An update on vitamin B12-related gene polymorphisms and B12 status.

BACKGROUND: Vitamin B12 is an essential micronutrient in humans needed for health maintenance. Deficiency of vitamin B12 has been linked to dietary, environmental and genetic factors. Evidence for the genetic basis of vitamin B12 status is poorly understood. However, advancements in genomic techniques have increased the knowledge-base of the genetics of vitamin B12 status. Based on the candidate gene and genome-wide association (GWA) studies, associations between genetic loci in several genes involved in vitamin B12 metabolism have been identified. OBJECTIVE: The objective of this literature review was to identify and discuss reports of associations between single-nucleotide polymorphisms (SNPs) in vitamin B12 pathway genes and their influence on the circulating levels of vitamin B12. METHODS: Relevant articles were obtained through a literature search on PubMed through to May 2017. An article was included if it examined an association of a SNP with serum or plasma vitamin B12 concentration. Beta coefficients and odds ratios were used to describe the strength of an association, and a P < 0.05 was considered as statistically significant. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. RESULTS: From 23 studies which fulfilled the selection criteria, 16 studies identified SNPs that showed statistically significant associations with vitamin B12 concentrations. Fifty-nine vitamin B12-related gene polymorphisms associated with vitamin B12 status were identified in total, from the following populations: African American, Brazilian, Canadian, Chinese, Danish, English, European ancestry, Icelandic, Indian, Italian, Latino, Northern Irish, Portuguese and residents of the USA. CONCLUSION: Overall, the data analyzed suggests that ethnic-specific associations are involved in the genetic determination of vitamin B12 concentrations. However, despite recent success in genetic studies, the majority of identified genes that could explain variation in vitamin B12 concentrations were from Caucasian populations. Further research utilizing larger sample sizes of non-Caucasian populations is necessary in order to better understand these ethnic-specific associations.

Elevated fetal adipsin/acylation-stimulating protein (ASP) in obese pregnancy: novel placental secretion via Hofbauer cells.

CONTEXT AND OBJECTIVE: Obesity in pregnancy is associated with increased risks of obesity in the offspring. We investigated the relationship between obesity in pregnancy and circulating maternal and fetal levels of adipose tissue-derived factors adipsin and acylation stimulating protein (ASP) in lean and obese mothers. DESIGN: Paired peripheral and cord blood samples were taken. Paired fat and placenta tissue were taken for explant culture. Media were assayed for secreted adipsin and ASP. Clinical parameters assayed included fasting insulin, glucose, and adipsin. SETTING: The study was conducted at a university hospital maternity unit. PATIENTS: Patients included 35 lean [body mass index (BMI) 19-25 kg/m(2), mean age 32 years and 39 obese (BMI) > 30 kg/m(2), mean age 32.49 years] pregnant Caucasian women, delivered by cesarean section at term. MAIN OUTCOME MEASURE: Identification of placental macrophages [Hofbauer cells (HBCs)], as a source of adipsin and ASP was determined. RESULTS: HBCs secreted both adipsin and ASP. Cord levels of adipsin (1663.78 ± 52.76 pg/mL) and ASP (354.48 ± 17.17 ng/mL) were significantly elevated in the offspring of obese mothers compared with their lean controls [1354.66 ± 33.87 pg/mL and 302.63 ± 14.98 ng/mL, respectively (P < .05 for both)]. Placentae from obese mothers released significantly more adipsin and ASP than placentae from lean mothers [546.0 ± 44 pg/mL · g vs 284.56 ± 43 pg/mL · g and 5485.75 ± 163.32 ng/mL · g vs 2399.16 ± 181.83 ng/mL · g, respectively (P < .05 for both)]. Circulating fetal adipsin and ASP positively correlated with maternal BMI (r = 0.611, P < .0001, and r = 0.391, P < .05, respectively). Fetal adipsin correlated positively with maternal (r = 0.482, P < .01) and fetal homeostasis model assessment of insulin resistance (r = 0.465, P < .01). CONCLUSIONS: We demonstrate novel secretion of adipsin and ASP by placental HBCs.

Telomere shortening & metabolic/vascular diseases.

Telomeres are specialized DNA-protein structures located at the ends of eukaryotic chromosomes whose length is progressively reduced in most somatic cells during ageing. Over the past decade, emerging evidence has shown that the telomeres are essential regulators of cellular life span and chromosome integrity in a dynamic fashion. By inducing genomic instability, replicative senescence and apoptosis, shortening of telomeres is thought to contribute to organismal ageing. While the aetiology of cardiovascular diseases and diabetes represent a complex interaction between various risk factors overlaid on different genetic backgrounds, the conventional risk factors often did not explain the inter-individual variability related to predisposition of disease states. This underscores the need for biological indicators of ageing in evaluating the aetiology of several age-related disorders, and recent studies indicate that telomere length could qualify as an ideal marker of biological ageing. Short telomeres have been detected in senescent endothelial cells and vascular smooth muscle cells from human atherosclerotic plaque as well as in myocardial tissue from patients with end-stage heart failure and cardiac hypertrophy. In addition, telomere shortening has been demonstrated in WBCs from patients with coronary heart disease, premature myocardial infarction, hypertension and diabetes mellitus. In this review, we discuss the telomere hypothesis of ageing as well as human studies that address the role of telomeres in cardiovascular, diabetes and other cardio-metabolic pathologies.

Differential gene expression of NADPH oxidase (p22phox) and hemoxygenase-1 in patients with Type 2 diabetes and microangiopathy.

AIMS: While the downstream effects of increased reactive oxygen species (ROS) in the pathogenesis of diabetes were well studied, only a few studies have explored the cellular sources of ROS. We examined whether protection against oxidative stress is altered in patients with diabetes and microangiopathy by examining changes in NADPH oxidase (p22(phox)) and hemoxygenase-1 (HO-1) levels. METHODS: NADPH oxidase (p22(phox)) and HO-1 gene expression were probed by RT-PCR using leucocytes from patients with Type 2 diabetes without (n = 19) and with microangiopathy (n = 20) and non-diabetic subjects (n = 17). Levels of lipid peroxidation as measured by thiobarbituric reactive substances (TBARS) and protein carbonyl content (PCO) were determined by fluorimetric and spectrophotometric methods, respectively. RESULTS: p22(phox) gene expression (mean +/- SE) was significantly (P < 0.05) higher in diabetic patients with (0.99 +/- 0.04) and without microangiopathy (0.86 +/- 0.05) compared with control subjects (0.66 +/- 0.05). Consistent with the mRNA data, the p22(phox) protein expression and NADPH oxidase activity was also increased in cells from diabetic patients compared with control subjects. However, HO-1 gene expression was significantly (P < 0.05) lower in patients with (0.73 +/- 0.03) and without microangiopathy (0.85 +/- 0.02) compared with control subjects (1.06 +/- 0.03). The mean (+/- SE) levels of TBARS were significantly (P < 0.05) higher in diabetic patients with (14.36 +/- 1.3 nM/ml) and without microangiopathy (12.20 +/- 1.3 nM/ml) compared with control subjects (8.58 +/- 0.7 nM/ml). The protein carbonyl content was also significantly (P < 0.05) higher in diabetic patients with (1.02 +/- 0.04 nmol/mg protein) and without microangiopathy (0.84 +/- 0.06 nmol/mg protein) compared with control subjects (0.48 +/- 0.02 nmol/mg protein). In diabetic subjects, increased p22(phox) gene expression was negatively correlated with HO-1 and positively correlated with TBARS, PCO, HbA(1c) and diabetes duration. In contrast, HO-1 gene expression was correlated negatively with p22phox, TBARS, PCO, HbA(1c) and diabetes duration. CONCLUSION: Our results indicate that increased oxidative damage is seen in Asian Indians with Type 2 diabetes and microangiopathy and is associated with increased NADPH oxidase (p22(phox)) and decreased HO-1 gene expression.

Telomere shortening occurs in Asian Indian Type 2 diabetic patients.

AIM: Telomere shortening has been reported in several diseases including atherosclerosis and Type 1 diabetes. Asian Indians have an increased predilection for Type 2 diabetes and premature coronary artery disease. The aim of this study was to determine whether telomeric shortening occurs in Asian Indian Type 2 diabetic patients. METHODS: Using Southern-blot analysis we determined mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leucocyte DNA. Type 2 diabetic patients without any diabetes-related complications (n = 40) and age- and sex-matched control non-diabetic subjects (n = 40) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Plasma level of malondialdehyde (MDA), a marker of lipid peroxidation, was measured by TBARS (thiobarbituric acid reactive substances) using a fluorescence method. RESULTS: Mean (+/- SE) TRF lengths of the Type 2 diabetic patients (6.01 +/- 0.2 kb) were significantly shorter than those of the control subjects (9.11 +/- 0.6 kb) (P = 0.0001). Among the biochemical parameters, only levels of TBARS showed a negative correlation with shortened telomeres in the diabetic subjects (r = -0.36; P = 0.02). However, telomere lengths were negatively correlated with insulin resistance (HOMA-IR) (r = -0.4; P = 0.01) and age (r = -0.3; P = 0.058) and positively correlated with HDL levels (r = 0.4; P = 0.01) in the control subjects. Multiple linear regression (MLR) analysis revealed diabetes to be significantly (P < 0.0001) associated with shortening of TRF lengths. CONCLUSIONS: Telomere shortening occurs in Asian Indian Type 2 diabetic patients.