Elina Hyppönen

Common genetic determinants of vitamin D insufficiency: a genome-wide association study

BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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. FUNDING Full funding sources listed at end of paper (see Acknowledgments).

Birth weight and risk of type 2 diabetes: A systematic review

CONTEXT Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. OBJECTIVE To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. DATA SOURCES AND STUDY SELECTION Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. DATA EXTRACTION Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. DATA SYNTHESIS Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. CONCLUSION In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Causal Relationship Between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.

Infant vitamin D supplementation and allergic conditions in adulthood: Northern Finland Birth Cohort 1966

Abstract: Allergen‐induced secretion of Th2‐type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)2D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n= 7,648), and atopy determined by skin‐prick test in a sub‐sample still living in northern Finland or the Helsinki area (n= 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4‐2.0, and OR 1.66, 95%CI 1.1‐1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99‐1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P= 0.01 for atopy, P= 0.001 for allergic rhinitis, and P= 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long‐term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.

25-Hydroxyvitamin D, IGF-1, and Metabolic Syndrome at 45 Years of Age A Cross-Sectional Study in the 1958 British Birth Cohort

OBJECTIVE—Hypovitaminosis D and reduced IGF-1 are associated, individually, with metabolic syndrome. Physiological interactions between vitamin D and IGF-1 are reported; this is the first study to investigate their combined associations with metabolic syndrome prevalence. RESEARCH DESIGN AND METHODS—Data on 25-hydroxyvitamin D (25(OH)D), IGF-1, and metabolic syndrome abnormalities (abdominal obesity; raised A1C, blood pressure, and triglycerides; and low HDL cholesterol) were collected from 6,810 British white subjects in the 1958 cohort, surveyed during 2002–2004 (age 45 years). RESULTS—IGF-1 concentrations increased with 25(OH)D up to ∼75–85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 (P = 0.025) on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D (P > 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P ≤ 0.006). Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1 (odds ratio for highest vs. lowest third of both 0.26 [95% CI 0.17–0.40], P < 0.0001; adjusted for sex, month, hour, inactivity, alcohol consumption, smoking, and social class). 25(OH)D was associated with the prevalence of high A1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations (P ≤ 0.004 for all comparisons). CONCLUSIONS—Serum 25(OH)D is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.

Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis

Background: Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D [25(OH)D]. Objective: The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans. Design: The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials. Results: A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. Conclusions: This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3 could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.

Vitamin D Status and Glucose Homeostasis in the 1958 British Birth Cohort: The role of obesity

OBJECTIVE—Obesity is a well-known risk factor for vitamin D deficiency. We evaluated the interrelationship between vitamin D status, body size, and glucose homeostasis, measured by HbA1c (A1C). RESEARCH DESIGN AND METHODS—Data are from the survey of the 45-year-old 1958 British birth cohort (2002–2004). Information on A1C, 25-hydroxyvitamin D [25(OH)D; an indicator of vitamin D status], and BMI was collected from 7,198 Caucasian subjects. RESULTS—25(OH)D was <75 nmol/l in 80% of the obese subjects (BMI ≥30 kg/m2) versus 68% of the other subjects (P < 0.0001). Serum 25(OH)D decreased and A1C increased by increasing BMI (P < 0.0001 for both comparisons). There was a nonlinear association between 25(OH)D and A1C: a steep linear decrease in A1C by 25(OH)D until 65 nmol/l and only smaller decreases with further increases. There was evidence for effect modification by BMI in the association between 25(OH)D and A1C (P < 0.0001), and differences appeared stronger for participants with higher compared with lower BMIs. After adjustment for sex, season, geographical location, physical activity, and social class, percent change in A1C by 10-nmol/l increase in 25(OH)D was −0.21 (95% CI −0.31 to −0.11) for BMI <25 kg/m2, −0.25 (−0.37 to −0.13) for BMI 25–29.9 kg/m2, −0.65 (−0.95 to −0.34) for BMI 30–34.9 kg/m2, and −1.37 (−2.09 to −0.64) for BMI ≥35 kg/m2. CONCLUSIONS—Body size was a strong determinant for 25(OH)D, with concentrations being suboptimal in most obese participants. Randomized controlled trials [using dosages sufficient to improve 25(OH)D also for the obese] are required to determine whether clinically relevant improvements in glucose metabolism can be obtained by vitamin D supplementation.

25-hydroxyvitamin D, insulin-like growth factor 1 and metabolic syndrome at age 45y: a cross-sectional study in the 1958 British birth cohort

OBJECTIVE—Hypovitaminosis D and reduced IGF-1 are associated, individually, with metabolic syndrome. Physiological interactions between vitamin D and IGF-1 are reported; this is the first study to investigate their combined associations with metabolic syndrome prevalence. RESEARCH DESIGN AND METHODS—Data on 25-hydroxyvitamin D (25(OH)D), IGF-1, and metabolic syndrome abnormalities (abdominal obesity; raised A1C, blood pressure, and triglycerides; and low HDL cholesterol) were collected from 6,810 British white subjects in the 1958 cohort, surveyed during 2002–2004 (age 45 years). RESULTS—IGF-1 concentrations increased with 25(OH)D up to ∼75–85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 (P = 0.025) on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D (P > 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P ≤ 0.006). Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1 (odds ratio for highest vs. lowest third of both 0.26 [95% CI 0.17–0.40], P < 0.0001; adjusted for sex, month, hour, inactivity, alcohol consumption, smoking, and social class). 25(OH)D was associated with the prevalence of high A1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations (P ≤ 0.004 for all comparisons). CONCLUSIONS—Serum 25(OH)D is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.

Obesity and Type 2 Diabetes Risk in Midadult Life: The Role of Childhood Adversity

OBJECTIVE. Child abuse has been associated with poorer physical health in adulthood, but less is known about childhood adversity more broadly, including neglect and family problems, or the pathways from adversity to adult disease. We have examined how different stressful emotional or neglectful childhood adversities are related to adiposity and glucose control in midadulthood, taking into account childhood factors, and whether the relationships are mediated by adult health behaviors and socioeconomic position. METHODS. This was a prospective longitudinal study of 9310 members of the 1958 British birth cohort who participated in a biomedical interview at 45 years of age. Primary outcomes consisted of continuous measures of BMI, waist circumference, and glycosylated hemoglobin at 45 years and categorical indicators: total obesity (BMI ≥ 30), central obesity (waist circumference: ≥102 cm for men and ≥88 cm for women), and glycosylated hemoglobin level of ≥6. RESULTS. The risk of obesity increased by 20% to 50% for several adversities (physical abuse, verbal abuse, witnessed abuse, humiliation, neglect, strict upbringing, physical punishment, conflict or tension, low parental aspirations or interest in education, hardly takes outings with parents, and father hardly reads to child). Adversities with the strongest associations with adiposity (eg, physical abuse) tended to be associated with glycosylated hemoglobin levels of ≥6, but in most cases associations were explained by adjustment for adulthood mediators such as adiposity. Effects of other adversities reflecting less severe emotional neglect and family environment were largely explained by childhood socioeconomic factors. CONCLUSIONS. Some childhood adversities increase the risk of obesity in adulthood and thereby increase the risk for type 2 diabetes. Research is needed to understand the interrelatedness of adversities, the social context of their occurrence, and trajectories from adversity to adult disease.

Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes

OBJECTIVE Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis. RESEARCH DESIGN AND METHODS We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status. RESULTS Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3). CONCLUSIONS Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.