Number of CAG repeats and mortality in middle aged and older men.

Dirk Vanderschueren, Terence W O'Neill, Fred Wu, Giulia Rastrelli, Mario Maggi, Ilpo T Huhtaniemi, Felipe F Casanueva, Geoff Hackett, Ian Laing, Jolanta Slowikowska-Hilczer, Helene Fachim, Fahmida Mannan, Parisa Ghaffari, Jos Tournoy, Leen Antonio, Michael J Cook, Adrian Heald

Journal: Clinical endocrinology 2023;99(6):559-565

PMID: 37718889

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Abstract

DESIGN

The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association.

PATIENTS AND MEASUREMENTS

Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI).

RESULTS

One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats.

CONCLUSIONS

Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Address: Department of Endocrinology and Diabetes, Salford Royal Hospital, Salford, UK.; The School of Medicine and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.; Centre for Health Informatics, Division of Informatics, Imaging and Data Science, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.; National Institute for Health and Care Research Applied Research Collaboration Greater Manchester, Manchester, UK.; Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.; Department of Public Health and Primary Care, Gerontology and Geriatrics Unit, KU Leuven-University of Leuven, Leuven, Belgium.; Department of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium.; Department of Biochemistry, Royal Preston Hospital, Preston, UK.; Aston University Medical School, Birmingham, UK.; Department of Medicine, Santiagode Compostela University, Complejo Hospitalario Universitariode Santiago (CHUS), CIBER de Fisiopatología Obesidady Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain.; Department of Metabolism, Institute of Reproductive and Developmental, Digestion and Reproduction, Imperial College London, London, UK.; "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy.; Department of Andrology and Reproductive Endocrinology, Medical University of Łódź, Łódź, Poland.; Department of Endocrinology, Manchester Royal Infirmary, The University of Manchester, Manchester, UK.; Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester, UK.; Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.

DOI: 10.1111/cen.14962

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MeSH Terms: Humans, Middle Aged, Male, Aged, Receptors, Androgen, Trinucleotide Repeats, Aging, Testosterone