 407 controls of European ancestry) and inflammatory cytokines data from a genome-wide association study summary of 8293 European participants. Inverse-variance weighted method, MR-Egger, and weighted median were performed to analyze and strengthen the final results. We investigated the effects of 41 inflammatory molecules on 8 types of DTCs. Subsequently, the effect of DTCs on positive inflammatory factors was analyzed by means of inverse MR. Molecular docking was exploited to predict therapeutic targets with TCM compounds. Interleukin-7, interleukin-16, macrophage colony-stimulating factor, monokine induced by interferon-gamma, and vascular endothelial growth factor may be significantly associated with various types of DTCs. Five TCM compounds (baicalin, berberine, curcumin, emodin, and salidroside) demonstrated better binding energies to both interleukin-7 and vascular endothelial growth factor than carboplatin. This study provides strong evidence to support the potential causality of some inflammatory cytokines on DTCs and indicates the potential molecular mechanism of TCM compounds in the treatment of DTCs. Key message What is already known on this topic The increasing evidence indicates that inflammatory cytokines are implicated in the pathogenesis of digestive tract cancers (DTCs). Nevertheless, the causal relationship between inflammatory cytokines and DTCs remains indistinct. Additionally, certain traditional Chinese medicine compounds have been demonstrated to treat DTCs by influencing inflammatory factors, yet their underlying potential mechanisms remain ambiguous. What this study adds In this study, Mendelian randomization analysis was performed for the first time regarding the causality between human inflammatory cytokines and eight types of DTCs, which revealed that inflammatory factors may play different roles in different types of DTCs. Moreover, molecular docking of key inflammatory factors was implemented, indicating the targets for drug actions. How this study might affect research, practice, or policy This research has the potential to reveal the causality between 41 inflammatory factors and 8 DTCs, offering novel perspectives for the prevention and management strategies of DTCs. Additionally, it indicates the targets for the actions of traditional Chinese medicine on the key inflammatory factors of these cancers.

Detection of SARS-CoV-2 variants related mutations in wastewater using RT-qPCR and variant-specific probes in Porto Alegre, Southern Brazil

ABSTRACT The COVID-19 pandemic has underscored the significance of monitoring genetic variations in pathogenic viruses to manage its transmission and identify emerging variants. Nonetheless, sequencing every positive patient case is impractical for large-scale testing of the population. Here, we introduce a cost-effective tool for identifying SARS-CoV-2 mutations associated with variants in wastewater. This approach relies on a wastewater surveillance system and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), as detailed in our previous study (Prandi et al. 2022), utilizing mutation-specific probes. Wastewater samples were analyzed for SARS-CoV-2 mutations corresponding to variants under monitoring (VUM) (P.2, alpha, beta, gamma, delta, and omicron) as part of a wastewater-based SARS-CoV-2 monitoring program. Our findings validate the efficacy of this method in detecting SARS-CoV-2 mutations linked to variants in wastewater, facilitating early detection of emerging variants and informing decision-making on control measures.

Drug Metabolizing Enzymes: An Exclusive Guide into Latest Research in Pharmaco-genetic Dynamics in Arab Countries.

Drug metabolizing enzymes play a crucial role in the pharmacokinetics and pharmacodynamics of therapeutic drugs, influencing their efficacy and safety. This review explores the impact of genetic polymorphisms in drug-metabolizing genes on drug response within Arab populations. We examine the genetic diversity specific to Arab countries, focusing on the variations in key drug-metabolizing enzymes such as CYP450, GST, and UGT families. The review highlights recent research on polymorphisms in these genes and their implications for drug metabolism, including variations in allele frequencies and their effects on therapeutic outcomes. Additionally, the paper discusses how these genetic variations contribute to the variability in drug response and adverse drug reactions among individuals in Arab populations. By synthesizing current findings, this review aims to provide a comprehensive understanding of the pharmacogenetic landscape in Arab countries and offer insights into personalized medicine approaches tailored to genetic profiles. The findings underscore the importance of incorporating pharmacogenetic data into clinical practice to enhance drug efficacy and minimize adverse effects, ultimately paving the way for more effective and individualized treatment strategies in the region.

Deep learning predicted perceived age is a reliable approach for analysis of facial ageing: A proof of principle study.

Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age-related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability. To determine if estimating PA using deep learning-based algorithms results in the same associations with morbidities and genetic variants as human-estimated perceived age. Self-supervised learning (SSL) and deep feature transfer (DFT) deep learning (DL) approaches were trained and tested on human-estimated PAs and their corresponding frontal face images of middle-aged to elderly Dutch participants (n = 2679) from a population-based study in the Netherlands. We compared the DL-estimated PAs with morbidities previously associated with human-estimated PA as well as genetic variants in the gene MC1R; we additionally tested the PA associations with MC1R in a new validation cohort (n = 1158). The DL approaches predicted PA in this population with a mean absolute error of 2.84 years (DFT) and 2.39 years (SSL). In the training-test dataset, we found the same significant (p < 0.05) associations for DL PA with osteoporosis, ARHL, cognition, COPD and cataracts and MC1R, as with human PA. We also found a similar but less significant association for SSL and DFT PAs (0.69 and 0.71 years per allele, p = 0.008 and 0.011, respectively) with MC1R variants in the validation dataset as that found with human, SSL and DFT PAs in the training-test dataset (0.79, 0.78 and 0.71 years per allele respectively; all p < 0.0001). Deep learning methods can automatically estimate PA from facial images with enough accuracy to replicate known links between human-estimated perceived age and several age-related morbidities. Furthermore, DL predicted perceived age associated with MC1R gene variants in a validation cohort. Hence, such DL PA techniques may be used instead of human estimations in perceived age studies thereby reducing time and costs.