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  • Author: André G Uitterlinden x
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Amnon Zung, Theo J Visser, André G Uitterlinden, Fernando Rivadeneira and Edith C H Friesema

Objective

The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T3) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan–Herndon–Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T3 levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT4) or liothyronine (LT3) treatment intending to overcome the T3 uptake resistance through alternative transporters.

Methods

The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT4 treatment and two periods (3 months each) of low- and high-dose LT3 were evaluated.

Results

A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T3 at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient.

Conclusion

We identified a 70 kb deletion encompassing exons 2–6 of the MCT8 gene in our AHDS patient. Both LT4 and LT3 administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.

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Wietske A Ester, Joyce B van Meurs, Nicolette J Arends, André G Uitterlinden, Maria A de Ridder and Anita C Hokken-Koelega

Context

Small for gestational age (SGA) subjects experience pre- and postnatal growth restriction, which might be influenced by polymorphisms in the IGF1 gene. The well-known −841(CA)n/192 bp polymorphism has been associated with birth size, cardiovascular disease, and IGF-1 levels, and is in linkage disequilibrium with the −G1245A single nucleotide polymorphism (SNP; rs35767).

Objective

To associate the −G1245A SNP with head circumference (HC) and brain sparing (a greater head compared with height SDS) in short SGA and SGA catch-up subjects.

Design

Gene association study.

Patients

We studied 635 SGA subjects out of which 439 remained short and 196 had a postnatal height >−2.00 SDS.

Measurements

The −G1245A SNP IGF1 gene polymorphism and head size.

Results

All SGA subjects had a postnatal head size below the population mean (−1.01 SDS, P<0.001). Whereas SGA catch-up subjects had a head size that was in proportion with their height, short SGA subjects displayed extensive brain sparing (HC – height: SGA CU: 0.01 versus short SGA: 1.75 SDS, P<0.001). The most severely SGA born subjects had a 0.4 SDS smaller postnatal head size and 0.6 SDS less brain sparing when carrying the −1245 A-allele in contrast to G-allele carriers (P=0.03). The association between the −G1245A SNP and head size remained significant after correction for birth weight and postnatal height SDS (P=0.03). Birth weight, birth length and postnatal height SDS were not related with the – G1245A SNP.

Conclusions

The −1245 A-allele of the IGF1 promoter SNP is associated with a small head size and less brain sparing in SGA born subjects and particularly those with the lowest birth weight.

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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.

Free access

Sarina G Kant, Iveta Cervenkova, Lukas Balek, Lukas Trantirek, Gijs W E Santen, Martine C de Vries, Hermine A van Duyvenvoorde, Michiel J R van der Wielen, Annemieke J M H Verkerk, André G Uitterlinden, Sabine E Hannema, Jan M Wit, Wilma Oostdijk, Pavel Krejci and Monique Losekoot

Objective

Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion.

Design

A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3.

Methods

Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants.

Results

A novel p.M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT.

Conclusions

Proportionate short stature can be caused by a mutation in F GFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.

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.

Free access

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.