| 1. |
- Benn, Diana E, et al.
(author)
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Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.
- 2006
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:3, s. 827-36
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Journal article (peer-reviewed)abstract
- CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.
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| 2. |
- Christoffersen, Christina, et al.
(author)
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The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles
- 2012
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In: Journal of Lipid Research. - 1539-7262. ; 53:10, s. 2198-2204
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Journal article (peer-reviewed)abstract
- ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 +/- 0.13 mu M, P = 0.003, and 1.23 +/- 0.10 mu M, P = 0.02, respectively) as compared with noncarriers (0.93 +/- 0.04 mu M). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 +/- 5% versus 90 +/- 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.-Christoffersen, C., M. Benn, P. M. Christensen, P. L. S. M. Gordts, A. J. M. Roebroek, R. Frikke-Schmidt, A. Tybjaerg-Hansen, B. Dahlback, and L. B. Nielsen. The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles. J. Lipid Res. 2012. 53: 2198-2204.
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| 3. |
- Marouli, Eirini, et al.
(author)
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Rare and low-frequency coding variants alter human adult height
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 4. |
- Navarese, Eliano P, et al.
(author)
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The spoils of war and the long-term spoiling of health conditions of entire nations.
- 2022
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 352:July 2022, s. 76-79
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Journal article (peer-reviewed)abstract
- The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population.
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| 5. |
- Nielsen, Jens, et al.
(author)
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Health consequences of armed conflict in Guinea-Bissau
- 2010
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In: Ugeskrift for Laeger. - 0041-5782. ; 172:2, s. 132-136
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Research review (peer-reviewed)abstract
- The present paper reviews studies carried out by the Bandim Health Project during the armed conflict in Guinea-Bissau, 1998-1999. Common health interventions like vaccination and breastfeeding, as well as focused interventions such as nutrition interventions aimed at malnourished children are effective measures. Population-based studies of health status gives important information about health conditions for groups at special risk, and provides information about which interventions are the most effective in an emergency.
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| 6. |
- Turcot, Valerie, et al.
(author)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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