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Kristin Holvik, Natasja M van Schoor, Elisabeth M W Eekhoff, Martin den Heijer, Dorly J H Deeg, Paul Lips and Renate de Jongh

Objective

The role of osteocalcin (OC) in cardiovascular disease (CVD) is unresolved. We aimed to study the association between plasma OC concentrations and the risk of non-fatal and fatal CVDs. We also aimed to investigate whether such an association, if present, would be mediated by established metabolic risk factors.

Design

A population-based longitudinal cohort study.

Methods

In 1995/1996, OC was determined in blood samples drawn from 1319 subjects aged 65–88 years participating in the Longitudinal Aging Study Amsterdam in 1995/1996. The self-reported CVD events were collected every 3 years until 2005/2006, and CVD deaths until 1st January 2007. Cox proportional hazards regression was performed, considering potential confounders (smoking, physical activity, and BMI) and mediators (blood pressure, plasma triglycerides, total and HDL cholesterol, fructosamine, and aortic calcification).

Results

During the median 4.1 years follow-up, 709 subjects (53.8%) suffered a CVD event. There was no overall association between OC and CVD: hazard ratio (HR) was 0.97 (95% CI 0.90–1.04) per nmol/l higher plasma OC, adjusted for age and sex. There was a statistical interaction between plasma OC, age, and sex on CVD (P=0.014). In those subjects aged ≥75 years, age-adjusted HRs (95% CI) were 0.86 (0.75–0.99) in men and 1.16 (1.03–1.31) in women per nmol/l higher plasma OC. Adjustment for covariates only slightly attenuated the association in older-old men, but did not affect the association in older-old women.

Conclusion

A higher plasma OC concentration was associated with a reduced risk of CVD in older-old men and with an increased risk of CVD in older-old women. We found no evidence that this was mediated by arterial calcification or metabolic risk factors.

Free access

Annenienke C van de Ven, Romana T Netea-Maier, Femmie de Vegt, H Alec Ross, Fred C G J Sweep, Lambertus A Kiemeney, Johannes W Smit, Ad R Hermus and Martin den Heijer

Objective

The aim of this study was to investigate the influence of age on the association between thyroid function and mortality.

Design

The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease.

Methods

TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002–2003. The number of deaths were established in 2012 (median follow-up time 9.4 years).

Results

Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1–5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5–22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5–15.0 pmol/l): HR 1.7 (95% CI 1.0–2.9). In these elderly, TSH levels within the high-normal range (3.0–4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0–2.0 mIU/l): HR 1.8 (95% CI 1.0–3.1).

Conclusions

The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups.

Free access

Kim Freriks, Theo C J Sas, Maaike A F Traas, Romana T Netea-Maier, Martin den Heijer, Ad R M M Hermus, Jan M Wit, Janiëlle A E M van Alfen-van der Velden, Barto J Otten, Sabine M P F de Muinck Keizer-Schrama, Martin Gotthardt, Philippe H Dejonckere, Gladys R J Zandwijken, Leonie A Menke and Henri J L M Timmers

Objective

Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment.

Design and methods

During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition.

Results

Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency.

Conclusion

Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

Free access

Annenienke C van de Ven, Romana T Netea-Maier, H Alec Ross, Teun A E van Herwaarden, Suzanne Holewijn, Jacqueline de Graaf, Bart L A Kiemeney, Doorlène van Tienoven, Jack F M Wetzels, Johannes W Smit, Fred C G J Sweep, Ad R M M Hermus and Martin den Heijer

Objective

Several cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past.

Methods

In an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age.

Results

Within 4 years, TSH decreased by 5.4% (95% CI 2.5–8.3%) and FT4 increased by 3.7% (95% CI 2.9–4.6%). Median urinary iodine concentration was 130 μg/l. Estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4 over time or with the presence of antibodies against thyroid peroxidase. Only FT4 appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17–1.84%) higher FT4 for each lower iodine quintile.

Conclusions

In this longitudinal study, we found an ongoing decrease in TSH and increase in FT4 in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.

Free access

Marco Medici, Wendy M van der Deure, Michael Verbiest, Sita H Vermeulen, Pia S Hansen, Lambertus A Kiemeney, Ad R M M Hermus, Monique M Breteler, Albert Hofman, Laszlo Hegedüs, Kirsten Ohm Kyvik, Martin den Heijer, André G Uitterlinden, Theo J Visser and Robin P Peeters

Objective

Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45–65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT4) levels.

Design and methods

Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT4 levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed.

Results

For TSH, eight PDE8B polymorphisms (P=4×10−17) remained significant in the meta-analysis. For FT4, two DIO1 (P=8×10−12) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT4, but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively).

Conclusions

Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT4 levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT4 levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.