Zinc absorption in adult humans: the effect of iron fortification

The effect of Fe fortification on the absorption of Zn was studied by radioisotopic labelling of single meals, followed by measurements of whole-body retention of 65Zn at 14 d after intake. Healthy adult volunteers participated in the study. Weaning cereal, wheat bread and infant formula, foods that are all frequently Fe-fortified, were evaluated in the study. The amounts of Fe added as FeSO4 were similar to the levels in commercial products in Europe and the USA, and were 200 or 500 mg Fe/kg (weaning cereal), 65 mg Fe/kg (white wheat flour) and 12 mg Fe/1 (infant formula). For comparison, Zn absorption was measured in the same subjects, from identical test meals containing no added Fe. No statistically significant differences were found when Zn absorption from the Fe-fortified test meals was compared with that from non-Fe-fortified test meals. Fractional Zn-absorption values from Fe-fortified v. non-fortified meals were 31·1 (sd 1·19) v. 30·7 (SD 7·0)% (weaning cereal; 200 mg Fe/kg), 37·7 (SD 16·6) v. 30·2 (SD 9·9)% (weaning cereal; 500 mg Fe/kg), 36·5 (SD 14·4) v. 38·2 (SD 18·1)% (bread; 65 mg Fe/kg flour) and 41·6 (SD 8·1) v. 38·9 (SD 14·5)% (infant formula; 12 mg Fe/1). The addition of Fe to foods at the currently used fortification levels was thus not associated with impaired absorption of Zn and the consumption of these Fe-fortified foods would not be expected to have a negative effect on Zn nutritio

Zinc absorption in adult humans: the effect of protein sources added to liquid test meals

The influence of different protein sources on Zn absorption was evaluated in healthy adults by radioisotopic labelling of single meals, followed by whole-body retention measurements 14 d after intake. Semi-synthetic liquid diets were used for the evaluation of different animal-protein sources and dephytinized soyabean-protein isolate ( ··01 g phytic acid/kg). Zn absorption was measured in the same subjects from identical test meals containing no added protein. No statistically significant differences were found in the Zn absorption from test meals containing bovine whey, casein or egg albumen when compared with test meals without added protein. Bovine serum albumin (BSA) and soyabean-protein isolate (< ··01 g phytic acid/kg) significantly reduced the mean absorption of Zn from 45-49% (no added protein) to 38·0 (SD 10·9) (BSA, P < ··05) and 33·9 (SD 12·6)% (soyabean-protein isolate < ··01 g phytic acid/kg, P < ··01). These results demonstrate that Zn absorption is inhibited by certain protein sources, such as BSA and dephytinized soyabean-protein isolate, while other proteins have little or no effec

Bioactivity of Cod and Chicken Protein Hydrolysates before and after in vitro Gastrointestinal Digestion

Bioactivity of cod (Gadus morhua) and chicken (Gallus domesticus) protein hydrolysates before and aft er in vitro gastrointestinal (GI) digestion was investigated using yeast Saccharomyces cerevisiae as a model organism. Both hydrolysates were exposed to in vitro GI digestion prior to cellular exposure to simulate digestion conditions in the human body and therefore investigate the role of modulations in the GI tract on the cell response. The eff ect of digested and undigested hydrolysates on intracellular oxidation, cellular metabolic energy and proteome level was investigated. No diff erence in the eff ect on intracellular oxidation activity was obtained between cod and chicken hydrolysates, while higher aff ect on intracellular oxidation was provided by digested hydrolysates, with relative values of intracellular oxidation of cod of (70.2±0.8) and chicken of (74.5±1.4) % than by undigested ones, where values of cod and chicken were (95.5±1.2) and (90.5±0.7) %, respectively. Neither species nor digestion had any eff ect on cellular metabolic energy. At proteome level, digested hydrolysates gave again signifi cantly stronger responses than undigested counterparts; cod peptides here also gave somewhat stronger response than chicken peptides. The knowledge of the action of food protein hydrolysates and their digests within live cells, also at proteome level, is important for further validation of their activity in higher eukaryotes to develop new functional food ingredients, such as in this case chicken and cod muscle-derived peptides

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease

Background and objectives: Cardiovascular risk factors have been implicated in the etiology of cerebral small vessel disease (CSVD); however, whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here, we use mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD. Methods: We used data from large-scale genome-wide association studies of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median MR, with validation using weighted median, MR-Egger, and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly. Results: MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits. Discussion: Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD

Genetic Risk Score for Intracranial Aneurysms:Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10(-3) per year [95% CI, -6.49×10(-3) to -3.14×10(-3)]; P=1.82×10(-8)), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P &lt; 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.</p

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec