GnRH and LHR gene variants predict adverse outcome in premenopausal breast cancer patients

Background: Breast cancer development and progression are dependent on estrogen activity. In premenopausal women, estrogen production is mainly regulated through the hypothalamic-pituitary-gonadal (HPG) axis. Methods: We have investigated the prognostic significance of two variants of genes involved in the HPG-axis, the GnRH (encoding gonadotropin-releasing hormone) 16Trp/Ser genotype and the LHR (encoding the luteinizing hormone receptor) insLQ variant, in retrospectively collected premenopausal breast cancer patients with a long follow-up (median follow-up of 11 years for living patients). Results: Carriership was not related with breast cancer risk (the case control study encompassed 278 premenopausal cases and 1,758 premenopausal controls). A significant adverse relationship of the LHR insLQ and GnRH 16Ser genotype with disease free survival (DFS) was observed in premenopausal (hormone receptor positive) breast cancer patients. In particular, those patients carrying both the GnRH 16Ser and LHR insLQ allele (approximately 25%) showed a significant increased risk of relapse, which was independent of traditional prognostic factors (hazard ratio 2.14; 95% confidence interval 1.32 to 3.45; P = 0.002). Conclusion: We conclude that the LHR insLQ and GnRH 16Ser alleles are independently associated with shorter DFS in premenopausal patients. When validated, these findings may provide a lead in the development of tailored treatment for breast cancer patients carrying both pol

A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation

Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (Pcombined= 3.4 × 10-9). Notably, a second SNP (rs6718438) located ∼450 bp away and in strong LD (r2= 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (Pcombined= 2.1 × 10-7). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height

Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women

Objective  To determine whether thyroid hormone (free thyroxine (fT4)) rather than TSH is directly related to bone mineral density (BMD).Design Cross-sectional population cohort study of peri-menopausal women. Methods  Of a sample of 6846 peri-menopausal Dutch women who participated in an osteoporosis-screening programme, a cohort of 2584 was randomly selected for the assessment of thyroid function (TSH, fT4 and thyroid peroxidase antibodies (TPO-Abs)). TPO-Ab-positive women, with a previous history of thyroid dysfunction, overt thyroid disease, subclinical hypothyroidism, osteoporosis or bilateral oophorectomy and those receiving thyroid hormone or hormone replacement therapy were excluded. Of 1477 eligible women, 1426 had TSH and fT4 within the reference range and 51 had low or undetectable serum TSH. BMD was measured at the lumbar spine and low BMD was defined as <0.937 g/cm2. Results  The mean BMD in the 51 women with low or undetectable serum TSH was 0.984 g/cm2 compared with 1.001 g/cm2 in the remaining 1426 (t=0.94, P=0.35); 33% of women with low or undetectable serum TSH had low BMD compared with 34% in 1426 euthyroid women. High fT4 but not low TSH in euthyroid women was related to low BMD by multiple logistic regression corrected for age, BMI and smoking (OR, 1.30; 95% CI, 1.02–1.69). Conclusions  Higher fT4 levels within the normal reference range but not low or undetectable serum TSH were independently related to decreased BMD at lumbar spine in peri-menopausal women