Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank Study

Abstract

Background While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Methods Study participants were 318 749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006-2010), and re-measured in 12 334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. Results After correction for multiple testing (P<0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration=1.12, 95% CI, 1.08-1.16), and inversely associated with varicose veins (0.90, 0.85-0.95), cataracts (0.97, 0.95-0.99), diabetes (0.92, 0.90-0.95), and iron deficiency anaemia (0.90, 0.86-0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Conclusions Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger

“…As IGFBP5 is known to directly antagonize IGF-1 signalling 21–23 , with evidence that exogenous growth hormone treatment can cause CTS 21 , we hypothesized that higher IGF-1 plasma levels would be associated with significantly increased risk of both TF and CTS in UK Biobank. We identified significant associations between IGF-1 and TF (hazard ratio (HR) per 1 SD = 1.04, 95% CI 1.01-1.07, p=0.02) and CTS (HR per 1 SD = 1.04, 95% CI 1.02-1.05, p=4.23×10 −6 ), which is concordant with a recent CTS-specific analysis in UKB 24 . If the protective effect of rs62175241 was mediated via antagonism of IGF-1 signaling, we hypothesized that this variant would be associated with attenuation of growth hormone-regulated phenotypes such as height and lean body mass.…”

Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study

“…We identified significant associations between plasma concentrations of IGF-1 and trigger finger (hazard ratio [HR] per 1 SD 1•04 [95% CI 1•01-1•07]; p=0•02) and carpal tunnel syndrome (HR per 1 SD 1•04 [1•02-1•05]; p=4•23 × 10 -⁶), which was concordant with another carpal tunnel syndrome-specific analysis in UK Biobank. 32 If the protective effect of rs62175241 was mediated via antagonism of IGF-1 signalling, we hypothesised that this variant would be associated with the attenuation of growth hormoneregulated phenotypes such as height and lean body mass. To investigate this hypothesis, we extracted growth phenotype summary statistics from UK Biobank and selected traits that met phenome-wide significance (p<1 × 10 -⁵).…”

“…10 To maximise specificity, patients with trigger finger were defined by the intersection of patients who had International Classification of Diseases(ICD)-10 codes for trigger finger (M65.3, M65. [30][31][32][33][34][35][36][37][38][39], and patients who had Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures (OPCS) codes for tendon release (T723; figure 1A). In sensitivity analyses, we explored including patients who had either ICD-10 or OPCS codes alone (termed the extended cohort).…”