Maija E. Miettinen

Association of Serum 25-Hydroxyvitamin D with Lifestyle Factors and Metabolic and Cardiovascular Disease Markers: Population-Based Cross-Sectional Study (FIN-D2D)

Objectives Low serum 25-hydroxyvitamin D (25OHD) level has been associated with an increased risk of several chronic diseases. Our aim was to determine lifestyle and clinical factors that are associated with 25OHD level and to investigate connection of 25OHD level with metabolic and cardiovascular disease markers. Design In total, 2868 Finnish men and women aged 45–74 years participated in FIN-D2D population-based health survey in 2007. Participants that had a serum sample available (98.4%; n = 2822) were included in this study. 25OHD was measured with chemiluminescent microparticle immunoassay method. Results The mean 25OHD level was 58.2 nmol/l in men (n = 1348) and 57.1 nmol/l in women (n = 1474). Mean 25OHD level was lower in the younger age groups than in the older ones (p<0.0001 both in men and women). This study confirmed that low physical activity (p<0.0001 both in men and women), smoking (p = 0.0002 in men and p = 0.03 in women) and high BMI (p<0.0001 in women) are factors that independently associate with low 25OHD level. Of the metabolic and cardiovascular disease markers high triglyceride concentration (p = 0.02 in men and p = 0.001 in women) and high apolipoprotein B/apolipoprotein A1 ratio (p = 0.04 in men and p = 0.03 in women) were independently associated with low 25OHD level. Conclusions Higher age did not predict lower 25OHD level in this study population of aged 45–74 years which may derive from a healthy life-style of “active pensioners”. Low physical activity and smoking came up as independent lifestyle factors associated with low 25OHD level. Defining the molecular mechanisms behind the associations of 25OHD with low physical activity and smoking are important objective in future studies. The association of 25OHD with BMI, high triglyceride concentration and apolipoprotein B/apolipoprotein A1 ratio may be related to the role of vitamin D in inflammation, but more detailed studies are needed.

Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring

Aims/hypothesisWe investigated whether single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentration in the metabolic pathway of vitamin D show different genotype distributions between Finnish families with an offspring with type 1 diabetes (cases) and families with a healthy offspring (controls).MethodsA total of 31 SNPs in eight genes were studied in case and control mothers and family members (offspring with type 1 diabetes and healthy siblings, healthy control children and fathers) (n = 2,854). The 25-hydroxyvitamin D concentration was studied in 474 case and 348 matched control mothers during pregnancy.ResultsThe genotype distributions of 13 SNPs (in the following genes: 7-dehydrocholesterol reductase NADSYN1/DHCR7, vitamin D receptor VDR, group-specific component GC and CYP27A1) that showed a nominal association with 25-hydroxyvitamin D concentration (p < 0.05) were compared between case and control families. SNPs in VDR had different genotype distributions between the case and control mothers (rs1544410, p = 0.007; rs731236, p = 0.003; rs4516035, p = 0.015), two SNPs (rs1544410 and rs731236) remaining significant after correction for multiple testing using a false discovery rate. The mean 25-hydroxyvitamin D concentrations during pregnancy did not differ between the case and control mothers.Conclusions/interpretationOur preliminary results suggest that the maternal genotypes of SNPs in VDR may influence the in utero environment and thus contribute to the early programming of type 1 diabetes in the fetus. It is possible that the effects are only relevant in the presence of vitamin D insufficiency.

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families.

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P=0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight ⩾4000 g were born in families with a T1D offspring than in the general Finnish population (P=0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight ⩾4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

Genetic determinants of serum 25-hydroxyvitamin D concentration during pregnancy and type 1 diabetes in the child

Objective The in utero environment plays an important role in shaping development and later life health of the fetus. It has been shown that maternal genetic factors in the metabolic pathway of vitamin D associate with type 1 diabetes in the child. In this study we analyzed the genetic determinants of serum 25-hydroxyvitamin D (25OHD) concentration during pregnancy in mothers whose children later developed type 1 diabetes and in control mothers. Study design 474 mothers of type 1 diabetic children and 348 mothers of non-diabetic children were included in the study. We previously selected 7 single nucleotide polymorphisms (SNPs) in four genes in the metabolic pathway of vitamin D vitamin based on our previously published data demonstrating an association between genotype and serum 25OHD concentration. In this re-analysis, possible differences in strength in the association between the SNPs and serum 25OHD concentration in mothers of type 1 diabetic and non-diabetic children were investigated. Serum 25OHD concentrations were previously shown to be similar between the mothers of type 1 diabetic and non-diabetic children and vitamin D deficiency prevalent in both groups. Results Associations between serum 25OHD concentration and 2 SNPs, one in the vitamin D receptor (VDR) gene (rs4516035) and one in the group-specific component (GC) gene (rs12512631), were stronger during pregnancy in mothers whose children later developed type 1 diabetes than in mothers whose children did not (pinteraction = 0.03, 0.02, respectively). Conclusions We show for the first time that there are differences in the strength of genetic determinants of serum 25OHD concentration during pregnancy between the mothers of type 1 diabetic and non-diabetic children. Our results emphasize that the in utero environment including maternal vitamin D metabolism should be important lines of investigation when searching for factors that lead to early programming of type 1 diabetes.

Comment on: Sørensen et al. Maternal Serum Levels of 25-Hydroxy-Vitamin D During Pregnancy and Risk of Type 1 Diabetes in the Offspring. Diabetes 2012;61:175–178

Sorensen et al. (1) report that in Norway, low concentration of 25-hydroxy-vitamin D [25(OH)D] in mothers during pregnancy was associated with an increased risk of type 1 diabetes in the offspring. We would like to point out that one putative confounding factor in their study might have been the intake of n-3 polyunsaturated fatty acids. Childhood n-3 fatty acid intake and status have been linked with the development of pretype 1 diabetes (2), while reasonably powered prospective studies of exposure during pregnancy are …

The effect of age and gender on the genetic regulation of serum 25-hydroxyvitamin D - the FIN-D2D population-based study.

In addition to sunlight and dietary sources, several genes in the metabolic pathway of vitamin D affect serum 25-hydroxyvitamin D (25OHD) concentration. It is not known whether this genetic regulation is influenced by host characteristics. We investigated the effect of age and gender on the genetic regulation of serum 25OHD concentration. In total, 2868 Finnish men and women aged 45-74 years participated in FIN-D2D population-based health survey in 2007. Of the 2822 participants that had serum 25OHD concentration available, 2757 were successfully genotyped. Age and gender-dependent association of SNPs with serum 25OHD concentration was studied in 10 SNPs with previously found association with vitamin D metabolites. Associations of 3 SNPs with serum 25OHD concentration were dependent on age with greater effects on younger (≤60 y) than older (>60 y) adults (rs10783219 in VDR, rs12512631 in GC and rs3794060 in NADSYN1/DHCR7; pinteraction = 0.03, 0.02 and 0.01, respectively). The results suggested a novel association between serum 25OHD concentration and rs8082391 in STAT5B gene in men but not in women (pinteraction = 0.01). After multiple testing correction with false discovery rate method, two age-dependent interactions (rs3794060 in NADSYN1/DHCR7 gene and rs12512631 in GC gene) remained statistically significant. This is the first study to suggest that genetic regulation of serum 25OHD concentration is age-dependent. Our results also indicated a novel association between serum 25OHD concentration and SNP in STAT5B gene in men. The results need to be confirmed in future studies preferably in a larger sample.

Dietary gluten and type 1 diabetes

A potential association that deserves closer scrutiny

Association of serum 25-hydroxyvitamin D concentration with HLA-B, -DRB1 and -DQB1 genetic polymorphisms

Background/Objectives:The human leukocyte antigen (HLA) gene region associates with the risk for several autoimmune diseases, including type 1 diabetes. An association between vitamin D deficiency and several autoimmune diseases has been suggested. We tested the association between serum 25-hydroxyvitamin D (25OHD) concentrations and HLA alleles in pregnant Finnish women.Subjects/Methods:HLA-B (n=395), HLA-DRB1 (n=501) and HLA-DQB1 (n=475) alleles were genotyped in pregnant women (mothers of children who later developed type 1 diabetes and mothers of non-diabetic children). HLA-B alleles were divided into supertypes that share similar peptide-binding specificity. Serum 25OHD concentration had been previously measured in these women from sera collected during the first trimester of pregnancy. Multiple testing was controlled for using the false discovery rate method.Results:An association was found between 25OHD concentration and HLA-B44 supertype (P=0.009); women with HLA-B44 supertype (B*18, B*37, B*40 and B*44 alleles) had lower 25OHD concentrations. No association was found between HLA-DRB1 or -DQB1 alleles and 25OHD concentration.Conclusions:In this study we found for the first time an association between HLA genetic polymorphisms and 25OHD concentration. In future studies, the mechanistic background of this association and the role of vitamin D in the regulation of HLA gene expression should be investigated.