MON-152 - Health Consequences of Androgen Receptor CAG Repeat Length in the Population-Based UK Biobank Cohort

Background: Longer cytosine-adenine-guanine (CAG) trinucleotide repeat lengths within exon 1 of the androgen receptor gene (AR) result in lower sensitivity to androgen hormones. Unusually long AR CAG repeats (36 or more) are characteristic of spinal and bulbar muscular atrophy, an X-linked progressive neuromuscular disorder in men. Furthermore, repeat length variation within ‘non-pathological’ ranges has been reported to be associated with sensitivity to the effects of testosterone and circulating testosterone levels.

Aims &

Methods: To examine the health consequences of normal variation in AR CAG lengths in men, we analysed whole genome sequencing data in up to 158,267 unrelated men, mean (SD) age 57.0 (8.1) years, of European ancestry from the population-based UK Biobank cohort. We explored its relationship with circulating total testosterone and a range of androgen-related health outcomes.

Results: Mean CAG length was 22.9 repeats (SD 3.0, range 5-46). Only 22 men (0.014%) had a CAG length >= 40 repeats, and 159 men (0.100%) had 36-39 repeats. CAG length showed a strong positive association with testosterone: beta (per repeat) 0.024 SD, P=2e-166; and a weaker association with SHBG: 0.001 ln nmol/L, P=5e-04. Longer CAG length also conferred less male pattern balding (-0.019 categories, P=2e-96), later voice breaking (0.002 categories, P=3e-17), greater bone density (0.001 g/cm 2 , P=7e-14), lower coronary artery disease risk (odds ratio 0.99, P=6e-4) and shorter adult height (-0.019 cm, P=9e-04). Weaker association was seen with lower haematocrit (-0.006%, P=0.02), but not with lean mass index (P=0.3), grip strength (P=0.5), self-rated health (P=0.7), or prostate cancer (P=0.8). For all significant findings, there was no evidence for a threshold effect in CAG repeat lengths.

Interpretation &

Discussion: Despite compensatory higher circulating testosterone, increasing AR CAG repeat lengths within the normal range appear to confer steadily decreasing testosterone effects in men. This is indicated by less male pattern balding, later puberty timing, shorter height, and modestly lower haematocrit. Greater bone density is likely explained by aromatisation of the compensatory testosterone response and consequent greater oestrogen effects. These findings suggest that normal variation in AR CAG repeat lengths should be considered in the evaluation and treatment of testosterone insufficiency in men.

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