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1.  Associations of childhood 25-hydroxyvitamin D2 and D3 and cardiovascular risk factors in adolescence: prospective findings from the Avon Longitudinal Study of Parents and Children 
Background
Studies of the associations of circulating total 25-hydroxyvitamin D (25(OH)D) with cardiovascular disease risk factors in adults have reported inconsistent findings. We aimed to compare prospective associations of two analogues of childhood 25(OH)D (25(OH)D2 and 25(OH)D3) with cardiovascular risk factors measured in adolescence.
Methods and results
We examined associations of childhood (ages 7–12 years) 25(OH)D2 and 25-25(OH)D3 with a range of cardiovascular risk factors (blood pressure, fasting lipids, glucose, insulin and C-reactive protein (CRP)) determined in adolescence (mean age 15.4 years). Data were from 2470 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based cohort. After adjustments for age, gender, socioeconomic position and BMI, there were no associations of 25(OH)D2 with cardiovascular risk factors. There was a positive association of season-adjusted (and unadjusted) 25(OH)D3 with high-density lipoprotein cholesterol (HDL-C) (mean change per doubling of 25(OH)D3: 0.03 mmol/l; 95% confidence interval (CI): 0.001 to 0.05, p = 0.02) and an inverse association with fasting insulin (relative difference of −4.59% per doubling; 95% CI: −8.37 to −0.59, p = 0.03). Participants with total 25(OH)D concentration <50 nmol/l had 0.04 mmol/l lower HDL-C (95% CI: −0.07 to −0.01) and 5.54% higher fasting insulin (95% CI: 0.82 to 10.47) compared with participants with total 25(OH)D ≥72 nmol/l.
Conclusions
In the first prospective study of children/adolescents, we have shown that higher 25(OH)D3 concentrations in childhood are associated with higher levels of HDL-C and lower fasting insulin in adolescence.
doi:10.1177/2047487312465688
PMCID: PMC3931583  PMID: 23185083
Vitamin D; cardiovascular diseases; paediatrics; ALSPAC
2.  Associations of 25-Hydroxyvitamin D2 and D3 with Cardiovascular Risk Factors in Childhood: Cross-Sectional Findings from the Avon Longitudinal Study of Parents and Children 
Context
Studies in adults have reported associations of low circulating total 25-hydroxyvitamin D with increased cardiovascular disease and risk factors. Evidence of associations in children, however, is limited, and it is unknown whether associations with risk factors differ for each 25-hydroxyvitamin D analog [25-hydroxyvitamin D2 (25[OH]D2) and 25-hydroxyvitamin D2 (25[OH]D3)].
Objective
The objective of the study was to compare associations of 25(OH)D2 and 25(OH)D3 with cardiovascular risk factors in children.
Design/Setting
The design of the study was a cross-sectional study of 4274 children (mean age 9.9 yr) from the Avon Longitudinal Study of Parents and Children.
Main Outcomes
The main outcomes included blood pressure, lipids [triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C)], apolipoproteins (Apo-A1 and Apo-B), adiponectin, leptin, C-reactive protein, and IL-6.
Results
In confounder-adjusted models, 25(OH)D2 was inversely associated with Apo-A1 (change per doubling of exposure: −0.74mg/dl; 95% confidence interval −0.14, −0.04) and triglycerides (relative percentage change per doubling of exposure: −1.64%; −3.27, 0.01) and positively associated with C-reactive protein (8.42%; 3.40, 13.58) and IL-6 (5.75%; 1.83, 9.25). 25(OH)D3 was positively associated with HDL-C (0.04 mmol/liter; 0.02, 0.06), Apo-A1 (1.96 mg/dl; 0.65, 3.24), and adiponectin (0.47 μg/ml; 0.15, 0.79). There was statistical evidence that associations of 25(OH)D2 and 25(OH)D3 with HDL-C, Apo-A1, and IL-6 differed from each other (all P values for differences ≤0.02).
Conclusions
Higher circulating 25(OH)D3 was associated with cardioprotective levels of HDL-C, Apo-A1, and adiponectin in children. Associations of 25(OH)D2 with cardiovascular risk factors were in mixed directions. It is necessary to see whether these associations are replicated in large prospective studies.
doi:10.1210/jc.2011-2335
PMCID: PMC3927053  PMID: 22344194
3.  Circulating Docosahexaenoic Acid Levels Are Associated with Fetal Insulin Sensitivity 
PLoS ONE  2014;9(1):e85054.
Background
Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies.
Methods and Principal Findings
In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity.
Conclusion
Low circulating DHA levels are associated with compromised fetal insulin sensitivity, and may be involved in perinatally “programming” the susceptibility to type 2 diabetes in the offspring of gestational diabetic mothers.
doi:10.1371/journal.pone.0085054
PMCID: PMC3890289  PMID: 24454790
4.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
Background
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
Methods
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
Results
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Conclusions
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
Impact
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
doi:10.1158/1055-9965.EPI-12-1248
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
5.  Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study 
Lancet  2013;381(9884):2176-2183.
Summary
Background
Maternal vitamin D status in pregnancy is a suggested determinant of bone-mineral content (BMC) in offspring, but has been assessed in small studies. We investigated this association in a large prospective study.
Methods
Eligible participants were mother-and-singleton-offspring pairs who had participated in the Avon Longitudinal Study of Parents and Children, and in which the mother had recorded measurements of 25(OH)D concentration in pregnancy and the offspring had undergone dual-energy x-ray absorptiometry at age 9–10 years. 25(OH)D concentrations in pregnancy were assessed per 10·0 nmol/L and classified as sufficient (more than 50·00 nmol/L), insufficient (49·99–27·50 nmol/L), or deficient (lower than 27·50 nmol/L). Associations between maternal serum 25(OH)D concentrations and offspring total body less head (TBLH) and spinal BMC were assessed by trimester.
Results
3960 mother-and-offspring pairs, mainly of white European origin, were assessed (TBLH BMC n=3960, spinal BMC n=3196). Mean offspring age was 9·9 years. 2644 (67%) mothers had sufficient, 1096 (28%) insufficient, and 220 (6%) deficient 25(OH)D concentrations in pregnancy, but TBLH and spinal BMC did not differ between offspring of mothers in the lower two groups versus sufficient 25(OH)D concentration. No associations with offspring BMC were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH BMC confounder-adjusted mean difference −0·03 g per 10·0 nmol/L, 95% CI −1·71 to 1·65; spinal BMC 0·04 g per 10·0 nmol/L, 95% CI −0·12 to 0·21).
Conclusions
We found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood.
Funding
UK Medical Research Council, Wellcome Trust, and University of Bristol.
doi:10.1016/S0140-6736(12)62203-X
PMCID: PMC3691477  PMID: 23518316
6.  Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial 
Trials  2013;14:100.
Background
Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function.
Methods/Design
The ‘Vitamin D to prevent lung injury following oesophagectomy trial’ is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres.
Discussion
This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy.
Trial registration
Current Controlled Trials ISRCTN27673620
doi:10.1186/1745-6215-14-100
PMCID: PMC3680967  PMID: 23782429
Acute lung injury; One lung ventilation; Oesophagectomy; Vitamin D
7.  Birth outcomes and infant mortality among First Nations Inuit, and non-Indigenous women by northern versus southern residence, Quebec 
Background
In circumpolar countries such as Canada, northern regions represent a unique geographical entity climatically, socioeconomically and environmentally. There is a lack of comparative data on birth outcomes among Indigenous and non-Indigenous subpopulations within northern regions and compared with southern regions.
Methods
A cohort study of all births by maternal mother tongue to residents of northern (2616 First Nations (North American Indians), 2388 Inuit and 5006 non-Indigenous) and southern (2563 First Nations, 810 643 non-Indigenous) Quebec, 1991–2000.
Results
Compared with births to southern non-Indigenous mother tongue women, births to northern women of all three mother tongue groups were at substantially elevated risks of infant death (adjusted OR (aOR) 1.7–2.9), especially postneonatal death (aOR 2.2–4.4) after controlling for maternal education, age, marital status and parity. The risk elevation in perinatal death was greater for southern First Nations (aOR 1.6) than for northern First Nations (aOR 1.2). Infant macrosomia was highly prevalent among First Nations in Quebec, especially in the north (31% vs 24% in the south). Within northern regions, Inuit births were at highest risk of preterm delivery (aOR 1.4) and infant death (aOR 1.6).
Conclusion
All northern infants (First Nations, Inuit or non-Indigenous) were at substantially elevated risk of infant death in Quebec, despite a universal health insurance system. Southern First Nations newborns have not benefited from the more advanced perinatal care facilities in southern regions. Environmental influences may partly account for the very high prevalence of macrosomia among First Nations in northern Quebec.
doi:10.1136/jech.2009.092619
PMCID: PMC3133748  PMID: 21051777 CAMSID: cams1702
8.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
Context
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
Objective
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures
We measured fat mass, by DXA, and bone turnover markers.
Results
Among women, fat mass was inversely related to age in controls (P=.01), but not in HBM cases (P=.96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P<.001). Increased fat mass in male HBM cases was less marked (gender interaction P=.03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2,5.4] kg; P<.002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P<.001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P=.04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P<.001).
Conclusions
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
doi:10.1210/jc.2012-3342
PMCID: PMC3589712  PMID: 23337721
9.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
Context:
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
Objective:
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants:
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures:
We measured fat mass, by DXA, and bone turnover markers.
Results:
Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001).
Conclusions:
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
doi:10.1210/jc.2012-3342
PMCID: PMC3589712  PMID: 23337721
10.  Associations of Circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade 
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with PSA-detected prostate cancer in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs localized) and Gleason grade (high-grade (≥7) vs low-grade (<7)). Pre-determined categories of total 25(OH)D were defined as: high: ≥30ng/mL; adequate: 20-<30ng/mL; insufficient: 12-<20ng/mL; deficient: <12ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a two-fold increased risk of advanced versus localized cancer (OR for deficient vs adequate total 25(OH)D=2.33, 95% CI: 1.26,4.28) and high-grade versus low-grade cancer (OR for deficient vs adequate total 25(OH)D=1.78, 95% CI: 1.15,2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low- Gleason grade), but there was no evidence of an association with overall prostate cancer risk.
doi:10.1002/ijc.27327
PMCID: PMC3378478  PMID: 22033893
Prostate cancer; vitamin D; 25-hydroxyvitamn D
11.  Serum 25-Hydroxyvitamin D3 and D2 and Non-Clinical Psychotic Experiences in Childhood 
PLoS ONE  2012;7(7):e41575.
Objective
Non-clinical psychotic experiences are common and distressing. It has been hypothesized that early life vitamin D deficiency may be a risk factor for psychosis-related outcomes, but it is not known if circulating concentrations of 25-hydroxyvitamin D (25(OH)D) during childhood are associated with psychosis-related outcomes or whether the two different forms of 25(OH)D, (25(OH)D3 and 25(OH)D2, have similar associations with psychosis-related outcomes.
Methods
We investigated the association between serum 25(OH)D3 and 25(OH)D2 concentrations and psychotic experiences in a prospective birth cohort study. Serum 25(OH)D3 and 25(OH)D2 concentrations were measured at mean age 9.8 years and psychotic experiences assessed at mean age 12.8 years by a psychologist (N = 3182).
Results
Higher 25(OH)D3 concentrations were associated with lower risk of definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.75–0.95)). Higher concentrations of 25(OH)D2 were associated with higher risk of suspected and definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 1.26 (1.11, 1.43)). Higher 25(OD)D2 concentrations were also weakly associated with definite psychotic experiences (adjusted OR (95% CI) 1.17 (0.96, 1.43), though with wide confidence intervals including the null value.
Conclusions
Our findings of an inverse association of 25(OH)D3 with definite psychotic experiences is consistent with the hypothesis that vitamin D may protect against psychosis-related outcomes.
doi:10.1371/journal.pone.0041575
PMCID: PMC3405076  PMID: 22848531
12.  The Association of 25-Hydroxyvitamin D3 and D2 with Behavioural Problems in Childhood 
PLoS ONE  2012;7(7):e40097.
Background
Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D3 (the active vitamin D3 metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans.
Methods
We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D3 and 25(OH)D2– and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D3 and 25(OH)D2 concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome.
Results
Higher 25(OH)D3 concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D3 or 25(OH)D2 concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D.
Conclusions
Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans.
doi:10.1371/journal.pone.0040097
PMCID: PMC3393748  PMID: 22808099
13.  Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets 
The Journal of Endocrinology  2004;183(3):R1-R9.
MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemic-rickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renal-tubules. Using a specific competitive ELISA we measured a five fold increase (P=0·007) of serum ASARM-peptide(s) in human HYP patients (normal subjects 3·25 μM n=9; S.E.M.=0·51 and HYP-patients 15·74 μM, n=9; S.E.M.=3·32). A 6·23 fold increase (P=0·008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3·73 μM, S.E.M.=0·57, n=3; and hyp-mice 23·4 μM, n=3, S.E.M.=4·01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.
doi:10.1677/joe.1.05989
PMCID: PMC3357083  PMID: 15590969
14.  Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women 
The P2X7 receptor gene (P2RX7) is highly polymorphic with five previously described loss-of-function (LOF) single-nucleotide polymorphisms (SNP; c.151+1G>T, c.946G>A, c.1096C>G, c.1513A>C and c.1729T>A) and one gain-of-function SNP (c.489C>T). The purpose of this study was to determine whether the functional P2RX7 SNPs are associated with lumbar spine (LS) bone mineral density (BMD), a key determinant of vertebral fracture risk, in post-menopausal women. We genotyped 506 post-menopausal women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) for the above SNPs. Lumbar spine BMD was measured at baseline and at 6–7 year follow-up. P2RX7 genotyping was performed by homogeneous mass extension. We found association of c.946A (p.Arg307Gln) with lower LS-BMD at baseline (P=0.004, β=−0.12) and follow-up (P=0.002, β=−0.13). Further analysis showed that a combined group of subjects who had LOF SNPs (n=48) had nearly ninefold greater annualised percent change in LS-BMD than subjects who were wild type at the six SNP positions (n=84; rate of loss=−0.94%/year and −0.11%/year, respectively, P=0.0005, unpaired t-test). This is the first report that describes association of the c.946A (p.Arg307Gln) LOF SNP with low LS-BMD, and that other LOF SNPs, which result in reduced or no function of the P2X7 receptor, may contribute to accelerated bone loss. Certain polymorphic variants of P2RX7 may identify women at greater risk of developing osteoporosis.
doi:10.1038/ejhg.2011.245
PMCID: PMC3330223  PMID: 22234152
P2RX7; LS-BMD; single-nucleotide polymorphisms
15.  North-South Gradients in Adverse Birth Outcomes for First Nations and Others in Manitoba, Canada 
Objective
to determine the relationship of north-south place of residence to adverse birth outcomes among First Nations and non-First Nations in Manitoba, Canada, a setting with universal health insurance.
Study Design
Live birth records (n=151,472) for the province of Manitoba, Canada 1991–2000 were analyzed, including 25,743 First Nations and 125,729 non-First Nations infants. North-south and rural-urban residence was determined for each birth through geocoding.
Results
Comparing First Nations to non-First Nations, crude rates in North (and South) were: 7.0% versus 8.4% (9.3% versus 7.5%) for preterm birth; 6.1% versus 8.4% (8.7% versus 10.0%) for small-for-gestational-age birth, 4.2% versus 6.5% (6.2% versus 5.7%) for low birth weight, and 20.6% versus 13.7% (17.0% versus 11.0%) for large-for-gestational-age birth; and mortality per 1000 - neonatal 3.2 versus 6.2 (3.8 versus 3.3), post-neonatal 6.4 versus 6.4 (5.8 versus 1.5), and infant 9.5 versus 12.6 (9.6 versus 4.8). Adjusting for observed maternal and infant characteristics and rural versus urban residence, the North was high risk for large-for-gestational-age birth for both First Nations and non-First Nations. First Nations’ risk of preterm, small-for-gestational-age and low birth weight was lowest in the North, but for non-First Nations, the North was lower only for small-for-gestational-age. First Nations mortality indicators were similar North to South, but for non-First Nations, the North was high risk.
Conclusion
North-South place of residence does matter for adverse birth outcomes, but the effects may differ by ethnicity and could require different intervention strategies.
PMCID: PMC3329440  PMID: 22523523 CAMSID: cams2159
North-south residence; First Nations; preterm birth; fetal growth; infant mortality; Aboriginal; North American Indian
16.  Neighborhood Socioeconomic Characteristics, Birth Outcomes and Infant Mortality among First Nations and Non-First Nations in Manitoba, Canada 
Objective
Little is known about the possible impacts of neighborhood socioeconomic status on birth outcomes and infant mortality among Aboriginal populations. We assessed birth outcomes and infant mortality by neighborhood socioeconomic status among First Nations and non-First Nations in Manitoba.
Study Design
We conducted a retrospective birth cohort study of all live births (26,176 First Nations, 129,623 non-First Nations) to Manitoba residents, 1991–2000. Maternal residential postal codes were used to assign four measures of neighborhood socioeconomic status (concerning income, education, unemployment, and lone parenthood) obtained from 1996 census data.
Results
First Nations women were much more likely to live in neighborhoods of low socioeconomic status. First Nations infants were much more likely to die during their first year of life [risk ratio (RR) =1.9] especially during the postneonatal period (RR=3.6). For both First Nations and non-First Nations, living in neighborhoods of low socioeconomic status was associated with an increased risk of infant death, especially postneonatal death. For non-First Nations, higher rates of pre-term and small-for-gestational-age birth were consistently observed in low socioeconomic status neighborhoods, but for First Nations the associations were less consistent across the four measures of socioeconomic status. Adjusting for neighborhood socioeconomic status, the disparities in infant and postneonatal mortality between First Nations and non-First Nations were attenuated.
Conclusion
Low neighborhood socioeconomic status was associated with an elevated risk of infant death even among First Nations, and may partly account for their higher rates of infant mortality compared to non-First Nations in Manitoba.
PMCID: PMC3266303  PMID: 22287997 CAMSID: cams1725
Aboriginal health; first nations; neighborhood socioeconomic status; birth outcome; infant mortality
17.  Urban Living is Not Associated with Better Birth and Infant Outcomes among Inuit and First Nations in Quebec 
Objective
There is limited and inconsistent evidence concerning rural versus urban differences in birth and infant outcomes for Indigenous peoples. We assessed birth and infant outcomes among Inuit, First Nations and French mother tongue groups by rural versus urban residence in Quebec, Canada.
Study Deign
A retrospective birth cohort study of 5,184 First Nations, 2,527 Inuit and 652,940 French mother tongue (the majority reference) births in Quebec, 1991–2000.
Results
In general, rural living was associated with slightly less favorable birth outcomes for French mother tongue women, but somewhat better outcomes for Indigenous women. For both Inuit and First Nations, rural births were half as likely to be small-for-gestational-age compared to urban births. Among First Nations, the difference in infant mortality rates comparing urban to rural areas was not statistically significant. Compared to infants of French mother tongue women, Inuit and First Nations infants were much less likely to be small-for-gestational-age in rural areas, while such an “advantage” diminished for First Nations and reversed for Inuit in urban areas. The disparities in infant mortality among First Nations versus French mother tongue births were greater in urban than in rural areas. These patterns of results remained after adjusting for maternal characteristics.
Conclusion
Living in urban areas was not associated with better birth and infant outcomes for Inuit and First Nations in Quebec despite universal health insurance coverage, strongly indicating a need for improved socioeconomic conditions, perinatal and infant care for Indigenous people living in urban areas.
PMCID: PMC3266304  PMID: 22287996 CAMSID: cams1726
Indigenous health; infant mortality; fetal growth restriction; rural; urban
18.  Community Remoteness, Perinatal Outcomes and Infant Mortality among First Nations in Quebec 
Objective
Little is known about community remoteness in relation to birth outcomes among Indigenous populations. We assessed whether community remoteness matters for perinatal outcomes and infant mortality in Quebec First Nations communities.
Study Design
A retrospective cohort study of all births (n=11,033) to residents of First Nations communities in Quebec 1991–2000, using linked vital statistics data. First Nations communities were grouped by community remoteness into four zones from the least to most remote.
Results
Preterm birth rates declined progressively from the least remote (8.0%) to the most remote (5.7%) zones (p=0.002). In contrast, total fetal and infant mortality rose progressively from the least remote (10.4 per 1000) to the most remote (22.7 per 1000) zones (p<0.001). The excess infant mortality in the more remote zones was mainly due to higher rates of postneonatal mortality. Similar patterns were observed after adjusting for maternal age, education, parity and marital status. Substantially elevated risks in most remote communities remained for perinatal death (adjusted OR=2.1), postneonatal death (adjusted OR=2.7), and total fetal and infant death (adjusted OR=2.3).
Conclusion
Living in more remote First Nations communities was associated with a substantially higher risk of fetal and infant death, especially postneonatal death, despite a lower risk of preterm delivery. There is a need for more effective perinatal and infant care programs in more remote First Nations communities to reduce perinatal and infant mortality.
PMCID: PMC3265536  PMID: 22282717 CAMSID: cams1727
Community remoteness; first nations; preterm birth; perinatal mortality; infant mortality
19.  Individual- and Community-Level Disparities in Birth Outcomes and Infant Mortality among First Nations, Inuit and Other Populations in Quebec 
Objective
We assessed individual- and community-level disparities and trends in birth outcomes and infant mortality among First Nations (North American Indians) and Inuit versus other populations in Quebec, Canada.
Methods
A retrospective birth cohort study of all births to Quebec residents, 1991–2000. At the individual level, we examined outcomes comparing births to First Nations and Inuit versus other mother tongue women. At the community level, we compared outcomes among First Nations and Inuit communities versus other communities.
Results
First Nations and Inuit births were much less likely to be small-for-gestational-age but much more likely to be large-for-gestational-age compared to other births at the individual or community level, especially for First Nations. At both levels, Inuit births were 1.5 times as likely to be preterm. At the individual level, total fetal and infant mortality rates were 2 times as high for First Nations, and 3 times as high for Inuit. Infant mortality rates were 2 times as high for First Nations, and 4 times as high for Inuit. There were no reductions in these disparities between 1991–1995 and 1996–2000. Modestly smaller disparities in total fetal and infant mortality were observed for First Nations at the community level (risk ratio=1.6), but for Inuit there were similar disparities at both levels. These disparities remained substantial after adjusting for maternal characteristics.
Conclusion
There were large and persistent disparities in fetal and infant mortality among First Nations and Inuit versus other populations in Quebec based on individual- or community-level assessments, indicating a need to improve socioeconomic conditions as well as perinatal and infant care for Aboriginal peoples.
PMCID: PMC3265542  PMID: 22282716 CAMSID: cams1728
Health disparities; aboriginal people; preterm birth; fetal growth; fetal and infant mortality
20.  Genome wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone 
Nature genetics  2010;42(6):520-524.
Paget’s disease of bone (PDB) is a common disorder with a strong genetic component characterised by focal increases in bone turnover which in some cases is caused by SQSTM1 mutations. To identify additional susceptibility genes we performed a genome wide association study in 750 PDB cases without SQSTM1 mutations and 1002 controls and identified three candidate loci for the disease which were replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 close to the CSF1 gene (P = 5.38 × 10−24) and significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10−13) and with rs3018362 on 18q21 close to the TNFRSF11A gene (P = 5.27 × 10−13). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as novel candidate genes for disease susceptibility.
doi:10.1038/ng.562
PMCID: PMC3217192  PMID: 20436471
21.  Maternal Glucose Tolerance in Pregnancy Affects Fetal Insulin Sensitivity 
Diabetes Care  2010;33(9):2055-2061.
OBJECTIVE
Offspring of mothers with impaired glucose tolerance are far more likely to develop type 2 diabetes. We tested the hypothesis that maternal glucose tolerance in pregnancy affects fetal insulin sensitivity or β-cell function.
RESEARCH DESIGN AND METHODS
In a prospective singleton pregnancy cohort study, we analyzed glucose, insulin, and proinsulin concentrations in maternal blood at the 50-g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation and in venous cord blood (n = 248). The cord blood glucose-to-insulin ratio and proinsulin concentration were used as indicators of fetal insulin sensitivity and the proinsulin-to-insulin ratio was used as an indicator of fetal β-cell function.
RESULTS
Higher OGTT blood glucose levels were associated with significantly lower cord plasma glucose-to-insulin ratios (r = −0.31, P < 0.001) and higher proinsulin concentrations (r = 0.31, P < 0.001) but not with proinsulin-to-insulin ratios. In a comparison of gestational diabetic (n = 26) versus euglycemic pregnancy, cord blood glucose-to-insulin ratios were substantially lower (geometric mean 10.1 vs. 20.0 mg/dl/μU/ml; P < 0.001), whereas proinsulin concentrations were much higher (24.4 vs. 13.8 pmol/l; P < 0.001), despite similar cord blood glucose concentrations indicating adequate management of diabetes. The differences remained significant after controlling for prepregnancy and fetal adiposity, family history of diabetes, gestational age, and other potential confounders. Significant changes in the glucose-to-insulin ratio and proinsulin concentration were also observed in obese (n = 31) mothers, but the differences became not statistically significant after adjustment for maternal glucose tolerance and fetal adiposity.
CONCLUSIONS
Maternal glucose intolerance may impair fetal insulin sensitivity (but not β-cell function) and consequently “program” the susceptibility to type 2 diabetes.
doi:10.2337/dc10-0819
PMCID: PMC2928362  PMID: 20573751
22.  Low bone mineral density in men with chronic obstructive pulmonary disease 
Respiratory Research  2011;12(1):101.
Background
Osteoporosis is common in patients with COPD but the likely multi-factorial causes contributing to this condition (e.g. sex, age, smoking, therapy) mask the potential contribution from elements related to COPD. In order to study osteoporosis and bone mineral density (BMD) related to COPD, we studied a well-defined group of patients and controls.
Methods
BMD, forced expiratory volume in one second (FEV1), circulating bone biomarkers and biochemistry were determined in 30 clinically stable male ex-smokers with confirmed COPD and 15 age matched "ex-smoker" male controls. None of the patients were on inhaled corticosteroids or received more than one short course of steroids.
Results
Mean (SD) FEV1% predicted of patients was 64(6)%, the majority having Global Initiative for Chronic Obstructive Lung Disease (GOLD) II airflow obstruction. There were 5/30 patients and 1/15 controls who were osteoporotic, while a further 17 patients and 5 controls were osteopenic. The BMD at the hip was lower in patients than controls, but not at the lumbar spine. Mean values of procollagen type 1 amino-terminal propeptide and osteocalcin, both markers of bone formation, and Type 1 collagen β C-telopeptide, a marker of bone resorption, were similar between patients and controls. However, all bone biomarkers were inversely related to hip BMD in patients (r = -0.51, r = -0.67, r = -0.57, p < 0.05) but did not relate to lumbar spine BMD. 25-OH Vitamin D was lower in patients.
Conclusions
Men with COPD had a greater prevalence of osteoporosis and osteopenia than age matched male controls, with a marked difference in BMD at the hip. Bone biomarkers suggest increased bone turnover.
doi:10.1186/1465-9921-12-101
PMCID: PMC3161864  PMID: 21812978
bone biomarkers; bone mineral density; chronic obstructive pulmonary disease; osteoporosis
23.  Receptors and effects of gut hormones in three osteoblastic cell lines 
BMC Physiology  2011;11:12.
Background
In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells.
Methods
mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB]) were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63) showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP), procollagen type 1 amino-terminal propeptides (P1NP), and osteocalcin production.
Results
The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor) expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and obestatin. ALP showed higher levels in Saos-2 after GIP, GHR and OB and in TE-85 after GHR. P1NP showed higher levels after GIP and OB in Saos-2. Decreased levels of P1NP were observed in TE-85 and MG-63 after GLP-1, GLP-2 and OB. MG-63 showed opposite responses in osteocalcin levels after GLP-2.
Conclusions
These results suggest that osteoblast activity modulation varies according to different development stage under different nutrition related-peptides.
doi:10.1186/1472-6793-11-12
PMCID: PMC3162581  PMID: 21801348
24.  Birth Outcomes and Infant Mortality by the Degree of Rural Isolation Among First Nations and Non-First Nations in Manitoba, Canada 
Context
It is unknown whether rural isolation may affect birth outcomes and infant mortality differentially for Indigenous versus non-Indigenous populations. We assessed birth outcomes and infant mortality by the degree of rural isolation among First Nations (North American Indians) and non-First Nations populations in Manitoba, Canada, a setting with universal health insurance.
Methods
A geocoding-based birth cohort study of 25,143 First Nations and 125,729 non-First Nations live births to Manitoban residents, 1991–2000. Degree of rural isolation was defined by an indicator of urban influence (no, weak, moderate/strong) based on the percentage of the workforce commuting to urban areas.
Findings
Preterm birth and low birth weight rates were somewhat lower in all rural areas regardless of the degree of isolation as compared to urban areas for both First Nations and non-First Nations. Infant mortality rates were not significantly different across areas for First Nations (10.7, 9.9, 7.9, and 9.7 per 1,000 in rural areas with no, weak, moderate/strong urban influence, and urban areas, respectively), but rates were significantly lower in less isolated areas for non-First Nations (7.4, 6.0, 5.6, and 4.6 per 1,000, respectively). Adjusted odds ratios showed similar patterns.
Conclusions
Living in less isolated areas was associated with lower infant mortality only among non-First Nations. First Nations infants do not seem to have similarly benefited from the better health care facilities in urban centers, suggesting a need to improve urban First Nations’ infant care in meeting the challenges of increasing urban migration.
doi:10.1111/j.1748-0361.2010.00279.x
PMCID: PMC3035640  PMID: 20447004 CAMSID: cams1530
birth outcomes; infant mortality; North American Indians; rural and urban; rural isolation
25.  Large prospective birth cohort studies on environmental contaminants and child health – Goals, challenges, limitations and needs 
Medical hypotheses  2009;74(2):318-324.
SUMMARY
The adverse health effects of environmental contaminants (ECs) are a rising public health concern, and a major threat to sustainable socioeconomic development. The developing fetuses and growing children are particularly vulnerable to the adverse effects of ECs. However, assessing the health impact of ECs presents a major challenge, given that multiple outcomes may arise from one exposure, multiple exposures may result in one outcome, and the complex interactions between ECs, and between ECs, nutrients and genetic factors, and the dynamic temporal changes in EC exposures during the life course. Large-scale prospective birth cohort studies collecting extensive data and specimen starting from the prenatal or pre-conception period, although costly, hold promise as a means to more clearly quantify the health effects of ECs, and to unravel the complex interactions between ECs, nutrients and genotypes. A number of such large-scale studies have been launched in some developed counties. We present an overview of “why”, “what” and “how” behind these efforts with an objective to uncover major unidentified limitations and needs. Three major limitations were identified: (1) limited data and bio-specimens regarding early life EC exposure assessments in some birth cohort studies; (2) heavy participant burdens in some birth cohort studies may bias participant recruitment, and risk substantial loss to follow-up, protocol deviations limiting the quality of data and specimens collection, with an overall potential bias towards the null effect; (3) lack of concerted efforts in building comparable birth cohorts across countries to take advantage of natural “experiments” (large EC exposure level differences between countries) for more in-depth assessments of dose–response relationships, threshold exposure levels, and positive and negative effect modifiers. Addressing these concerns in current or future large-scale birth cohort studies may help to produce better evidence on the health effects of ECs.
doi:10.1016/j.mehy.2009.08.044
PMCID: PMC3035639  PMID: 19765909 CAMSID: cams1529

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