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Willem de Ronde, Albert Hofman, Huibert A P Pols and Frank H de Jong

Objective: The origin of oestrogens in men is only partly understood. From infusion studies with radioactively labelled hormones, we know that oestradiol (E2) and oestrone (E1) are either directly secreted by the testes and adrenal glands or peripherally produced from testicular or adrenal androgens.

Design and methods: We determined E2, E1, androstenedione, testosterone and dehydroepiandroster-one sulphate (DHEAS) in 292 elderly men and 367 postmenopausal women. We considered post-menopausal women as men without testes, assuming that the postmenopausal ovary is not endocrinologically active and that the testes do not contribute to circulating levels of DHEAS. Subjects were stratified by DHEAS levels to adjust for differences in DHEAS levels between sexes. For men and women separately, mean levels of E2, E1, androstenedione and testosterone were calculated per DHEAS stratum. The relative direct and indirect contributions of the testes to steroid levels in men were calculated by the formula [(Cm −Cf)/Cm] × 100%, in fwhich Cm and Cf represent the mean concentrations of the steroid in men and women respectively.

Results: The relative contributions (%) of the testes to hormone levels per DHEAS stratum (<2, 2–4, 4–6 and >6 μmol/l) respectively were, for E2, 72%, 60%, 52% and 44%; for E1, 54%, 47%, 35% and 34%; for androstenedione, 14%, 4%, 12% and 0%; and, for testosterone, 88%, 88%, 87% and 83%.

Conclusions: We conclude that in elderly men dependent on DHEAS levels, 44–72% of E2 and 34–54% of E1 originate directly or indirectly from the testes.

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Charlotte van Noord, Miriam C J M Sturkenboom, Sabine M J M Straus, Albert Hofman, Jan A Kors, Jacqueline C M Witteman and Bruno H Ch Stricker

Aims

To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death.

Methods

This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis.

Results

Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (−33.7 ms (−48.8; −18.6) and −44.4 ms (−58.7; −30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02–4.06); HR 3.05 (1.99–4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34–0.80)).

Conclusion

In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

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Layal Chaker, Sanaz Sedaghat, Ewout J Hoorn, Wendy P J Den Elzen, Jacobijn Gussekloo, Albert Hofman, M Arfan Ikram, Oscar H Franco, Abbas Dehghan and Robin P Peeters

Objectives

Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally.

Design

Prospective cohort study.

Methods

Participants aged ≥45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR <60 mL/min/1.73 m2 according to the CKD-EPI formula.

Results

We included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (β): −1.75 mL/min; 95% confidence interval (CI): −2.17, −1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (β: −0.06 mL/min; CI: −0.11, −0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend = 0.04).

Conclusions

Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.

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Dennis O Mook-Kanamori, Büşra Durmuş, Ulla Sovio, Albert Hofman, Hein Raat, Eric A P Steegers, Marjo-Riitta Jarvelin and Vincent W V Jaddoe

Objective

To examine whether infant growth rates are influenced by fetal growth characteristics and are associated with the risks of overweight and obesity in early childhood.

Design

This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward.

Methods

Fetal growth characteristics (femur length (FL) and estimated fetal weight (EFW)) were assessed in the second and third trimesters and at birth (length and weight). Infant peak weight velocity (PWV), peak height velocity (PHV), and body mass index at adiposity peak (BMIAP) were derived for 6267 infants with multiple height and weight measurements.

Results

EFW measured during the second trimester was positively associated with PWV and BMIAP during infancy. Subjects with a smaller weight gain between the third trimester and birth had a higher PWV. FL measured during the second trimester was positively associated with PHV. Gradual length gain between the second and third trimesters and between the third trimester and birth were associated with higher PHV. Compared with infants in the lowest quintile, the infants in the highest quintile of PWV had strongly increased risks of overweight/obesity at the age of 4 years (odds ratio (95% confidence interval): 15.01 (9.63, 23.38)).

Conclusion

Fetal growth characteristics strongly influence infant growth rates. A higher PWV, which generally occurs in the first month after birth, was associated with an increased risk of overweight and obesity at 4 years of age. Longer follow-up studies are necessary to determine how fetal and infant growth patterns affect the risk of disease in later life.

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Catherine E de Keyser, Filipe Valerio de Lima, Frank H de Jong, Albert Hofman, Yolanda B de Rijke, André G Uitterlinden, Loes E Visser and Bruno H Stricker

Objective

Statins, or HMG-CoA reductase inhibitors, decrease cholesterol production. Because cholesterol is a precursor of the testosterone biosynthesis pathway, there is some concern that statins might lower serum testosterone levels. The objective of the present study was to investigate the association between the use of statins and serum testosterone levels in men.

Design

Cross-sectional study within the prospective population-based Rotterdam Study.

Subjects and methods

We included 4166 men with available data on total testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, and medication use. Multivariable linear regression analysis was used to compare the differences in serum testosterone levels (nmol/l) between current, past, and never statin users. We considered dose and duration of use. Analyses were adjusted for age, BMI, cardiovascular disease, diabetes mellitus, hypertension, and estradiol levels.

Results

We identified 577 current (mean age 64.1 years), 148 past (mean age 64.6 years), and 3441 never (mean age 64.6 years) statin users. Adjusted for all covariables, current statin use of 1–≤6 months or >6 months was significantly associated with lower total testosterone levels as compared to non-users (β −1.24, 95% CI −2.17, −0.31, and β −1.14, 95% CI −2.07, −0.20 respectively). Current use of 1–≤6 months was also associated with significantly lower non-SHBG-bound testosterone levels (β −0.42, 95% CI −0.82, −0.02). There was a trend toward lower testosterone levels at higher statin doses both for total (P trend 2.9×10−5) and non-SHBG-bound (P trend 2.0×10−4) testosterone. No association between past statin use and testosterone levels was found.

Conclusion

We showed that current use of statins was associated with significantly lower serum total and non-SHBG-bound testosterone levels. The clinical relevance of this association should be further investigated.

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Dennis O Mook-Kanamori, J J Miranda Geelhoed, Eric A P Steegers, Jacqueline C M Witteman, Albert Hofman, Henriëtte A Moll, Cornelia M van Duijn, Anita C S Hokken-Koelega and Vincent W V Jaddoe

Objective

The aim of this study was to examine whether the insulin gene variable number of tandem repeats (INS VNTR) is associated with growth patterns in fetal life and infancy.

Design and methods

This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood. Fetal growth was assessed by ultrasounds in early, mid-, and late pregnancy. Anthropometry in infancy was assessed at birth and at the ages of 6 weeks, 6 months, and 14 months. DNA for genotyping of the INS VNTR promoter region was available in 859 children.

Results

The genotype distribution was I/I 50.8%, I/III 40.0%, and III/III 9.2%. III/III individuals had a shorter gestational age (P<0.005 versus I/I) and a lower birth weight (P<0.05 versus I/I). There were no differences in birth weight after adjusting for gestational age. Class III homozygotes had a smaller abdominal circumference/head circumference (HC) ratio (P<0.005 versus I/I) in mid-pregnancy, but not in late pregnancy. Also, III/III subjects had a relative decrease in HC (SDS) from mid-pregnancy to the age of 14 months (P<0.05 versus I/I). No other differences in pre- and postnatal growth characteristics and patterns were found.

Conclusions

Class III homozygotes were born at an earlier gestational age. No association was found between INS VNTR and birth weight adjusted for gestational age. Our data suggest that the III/III genotype may be associated with asymmetrical growth in mid-pregnancy, but not in late pregnancy.

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Mojgan Yazdanpanah, Fakhredin A Sayed-Tabatabaei, Joop A M J L Janssen, Ingrid Rietveld, Albert Hofman, Theo Stijnen, Huibert A P Pols, Steven W J Lamberts, Jacqueline C M Witteman and Cornelia M van Duijn

Objective: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes.

Design: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older.

Methods: The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers.

Results: During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7–1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2–4.8, P = 0.01).

Conclusion: Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.

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Vera A A van Houten, Dennis O Mook-Kanamori, Lennie van Osch-Gevers, Eric A P Steegers, Albert Hofman, Henriëtte A Moll, Cornelia M van Duijn, Willem A Helbing, Anita C S Hokken-Koelega and Vincent W V Jaddoe

Background and objective

A common variant of the IGF-I gene has been shown to be associated with cardiovascular disease in adulthood. The objective of this study was to examine whether this variant of the IGF-I gene is associated with blood pressure and left heart dimensions in early childhood.

Research design and methods

This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life onwards. IGF-I promoter region was genotyped in DNA obtained from cord blood. Blood pressure (systolic and diastolic) and echocardiography (left ventricular mass, left atrial diameter and aortic root diameter) measurements were performed at the age of 2 years. Analyses were performed in 538 subjects.

Results

Eight alleles of the IGF-I promoter region were identified. In total, 43% of the subjects were homozygous for the 192 bp allele (wild type), 46% were heterozygous and 11% were non-carriers. Significantly lower systolic and diastolic blood pressures were found in non-carrier subjects (difference compared with homozygous subjects: −4.4 (95% confidence interval (CI) −7.8 to −1.1) mmHg and −3.5 (95% CI: −6.9 to −0.1) mm respectively). No significant differences were found for left heart dimensions at the age of 2 years. No association was found when we used a previously proposed alternative classification of the IGF-I gene.

Conclusion

The variant type of the IGF-I promoter region is associated with lower blood pressure but not with left heart dimensions at the age of 2 years. Follow-up studies are needed to examine whether these differences persist in later life.

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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.

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Stephanie C E Schuit, Frank H de Jong, Lisette Stolk, W Nadia H Koek, Joyce B J van Meurs, Mariette W C J Schoofs, M Carola Zillikens, Albert Hofman, Johannes P T M van Leeuwen, Huibert A P Pols and André G Uitterlinden

Objective: Postmenopausal estradiol (E2) levels vary widely between individuals and this variation is an important determinant of diseases such as osteoporosis. It has been suggested that the estrogen receptor alpha (ESR1) gene may influence peripheral E2 levels, but the role of common sequence variations in the ESR1 gene is unclear.

Methods: In 631 postmenopausal women and 528 men from the Rotterdam Study, a population-based, prospective cohort study of individuals aged 55 years and over, ESR1 PvuII-XbaI haplotypes were determined and correlated with plasma E2 levels.

Results: In women, haplotype 1 (T-A) was significantly associated with an allele-dose-dependent decrease in E2. After adjusting for age, body mass index, years since menopause and testosterone levels, plasma E2 levels decreased by 1.90 pmol/l per allele copy of this haplotype (P < 0.05). Extreme genotypes, representing 23 and 27% of the population, varied by 3.93 pmol/l. No association with plasma testosterone was observed. In a subset of 446 women, no association of genotype with plasma concentrations of dehydroepiandrosterone sulfate, androstenedione or estrone was seen. In men, none of the sex hormone levels was associated with the ESR1 PvuII-XbaI haplotypes.

Conclusion: We have demonstrated a role for genetic variations in the ESR1 gene in determining post-menopausal E2 levels in women.