ANZAC Research Institute Sydney
ANZAC Research Institute Sydney
Chasland L.C.,University of Western Australia |
Knuiman M.W.,University of Western Australia |
Divitini M.L.,University of Western Australia |
Chan Y.X.,University of Western Australia |
And 4 more authors.
Clinical Endocrinology | Year: 2017
Context: Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear. Objective: We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk. Participants: A total of 1649 men. Methods: Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H); low PA+high hormone (L/H); high PA+low hormone (H/L); and low PA+low hormone (L/L). Results: Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). Conclusions: Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2×2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men. © 2017 John Wiley & Sons Ltd.
PubMed | ANZAC Research Institute Sydney, Concord Hospital Sydney, University of Malaya and University of Sydney
Type: Journal Article | Journal: Molecular genetics & genomic medicine | Year: 2015
Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.