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PubMed2024

Genome-Wide Association Study of Accessory Atrioventricular Pathways.

IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. EXPOSURES: Sequence variants. MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs. RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Humans↗

PubMed1983

Possible mechanism for origin of chiral specificity during origins of life.

We have earlier (Origins of Life 10 (1980), 15-30) proposed a conformational theory for the origin of nucleic acid-directed adaptor-mediated ordered and proliferative synthesis of proteins and hence origin of life. Conjunction of L-amino acids and beta-D-ribonucleotides emerges as a natural consequence of a template fitting interaction in this theory of the origin of the genetic decoding apparatus. Here we propose an interesting new concept for the origin of chiral specificity, by showing that two autonomously developing systems of protein-synthesizing machinery, one manufacturing L-peptides (L-system) and the other, D-peptides (D-system) could have arisen and during early stages of evolution L-system could have developed a killer enzyme to destroy the D-system, causing the presently existing chiral specificity in all the evolved organisms on Earth. It would be interesting to look for such 'killer enzymes' in the present-day organisms. Of course, the existence of D-amino acid-containing antibiotics gives some credence to this theory.

Genetic Code↗

PubMed2000

Prevalence and inheritance of hip osteoarthritis in Iceland.

The purpose of this study was to: (I) assess the prevalence of hip osteoarthritis (OA) in Iceland and compare it with that in Southern Scandinavia, (II) determine the incidence of total hip replacement (THR) for primary OA in Iceland, (III) compare two different methods for defining radiographic hip OA, (IV) assess in a population-wide study in Iceland the genetic contribution t hip OA leading to THR, and (V) perform a genome-wide scan of a large Icelandic family to identify a chromosomal susceptibility locus for hip OA leading to THR. many Icelandic patients with hip OA have been well aware that this disease "goes in the family". by examining a large proportion of all Icelandic colon radiographs taken 1990-1996 the prevalence of radiographic hip OA in Iceland was found to be at least five-fold higher compared to Swedish and Danish studies that have used the same methods. A comparison of two methods for estimating hip OA from colon radiographs showed that a simple quantitative method of measuring joint space was more reliable than a qualitative method. The age-standardized incidence of THR for primary hip OA in Iceland between 1982 and 1996 was estimated and found to be about 50 percent higher than for Sweden. The higher Icelandic prevalence of hip OA may explain most of this difference. To investigate the contribution of heritability to hip OA leading to THR, information from two population-wide database in Iceland was combined: A national registry of THR between 1972 and 1996, and a genealogy database of all Icelandic genealogy records for the last 11 centuries made available by deCode Genetics. The genetic contribution to THR for OA was assessed by (a) identifying familial clusters of THR for OA, (b) applying the minimum founder test (MFT) to estimate the minimum number of ancestors to account for all patients with THR for OA, compared to the average number of founders for control lists, (c) calculating an average pairwise kinship coefficient (KC) for the patient and control lists, (d) estimating the relative risk (RR) for relatives of patients with THR for OA. A large number of familial clusters of patients with THR for OA were identified. MFT showed that OA patients descended from fewer founders than the control groups. The average pairwise KC among patients with OA was greater than in the population. RR for siblings of THR for OA patients was 3.05 (2.52, 3.10). Icelandic patients with THR for OA are thus significantly more related to each other than are matched controls. These findings support a significant genetic contribution to a common form of OA and encourages the search for genes conferring an increased susceptibility to OA. New techniques now make it possible to search the whole human genome for chromosomal susceptibility loci associating with OA. A genome wide scan was done to identify susceptibility loci for hip OA leading to THR, using DNA from a large Icelandic family with a very high prevalence of primary hip OA. A genome locus with a lod score of 2.58 was identified on chromosome 16p. A similar locus has been reported on from England. This is the first instance where what may be the same susceptibility locus for OA is independently described in two different populations with hip OA. We have identified other families with hip OA which link to the studied family and are continuing an expanded genome-wide scan. Continued studies of the kind outlined here will clarify the complex genetic background of OA and identify genetic variation associated with the disease. In addition to improving our understanding of the pathogenesis of OA and identifying new molecular targets for treatment, this will allow a better insight into the interactions between genetic background and environmental factors that initiate and drive OA.

Adult↗

PubMed1997

The ternary complex of EF-Tu and its role in protein biosynthesis.

The past year has seen a breakthrough in our structural understanding of how aminoacyl-tRNAs are selected and transported to the ribosomal A-site in order to decode genetic information contained in messenger RNA. All aminoacyl-tRNAs are recognized by the elongation factor EF-Tu in prokaryotes or EF-1alpha in eukaryotes. The recent determination of the structure of the ternary complex of aminoacyl-tRNA, EF-Tu and a GTP analogue shows how the CCA end of all aminoacyl-tRNA structures can be accommodated in a specific binding site on EF-Tu-GTP, and how part of the T-helix can be recognized by EF-Tu in a non-sequence-specific way. Furthermore, the structure of the ternary complex shows striking structural similarity to the structure of another prokaryotic elongation factor, EF-G, the tRNA translocase, in its GDP or empty form. This observation has led to the proposal of a general macromolecular mimicry of RNA and protein, which predicts elements of RNA-like structures will occur in other translation factors, such as initiation factors and release factors, that interact with similar sites on the ribosome.

Peptide Elongation Factor Tu↗

PubMed1999

tRNA discrimination at the binding step by a class II aminoacyl-tRNA synthetase.

Aminoacyl-tRNA synthetases preserve the fidelity of decoding genetic information by accurately joining amino acids to their cognate transfer RNAs. Here, tRNA discrimination at the level of binding by Escherichia coli histidyl-tRNA synthetase is addressed by filter binding, analytical ultracentrifugation, and iodine footprinting experiments. Competitive filter binding assays show that the presence of an adenylate analogue 5'-O-[N-(L-histidyl)sulfamoyl]adenosine, HSA, decreased the apparent dissociation constant (K(D)) for cognate tRNA(His) by more than 3-fold (from 3.87 to 1.17 microM), and doubled the apparent K(D) for noncognate tRNA(Phe) (from 7.3 to 14.5 microM). By contrast, no binding discrimination against mutant U73 tRNA(His) was observed, even in the presence of HSA. Additional filter binding studies showed tighter binding of both cognate and noncognate tRNAs by G405D mutant HisRS [Yan, W., Augustine, J., and Francklyn, C. (1996) Biochemistry 35, 6559], which possesses a single amino acid change in the C-terminal anticodon binding domain. Discrimination against noncognate tRNA was also observed in sedimentation velocity experiments, which showed that a stable complex was formed with the cognate tRNA(His) but not with noncognate tRNA(Phe). Footprinting experiments on wild-type versus G405D HisRS revealed characteristic alterations in the pattern of protection and enhancement of iodine cleavage at phosphates 5' to tRNA nucleotides in the anticodon and hinge regions. Together, these results suggest that the anticodon and core regions play major roles in the initial binding discrimination between cognate and noncognate tRNAs, whereas acceptor stem nucleotides, particularly at position 73, influence the reaction at steps after binding of tRNA.

Adenosine↗

PubMed1996

Protein synthesis editing by a DNA aptamer.

Potential errors in decoding genetic information are corrected by tRNA-dependent amino acid recognition processes manifested through editing reactions. One example is the rejection of difficult-to-discriminate misactivated amino acids by tRNA synthetases through hydrolytic reactions. Although several crystal structures of tRNA synthetases and synthetase-tRNA complexes exist, none of them have provided insight into the editing reactions. Other work suggested that editing required active amino acid acceptor hydroxyl groups at the 3' end of a tRNA effector. We describe here the isolation of a DNA aptamer that specifically induced hydrolysis of a misactivated amino acid bound to a tRNA synthetase. The aptamer had no effect on the stability of the correctly activated amino acid and was almost as efficient as the tRNA for inducing editing activity. The aptamer has no sequence similarity to that of the tRNA effector and cannot be folded into a tRNA-like structure. These and additional data show that active acceptor hydroxyl groups in a tRNA effector and a tRNA-like structure are not essential for editing. Thus, specific bases in a nucleic acid effector trigger the editing response.

Base Sequence↗

PubMed2003

A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set.

Alleles↗

PubMed1999

Conservation of a tRNA core for aminoacylation.

The core region of Escherichia coli tRNA(Cys)is important for aminoacylation of the tRNA. This core contains an unusual G15:G48 base pair, and three adenosine nucleotides A13, A22 and A46 that are likely to form a 46:[13:22] adenosine base triple. We recently observed that the 15:48 base pair and the proposed 46:[13:22] triple are structurally and functionally coupled to contribute to aminoacylation. Inspection of a database of tRNA sequences shows that these elements are only found in one other tRNA, the Haemophilus influenzae tRNA(Cys). Because of the complexity of the core, conservation of sequence does not mean conservation of function. We here tested whether the conserved elements in H. influenzae tRNA(Cys)were also important for aminoacylation of H. influenzae tRNA(Cys). We cloned and purified a recombinant H. influenzae cysteine-tRNA synthe-tase and showed that it depends on 15:48 and 13, 22 and 46 in a relationship analogous to that of E. coli cysteine-tRNA synthetase. The functional conservation of the tRNA core is correlated with sequence conservation between E.coli and H.influenzae cysteine-tRNA synthetases. As the genome of H. influenzae is one of the smallest and may approximate a small autonomous entity in the development of life, the dependence of this genome on G15:G48 and its coupling with the proposed A46:[A13:A22] triple for aminoacylation with cysteine suggests an early role of these motifs in the evolution of decoding genetic information.

Acylation↗

PubMed2002

Salivary electrolyte concentrations are associated with cystic fibrosis transmembrane regulator genotypes.

It is estimated that about one in 24 Belgian Caucasians is a cystic fibrosis (CF) heterozygote. Until now, CF heterozygotes can only be identified by genetic decoding (e.g. Inno-Lipa CF2 test), as they cannot be phenotypically distinguished from the general population. The aim of this study was to evaluate differences in salivary electrolyte concentrations (calcium, bicarbonate, chloride, potassium, sodium and phosphate) and salivary osmolarity between CF homozygotes (n=41), CF heterozygotes (n=56) and healthy controls (n=65). Differences between the three groups were investigated by means of non-parametric tests. Several significant differences between the three study groups and among, as well as between, the different cystic fibrosis transmembrane regulator (CFTR) genotypes were observed. Significant differences in salivary electrolyte concentrations between individuals with delta F508 mutation and those without, and between CF homozygotes and heterozygotes were observed. The concentrations of several salivary electrolytes, and salivary osmolarity were significantly higher in CFTR genotype individuals. Differences in salivary electrolyte concentrations may partly explain differences in caries between the three study groups.

Adolescent↗

PubMed2025

Exploring the causal relationship between plasma proteins and postherpetic neuralgia: a Mendelian randomization study.

BACKGROUND: The proteome represents a valuable resource for identifying therapeutic targets and clarifying disease mechanisms in neurological disorders. This study investigated potential causal relationships between plasma proteins and postherpetic neuralgia (PHN). METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics from the Decode Genetics dataset (4,907 plasma proteins) and the FinnGen database (490 PHN cases and 435,371 controls). Instrumental variables (IVs) were selected based on relevance, independence, and exclusivity. Causal associations were assessed using inverse-variance weighted (IVW), MR-Egger regression, simple mode, weighted mode, and weighted median methods. Sensitivity analyses, including leave-one-out tests, evaluated result robustness, while colocalization analysis examined shared causal variants between traits. RESULTS: Eight plasma proteins showed significant associations with PHN (PFDR < 0.05). Higher levels of ATRN, PIANP, and CD48 correlated with increased PHN risk, whereas elevated KIR2DL5A, GPI, SEMG2, EIF4B, and HFE2 levels were associated with reduced risk. Sensitivity analyses supported these findings and excluded genetic pleiotropy as a major confounding factor. Colocalization analysis did not detect shared causal variants (PPH4 < 0.8). CONCLUSION: These results suggest a potential causal role for eight plasma proteins in PHN pathogenesis. While these proteins may serve as biomarkers or therapeutic candidates, further validation is required. This study advances understanding of PHN pathophysiology and supports future investigations into diagnostic and therapeutic strategies.

Mendelian randomization↗

PubMed2001