Biomedical subjects

Daniel G MacArthur

Publications and source records attributed to Daniel G MacArthur.

6 recordsLinked to original sources

PubMed2026

Comparison of Performance of Publicly Available Polygenic Risk Scores to Predict Clinically Actionable Coronary Artery Calcium Scores: The BioHEART-CT Cohort.

AIM: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality globally. Polygenic Risk Scores (PRS) have been trained against major adverse cardiovascular outcomes (MACE) in large cohorts. Few studies have examined the effectiveness of these CAD MACE PRS tools in detecting individuals with subclinical coronary calcification. An association would provide an opportunity for clinical translation and targeting of CT imaging to new patients at risk for subclinical disease. METHODS: An analysis of 53 publicly available CAD PRS tools was completed in participants of the BioHEART-CT Discovery 1000 cohort presenting for clinically referred CT coronary angiography (CCTA). Associations between PRS and two binary CACS outcomes reflecting clinically significant coronary calcification were assessed: a) Absolute CACS (CACS ≥100 Agatston units [AU]; and b) Percentile CACS (CACS ≥75th age-/sex-adjusted percentile). Models were adjusted for genetic principal components, modifiable cardiovascular risk factors, and age/sex (in Absolute CACS). A subgroup analysis was performed using Framingham Risk Score (FRS) at baseline. RESULTS: Among 803 BioHEART-CT Discovery 1000 participants, 487 (60.6%) had any detectable coronary calcium. Most PRS tools demonstrated significant association with CACS outcomes, particularly evident when PRS was modelled as a continuous predictor. For Percentile CACS, 94.3% of PRS tools were significantly associated after full adjustment (median OR per PRS SD 1.41 (IQR 1.23-1.60). Quintile-based analysis revealed that individuals in the Top Quintile PRS had up to 7.99-fold increased odds of Percentile CACS ≥75th compared to those in the Bottom Quintile. Analysis by FRS group revealed positive performance, especially in individuals of Low FRS wherein incorporating a PRS increased pre-test probability from 14% to 26%. CONCLUSION: Whilst most CAD PRS tools have been developed against clinical events, we show their ability to predict clinically relevant coronary calcification. Utility appears strongest in individuals traditionally considered lower risk, presenting an opportunity for clinical translation for improved diagnosis in the primary prevention setting, with the potential to triage individuals into a CACS screening pathway.

coronary artery disease↗

PubMed2025

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.

Humans↗

PubMed2007

ACTN3: A genetic influence on muscle function and athletic performance.

A common variant of the ACTN3 gene, R577X, results in complete deficiency of the alpha-actinin-3 protein in the fast skeletal muscle fibers of more than a billion humans worldwide. We review the evidence that this genetic variant is strongly associated with elite athlete status and with normal variation in human muscle strength and sprinting speed.

Actinin↗

PubMed2006

Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks.

The functional allele (577R) of ACTN3, which encodes human alpha-actinin-3, has been reported to be associated with elite athletic status and with response to resistance training, while the nonfunctional allele (577X) has been proposed as a candidate metabolically thrifty allele. In a study of 992 adolescent Greeks, we show that there is a significant association (P=0.003) between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive manner. The R577X polymorphism is not associated with other power phenotypes related to 40 m sprint, nor with an endurance phenotype. Furthermore, the polymorphism is not associated with obesity-related phenotypes in our population, suggesting that the 577X allele is not a thrifty allele, and thus the persistence of this null allele must be explained in other terms.

Actinin↗

PubMed2004

A gene for speed? The evolution and function of alpha-actinin-3.

The alpha-actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. alpha-actinin-3 is the most-highly specialised of the four mammalian alpha-actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion ( approximately 18%) of the human population is totally deficient in alpha-actinin-3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent work in our laboratory has revealed a strong association between R577X genotype and performance in a variety of athletic endeavours. We are currently exploring the function and evolutionary history of the ACTN3 gene and other alpha-actinin family members. The alpha-actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution.

Actinin↗

PubMed2003

ACTN3 genotype is associated with human elite athletic performance.

There is increasing evidence for strong genetic influences on athletic performance and for an evolutionary "trade-off" between performance traits for speed and endurance activities. We have recently demonstrated that the skeletal-muscle actin-binding protein alpha-actinin-3 is absent in 18% of healthy white individuals because of homozygosity for a common stop-codon polymorphism in the ACTN3 gene, R577X. alpha-Actinin-3 is specifically expressed in fast-twitch myofibers responsible for generating force at high velocity. The absence of a disease phenotype secondary to alpha-actinin-3 deficiency is likely due to compensation by the homologous protein, alpha-actinin-2. However, the high degree of evolutionary conservation of ACTN3 suggests function(s) independent of ACTN2. Here, we demonstrate highly significant associations between ACTN3 genotype and athletic performance. Both male and female elite sprint athletes have significantly higher frequencies of the 577R allele than do controls. This suggests that the presence of alpha-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity, and provides an evolutionary advantage because of increased sprint performance. There is also a genotype effect in female sprint and endurance athletes, with higher than expected numbers of 577RX heterozygotes among sprint athletes and lower than expected numbers among endurance athletes. The lack of a similar effect in males suggests that the ACTN3 genotype affects athletic performance differently in males and females. The differential effects in sprint and endurance athletes suggests that the R577X polymorphism may have been maintained in the human population by balancing natural selection.

Actinin↗