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Indian Journal of Ophthalmology Jun 2023This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
PURPOSE
This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
METHODS
A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls.
RESULTS
Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14-4.05), the reverse was observed with p.R217H (OR 0.086-1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96-1.00).
CONCLUSION
The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co-inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.
Topics: Humans; Asian People; Case-Control Studies; Eye Proteins; Homeodomain Proteins; Keratoconus
PubMed: 37322657
DOI: 10.4103/IJO.IJO_2894_22 -
Diagnostics (Basel, Switzerland) Oct 2023The study aims to develop a decision pathway based on HEAR score and 0 h high-sensitivity cardiac troponin T (hs-cTnT) to safely avoid a second troponin test for...
The study aims to develop a decision pathway based on HEAR score and 0 h high-sensitivity cardiac troponin T (hs-cTnT) to safely avoid a second troponin test for suspected non-ST elevation myocardial infarction (NSTEMI) in emergency departments. A HEAR score consists of history, electrocardiogram, age, and risk factors. A HEAR pathway is established using a Bayesian approach based on a predefined safety threshold of NSTEMI prevalence in the rule-out group. In total, 7131 patients were retrospectively enrolled, 582 (8.2%) with index visit NSTEMI and 940 (13.2%) with 180-day major adverse cardiovascular events (MACE). For patients with a low-risk HEAR score (0 to 2) and low 0 h hs-cTnT (<14 ng/L), the HEAR pathway recommends early discharge without further testing. After the HEAR pathway had been applied to rule out NSTEMI, the negative predictive value of index visit NSTEMI was 100.0% (95% CI, 99.8% to 100.0%) and false-negative rate of 180-day MACE was 0.40% (95% CI, 0.18% to 0.87%). Compared with the 0 h hs-cTnT < limit of detection (LoD) strategy (<5 ng/L), the HEAR pathway could correctly reclassify 1298 patients without MACE as low risk and lead to a 18.2% decrease (95% CI, 17.4-19.1%) in the need for a second troponin test. The HEAR pathway may lead to a substantial and safe reduction in repeated troponin test for emergency department patients with suspected NSTEMI.
PubMed: 37892038
DOI: 10.3390/diagnostics13203217 -
Aging & Mental Health Sep 2020To compare quality of life (QOL) of family carers of persons with young- (YOD) to late-onset dementia (LOD). This was a cross-sectional comparison of 88 carers of...
To compare quality of life (QOL) of family carers of persons with young- (YOD) to late-onset dementia (LOD). This was a cross-sectional comparison of 88 carers of persons with YOD and 100 carers of persons with LOD. The Quality of Life - Alzheimer's Disease questionnaire (QOL-AD) was used to measure QOL of both carers and persons with dementia. Depressive symptoms were measured by the Geriatric Depression Scale (GDS) for carers and the Cornell Scale for Depression in Dementia for persons with dementia. Care burden was measured by the Relatives' Stress Scale. Activities of Daily Living (ADL) of the persons with dementia were assessed using the total score from the Lawton & Brody Instrumental-ADL scale and the Physical Self-Maintenance Scale. Multiple linear regression models with interactions between covariates and group (YOD versus LOD) were estimated. The QOL-AD scores of YOD-carers were significantly poorer compared to LOD-carers (mean difference 2.5 (95% CI 0.7; 4.3), = 0.006). Poorer QOL of carers was associated with more depressive symptoms (mean QOL-AD change -0.5 (-0.6; -0.3), < 0.001), but with no difference between the two groups. In contrast to LOD, QOL of carers of people with YOD was also significantly associated with symptom duration ( = 0.002), depressive symptoms of the persons with dementia ( = 0.030), ADL ( = 0.001), and carer burden ( = 0.002). YOD-carers reported significantly poorer QOL compared to LOD-carers. QOL was significantly associated with depressive symptoms in carers of both groups.
Topics: Activities of Daily Living; Age of Onset; Aged; Caregivers; Cross-Sectional Studies; Dementia; Humans; Quality of Life
PubMed: 31106576
DOI: 10.1080/13607863.2019.1617245 -
Thyroid : Official Journal of the... Jul 2018Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent...
BACKGROUND
Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).
METHODS
Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.
RESULTS
Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02).
CONCLUSIONS
The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.
Topics: Adult; DNA Copy Number Variations; Female; Genetic Linkage; Genetic Predisposition to Disease; Goiter, Nodular; Haplotypes; Humans; Introns; Male; Middle Aged; Pedigree; Phospholipase C beta; Thyroid Gland; Thyroidectomy
PubMed: 29897006
DOI: 10.1089/thy.2017.0312 -
Journal of Human Genetics Feb 2017Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery....
Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Genetic Linkage; Genome-Wide Association Study; Genotype; Hispanic or Latino; Humans; Insulin Resistance; Laminin; Lod Score; Male; Middle Aged; NFI Transcription Factors; Polymorphism, Single Nucleotide; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 27535031
DOI: 10.1038/jhg.2016.103 -
Proceedings of the National Academy of... Aug 2019The regulatory network of genes and molecules in sleep/wakefulness remains to be elucidated. Here we describe the methodology and workflow of the dominant screening of...
The regulatory network of genes and molecules in sleep/wakefulness remains to be elucidated. Here we describe the methodology and workflow of the dominant screening of randomly mutagenized mice and discuss theoretical basis of forward genetics research for sleep in mice. Our high-throughput screening employs electroencephalogram (EEG) and electromyogram (EMG) to stage vigilance states into a wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS). Based on their near-identical sleep/wake behavior, C57BL/6J (B6J) and C57BL/6N (B6N) are chosen as mutagenized and counter strains, respectively. The total time spent in the wake and NREMS, as well as the REMS episode duration, shows sufficient reproducibility with small coefficients of variance, indicating that these parameters are most suitable for quantitative phenotype-driven screening. Coarse linkage analysis of the quantitative trait, combined with whole-exome sequencing, can identify the gene mutation associated with sleep abnormality. Our simulations calculate the achievable LOD score as a function of the phenotype strength and the numbers of mice examined. A pedigree showing a mild decrease in total wake time resulting from a heterozygous point mutation in the gene is described as an example.
Topics: Animals; Calcium Channels, N-Type; Computer Simulation; Crosses, Genetic; Disorders of Excessive Somnolence; Ethylnitrosourea; Female; Genes, Dominant; Genetic Testing; Homozygote; Lod Score; Male; Mice, Inbred C57BL; Mutation; Pedigree; Phenotype; Reproducibility of Results; Sleep; Wakefulness
PubMed: 31337678
DOI: 10.1073/pnas.1906774116 -
Journal of Medical Genetics Sep 2017Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in...
BACKGROUND
Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%-20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative.
AIM
We investigated the cause of maturation arrest in five azoospermic infertile men of a large consanguineous Bedouin family.
METHODS AND RESULTS
Using whole genome genotyping and exome sequencing we identified a 4 bp deletion frameshift mutation in as the causative mutation with a Lod Score of 3.42. We demonstrate that the mutation results in a frameshift as well as exon skipping. Immunofluorescent staining with anti-TDRD9 antibody directed towards the N terminus demonstrated the presence of the protein in testicular biopsies of patients with an intracellular distribution comparable to a control biopsy. The mutation does not cause female infertility.
CONCLUSION
This is the first report of a recessive deleterious mutation in in humans. The clinical phenotype recapitulates that observed in the knockout mice where this gene was demonstrated to participate in long interspersed element-1 retrotransposon silencing. If this function is preserved in human, our data underscore the importance of maintaining DNA stability in the human male germ line.
Topics: Azoospermia; DNA Helicases; Frameshift Mutation; Genes, Recessive; Humans; Male; Phenotype; Protein Domains; RNA Splicing; Testis
PubMed: 28536242
DOI: 10.1136/jmedgenet-2017-104514 -
International Journal of Cardiology Feb 2019We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac... (Comparative Study)
Comparative Study
BACKGROUND
We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI).
METHODS
922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin <10, <14 or < 20 pmol/L and hs-cTnT≤14 ng/L), the 1 h-algorithm (hs-cTnT<12 ng/L and change <3 ng/L at 1 h), as well as the hs-cTnT limit-of-blank (LoB, <3 ng/L) and -detection (LoD, <5 ng/L) were compared. Outcomes were assessed as combined end-points of death and myocardial re-infarction.
RESULTS
True-negative rule-out using the DMS could be achieved in 50.9%-62.3% of all patients compared to 35.0%, 45.3% and 64.5% using LoB, LoD or the 1 h-algorithm, respectively. The DMS showed NPVs of 98.1%-98.3% compared to 99.2% for the 1 h-algorithm, 99.4% for the LoB and 99.3% for the LoD. Sensitivities were 93.5%-94.8%, as well as 96.8%, 98.7% and 98.1%, respectively. Addition of clinical low-risk criteria such as a HEART-score ≤ 3 to the DMS resulted in NPVs and sensitivities of 100% with a true-negative rule-out to 33.8%-41.6%. Rates of the combined end-point of death/MI within 30 days ranged between 0.2% and 0.3% for all fast-rule-out protocols.
CONCLUSION
Depending on the applied copeptin cut-off and addition of clinical low-risk criteria, the DMS might be an alternative to the hs-cTn-only-based algorithms for rapid AMI rule-out with comparable diagnostic measures and outcomes.
Topics: Aged; Algorithms; Biomarkers; Electrocardiography; Female; Glycopeptides; Humans; Immunoassay; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Prognosis; Prospective Studies; Time Factors; Troponin T
PubMed: 30404726
DOI: 10.1016/j.ijcard.2018.10.084 -
Journal of Diabetes Research 2019Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are...
Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal ( = 1,800). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels ( values: 1.15 × 10 and 3.39 × 10, respectively). We localized a significant (LOD score = 3.18) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common (MAF > 0.4) SNPs within the chromosome 11 QTL were associated with GSP (adjusted value < 5.87 × 10): an intronic variant (rs10790184) in the gene and a 3'UTR variant (rs8258) in the gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits ( values: 0.0062 to 1.78 × 10). A significant negative correlation was observed between %GA and HDL cholesterol ( = 1.12 × 10). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) samples, which allows the prospect of retrospective glycemic studies using archived samples.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Blood Pressure; Blood Proteins; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus; Family Health; Female; Genetic Predisposition to Disease; Genotype; Glycated Hemoglobin; Glycosylation; Humans; Hyperglycemia; Hypoglycemia; Lipids; Lod Score; Male; Middle Aged; Nepal; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Retrospective Studies; Risk Factors; Serum Albumin; Young Adult
PubMed: 31089471
DOI: 10.1155/2019/2310235 -
The Canadian Journal of Neurological... Sep 2019Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with...
BACKGROUND
Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility.
METHODS
Genome-wide linkage analysis performed using 400 microsatellite repeat markers spaced at 10 cM throughout the genome. The members of this family were phenotyped for each condition, migraine, vertigo, and motion sickness and analyzed separately. Statistical analysis was performed using two-point and multipoint linkage analysis employing a number of models including autosomal recessive or dominant patterns of inheritance with high and low genetic penetrance.
RESULTS
We identified a novel locus for migraine, 9q13-q22 (maximum two-point logarithm of odds [LOD] score-2.51). In addition, there are suggestive LOD scores that localize to different chromosomes for each phenotype; vertigo (chromosome 18, LOD score of 1.82) and motion sickness (chromosome 4, LOD score of 2.09).
CONCLUSIONS
Our analysis supports our hypothesis that the migraine-associated vertigo and motion sickness may involve distinct susceptibility genes.
Topics: Adolescent; Child; Female; Genetic Linkage; Genetic Predisposition to Disease; Humans; Male; Migraine Disorders; Motion Sickness; Pedigree; Vertigo; Young Adult
PubMed: 31258098
DOI: 10.1017/cjn.2019.64