Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.

Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case-control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC.

Responsivity of the Striatal Dopamine System to Methylphenidate-A Within-Subject I-123-ß-CIT-SPECT Study in Male Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods: Thirteen adolescent male patients (9-16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results: On-MPH status was associated with a highly significant change (-29.9%) of striatal DAT BP as compared to off-MPH (t = -4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion: Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.

Obesity and the risk of papillary thyroid cancer: a pooled analysis of three case-control studies.

BACKGROUND: There is a correlation between temporal trends of obesity prevalence and papillary thyroid cancer (PTC) incidence in the United States. Obesity is a well-recognized risk factor for many cancers, but there are few studies on the association between obesity and PTC risk. We investigated the association between anthropometric measurements and PTC risk using pooled individual data from three case-control populations. METHODS: Height and weight information were obtained from three independent case-control studies, including 1917 patients with PTC (1360 women and 557 men) and 2127 cancer-free controls from the United States, Italy, and Germany. Body mass index (BMI), body fat percentage, and body surface area (BSA) were calculated. An unconditional logistic regression model was used to calculate odds ratios (ORs) and confidence intervals (CIs) with respect to risk of PTC, adjusted by age, sex, race/ethnicity, and study site. RESULTS: In the pooled population, for both men and women, an increased risk of PTC was found to be associated with greater weight, BMI, body fat percentage, and BSA, whereas a reduced risk of PTC was associated with greater height, in the pooled population for both men and women. Compared with normal-weight subjects (BMI 18.5-24.9 kg/m2), the ORs for overweight (BMI 25-29.9 kg/m2) and obese (BMI≥30 kg/m2) subjects were 1.72 [CI 1.48-2.00] and 4.17 [CI 3.41-5.10] respectively. Compared with the lowest quartile of body fat percentage, the ORs for the highest quartile were 3.83 [CI 2.85-5.15] in women and 4.05 [CI 2.67-6.15] in men. CONCLUSION: Anthropometric factors, especially BMI and body fat percentage, were significantly associated with increased risk of PTC. Future studies of anthropometric factors and PTC that incorporate intermediate factors, including adiposity and hormone biomarkers, are essential to help clarify potential mechanisms of the relationship.

Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults.

OBJECTIVE: The objectives of the study was to compare pentagastrin- and calcium-stimulated serum human calcitonin (hCT) levels for nonsmoking healthy adults without evidence of thyroid disorders and determine reference ranges of basal and pentagastrin- and calcium-stimulated serum hCT levels. DESIGN: This was a healthy volunteer study including within-group and intergroup comparisons. SETTING: The study was conducted at a tertiary referral center. SUBJECTS: Subjects included 50 healthy, nonsmoking volunteers (25 female; aged 22-57 yr) without evidence of thyroid abnormality. INTERVENTIONS: hCT was measured using a calcitonin two-site automated chemiluminescent immunometric assay (the most common hCT assay in clinical practice) in serum samples obtained before and 2, 5, and 15 min after iv stimulation using pentagastrin, 0.5 microg/kg body weight, or calcium gluconate, 2.5 mg/kg. MAIN OUTCOME MEASURES: Reference ranges for basal, unstimulated, and pentagastrin- or calcium-stimulated hCT and pentagastrin and calcium tolerability in healthy adults were measured. RESULTS: The 95th percentile basal hCT values did not differ between males and females (5.0 vs. 5.7 pg/ml). The 95th percentile maximal stimulated hCT values rose distinctly after pentagastrin (peak men, 37.8 pg/ml; women, 26.2 pg/ml) and even more so after calcium (peak men, 131.1 pg/ml, women, 90.2 pg/ml). No hCT increase was detected in four of 25 men and 12 of 25 women after pentagastrin vs. none of 24 men and two of 18 women after calcium. Calcium was associated with fewer and less intense adverse effects than was pentagastrin. CONCLUSION: High-dose calcium is a more potent and better-tolerated hCT stimulator than is pentagastrin. The reference ranges for basal and stimulated hCT established via automated chemiluminescent assay were lower than those reported for other assays.