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ABSTRACT: The role of vitamin D beyond its importance for bone health is under much debate. In this article, we review recent evidence for genetic influences on 25-hydroxyvitamin D [25(OH)D] and discuss the uses of this information and its importance for public health.
Findings from large-scale genome-wide association meta-analyses on 25(OH)D confirmed the associations for loci nearby genes encoding vitamin D binding protein (GC, group component), 7-dehydrochlesterol reductase (DHCR7), 25-hydroxylase (CYP2R1) and 24-hydroxylase (CYP24A1), all influencing key sites for vitamin D metabolism. Findings from candidate gene studies have been inconsistent, with some implicating an association with 25(OH)D for loci near the gene encoding the hormonal vitamin D activation enzyme (CYP27B1).
The amount of variation in 25(OH)D explained by genetic determinants is small compared with environmental exposures. Information on genetic variants affecting 25(OH)D can be used as tools for Mendelian randomization analyses on vitamin D, and they provide some potential for the use as drug targets.
Current opinion in nephrology and hypertension 07/2011; 20(4):331-6. · 3.96 Impact Factor
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Delilah Zabaneh,
Tom R Gaunt,
Meena Kumari,
Fotios Drenos,
Sonia Shah, Diane Berry,
Chris Power,
Elina Hypponen,
Tina Shah,
Jutta Palmen, [......],
Santiago Rodriguez,
Shah Ebrahim,
Michael G Marmot,
George Davey Smith,
Debbie A Lawlor,
Mika Kivimaki,
John Whittaker,
Aroon D Hingorani,
Ian N Day,
Steve E Humphries
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ABSTRACT: We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.
Annals of Human Genetics 07/2011; 75(4):456-67. · 2.57 Impact Factor
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ABSTRACT: Parent-offspring associations in adiposity are well known, but the extent to which they are explained by modifiable environmental and lifestyle factors remains to be elucidated.
The objectives were to assess whether 1) parent-offspring associations in body mass index (BMI; in kg/m(2)) persist from childhood to midadulthood, 2) parental BMI is associated with the offspring's adult lifestyle, and 3) parent-offspring BMI associations in midadulthood are explained by lifestyle factors.
Participants in the 1958 British Birth Cohort Study and their parents (n = 9346) were examined. Parental BMI was assessed in 1969; offspring (ie, cohort members) BMI was ascertained prospectively at 11 and 44-45 y. Lifestyle factors of the offspring, including diet, physical activity, alcohol consumption, and smoking, were assessed prospectively in adulthood.
Maternal and paternal BMI were positively associated with offspring BMI in both childhood and midadulthood, and the strength of the association did not diminish with offspring age. Maternal BMI was associated with several offspring lifestyle factors across adulthood; fewer associations were observed for paternal BMI. Parent-offspring BMI associations in adulthood were largely maintained after adjustment for multiple lifestyle and socioeconomic factors at different life stages: if parental BMI was 1 unit higher, offspring BMI at 44-45 y was higher by between 0.21 and 0.29 units in adjusted models.
Strong parent-offspring BMI associations are maintained into midlife. These associations are largely unaffected by adjustment for a wide range of lifestyle factors. Offspring of obese parents are an important target for interventions aimed at reducing population levels of overweight and obesity.
American Journal of Clinical Nutrition 10/2010; 92(4):946-53. · 6.67 Impact Factor
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Thomas J Wang,
Feng Zhang,
J Brent Richards,
Bryan Kestenbaum,
Joyce B van Meurs, Diane Berry,
Douglas P Kiel,
Elizabeth A Streeten,
Claes Ohlsson,
Daniel L Koller, [......],
Marjo-Riitta Järvelin,
David Karasik,
David S Siscovick,
Michael J Econs,
Stephen B Kritchevsky,
Jose C Florez,
John A Todd,
Josee Dupuis,
Elina Hyppönen,
Timothy D Spector
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ABSTRACT: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.
Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.
Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.
Full funding sources listed at end of paper (see Acknowledgments).
The Lancet 07/2010; 376(9736):180-8. · 38.28 Impact Factor
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ABSTRACT: Vitamin D deficiency has been suggested as a cardiovascular risk factor, but little is known about underlying mechanisms or associations with inflammatory or hemostatic markers. Our aim was to investigate the association between 25-hydroxyvitamin D [25(OH)D, a measure for vitamin D status] concentrations with pre-clinical variations in markers of inflammation and hemostasis.
Serum concentrations of 25(OH)D, C-reactive protein (CRP), fibrinogen, D-dimer, tissue plasminogen activator (tPA) antigen, and von Willebrand factor (vWF) were measured in a large population based study of British whites (aged 45 y). Participants for the current investigation were restricted to individuals free of drug treated cardiovascular disease (n = 6538). Adjusted for sex and month, 25(OH)D was inversely associated with all outcomes (p < or =0.015 for all), but associations with CRP, fibrinogen, and vWF were explained by adiposity. Association with tPA persisted after full adjustment (body mass index, waist circumference, physical activity, TV watching, smoking, alcohol consumption, social class, sex, and month), and average concentrations were 18.44% (95% CI 8.13, 28.75) lower for 25(OH)D > or =75 nmol/l compared to < 25 nmol/l. D-dimer concentrations were lower for participants with 25(OH)D 50-90 nmol/l compared to others (quadratic term p = 0.01). We also examined seasonal variation in hemostatic and inflammatory markers, and evaluated 25(OH)D contribution to the observed patterns using mediation models. TPA concentrations varied by season (p = 0.02), and much of this pattern was related to fluctuations in 25(OH)D concentrations (p < or =0.001). Some evidence of a seasonal variation was observed also for fibrinogen, D-dimer and vWF (p < 0.05 for all), with 25(OH)D mediating some of the pattern for fibrinogen and D-dimer, but not vWF.
Current vitamin D status was associated with tPA concentrations, and to a lesser degree with fibrinogen and D-dimer, suggesting that vitamin D status/intake may be important for maintaining antithrombotic homeostasis.
PLoS ONE 01/2010; 5(5):e10801. · 4.09 Impact Factor
