Does bariatric surgery improve adipose tissue function?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134250/1/obr12429_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134250/2/obr12429.pd

Associations between genetic variations in the FURIN gene and hypertension

<p>Abstract</p> <p>Background</p> <p>Hypertension is a complex disease influenced by multiple genetic and environmental factors. The Kazakh ethnic group is characterized by a relatively high prevalence of hypertension. Previous research indicates that the FURIN gene may play a pivotal role in the renin-angiotensin system and maintaining the sodium-electrolyte balance. Because these systems influence blood pressure regulation, we considered FURIN as a candidate gene for hypertension. The purpose of this study was to systematically investigate the association between genetic variations in the FURIN gene and essential hypertension in a Xinjiang Kazakh population.</p> <p>Methods</p> <p>We sequenced all exons and the promoter regions of the FURIN gene in 94 hypertensive individuals to identify genetic variations associated with the disorder. Genotyping was performed using the TaqMan polymerase chain reaction method for four representative common single nucleotide polymorphisms (SNPs, -7315C > T, 1970C > G, 5604C > G, 6262C > T) in 934 Kazakh Chinese people. One SNP (1970C > G) was replicated in 1,219 Uygur Chinese people.</p> <p>Results</p> <p>Nine novel and seven known single nucleotide polymorphisms were identified in the FURIN gene. The results suggest that 1970C > G was associated with a hypertension phenotype in Kazakh Chinese (additive model, <it>P </it>= 0.091; dominant model, <it>P = </it>0.031, allele model, <it>P </it>= 0.030), and after adjustment with logistic regression analysis, ORs were 1.451 (95%CI 1.106-1.905, <it>P </it>= 0.008) and 1.496 (95% 1.103-2.028, <it>P </it>= 0.01) in additive and dominant models, respectively. In addition, the association between 1970C > G and hypertension was replicated in Uygur subjects (additive model, <it>P </it>= 0.042; dominant model, <it>P </it>= 0.102; allele model, <it>P </it>= 0.027) after adjustment in additive and dominant models, ORs were 1.327 (95% 1.07-1.646), <it>P </it>= 0.01 and 1.307 (95%CI 1.015-1.681, <it>P </it>= 0.038), respectively. G allele carriers exhibited significant lower urinary Na⁺excretion rate than non-carriers in the Kazakh Chinese population (152.45 ± 76.04 uM/min vs 173.33 ± 90.02 uM/min, <it>P </it>= 0.007).</p> <p>Conclusion</p> <p>Our results suggest that the FURIN gene may be a candidate gene involved in human hypertension, and that the G allele of 1970C > G may be a modest risk factor for hypertension in Xinjiang Kazakh and Uygur populations.</p

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention

Apolipoprotein E Genotype and Cardiovascular Diseases in the Elderly

The apolipoprotein E (APOE) genotype is a genetic risk factor for dementia, Alzheimer’s disease, and cardiovascular disease (CVD). It includes three alleles (e2, e3, e4) that are located on chromosome 19q3.2. The e3 allele is the most common and is more common in people of Northern European ancestry and less common in those of Asian ancestry. Those with at least one e4 allele are at increased risk for CVD outcomes. It is well established that the presence of an e4 allele is linked to higher low-density lipoprotein cholesterol levels, even at young ages. Even though most CVD occurs in older people, there are few studies of the effects of APOE on CVD in older people. This review addresses recent research on the links between APOE, CVD, and vascular mechanisms by which APOE may affect CVD in the elderly

Multiple splice defects in ABCA1 cause low HDL-C in a family with Hypoalphalipoproteinemia and premature coronary disease

<p>Abstract</p> <p>Background</p> <p>Mutations at splice junctions causing exon skipping are uncommon compared to exonic mutations, and two intronic mutations causing an aberrant phenotype have rarely been reported. Despite the high number of functional <it>ABCA1 </it>mutations reported to date, splice variants have been reported infrequently. We screened DNA from a 41 year-old male with low HDL-C (12 mg/dL [0.31 mmol/L]) and a family history of premature coronary heart disease (CHD) using polymerase chain reaction single-strand conformation polymorphism (SSCP) analysis.</p> <p>Methods</p> <p>Family members with low levels of HDL-C (n = 6) were screened by SSCP for mutations in <it>ABCA1</it>. Samples with altered SSCP patterns were sequenced directly using either an ABI 3700 or ABI3730Xl DNA Analyzer. To screen for splicing defects, cDNA was isolated from the proband's RNA and was sequenced as above. A series of minigenes were constructed to determine the contribution of normal and defective alleles.</p> <p>Results</p> <p>Two novel splice variants in <it>ABCA1 </it>were identified. The first mutation was a single base pair change (T->C) in IVS 7, 6 bps downstream from the exon7/intron7 junction. Amplification of cDNA and allelic subcloning identified skipping of Exon 7 that results in the elimination of 59 amino acids from the first extracellular loop of the ABCA1 protein. The second mutation was a single base pair change (G->C) at IVS 31 -1, at the intron/exon junction of exon 32. This mutation causes skipping of exon 32, resulting in 8 novel amino acids followed by a stop codon and a predicted protein size of 1496 AA, compared to normal (2261 AA). Bioinformatic studies predicted an impact on splicing as confirmed by <it>in vitro </it>assays of constitutive splicing.</p> <p>Conclusion</p> <p>In addition to carnitine-acylcarnitine translocase (CACT) deficiency and Hermansky-Pudlak syndrome type 3, this represents only the third reported case in which 2 different splice mutations has resulted in an aberrant clinical phenotype.</p

Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

Background: Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings: We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions: Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo

Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

<p>Abstract</p> <p>Background</p> <p>Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including <it>LPL</it>, <it>APOA5 </it>and <it>APOE</it>. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.</p> <p>Methods</p> <p>A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the <it>LPL</it>-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the <it>APOA5</it>-S19W (rs3135506) and -1131T/C (rs662799) variants, and the <it>APOE </it>polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.</p> <p>Results</p> <p>We found a significant lowering effect of the <it>LPL</it>-HindIII and S447X polymorphisms (<it>p </it>< 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the <it>APOE</it>-ε4 allele were significantly associated with an independent additive TG-raising effect (<it>p </it>< 0.05, <it>p </it>< 0.01, <it>p </it>< 0.001, <it>p </it>< 0.0001 and <it>p </it>< 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (<it>p </it>< 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; <it>p </it>= 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; <it>p </it>< 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; <it>p </it>< 0.001) were associated with HTG.</p> <p>Conclusion</p> <p>Our results showed a significant independent additive effect on TG levels of the <it>LPL </it>polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of <it>APOA5</it>, and the ε4 allele of <it>APOE </it>in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.</p

The effect of ABCA1 gene polymorphisms on ischaemic stroke risk and relationship with lipid profile

<p>Abstract</p> <p>Background</p> <p>Ischaemic stroke is a common disorder with genetic and environmental components contributing to overall risk. Atherothromboembolic abnormalities, which play a crucial role in the pathogenesis of ischaemic stroke, are often the end result of dysregulation of lipid metabolism. The ATP Binding Cassette Transporter (<it>ABCA1</it>) is a key gene involved in lipid metabolism. It encodes the cholesterol regulatory efflux protein which mediates the transfer of cellular phospholipids and cholesterol to acceptor apolipoproteins such as apolipoprotein A-I (ApoA-I). Common polymorphisms in this gene affect High Density Lipoprotein Cholesterol (HDL-C) and Apolipoprotein A-I levels and so influence the risk of atherosclerosis. This study has assessed the distribution of <it>ABCA1 </it>polymorphisms and haplotype arrangements in patients with ischaemic stroke and compared them to an appropriate control group. It also examined the relationship of these polymorphisms with serum lipid profiles in cases and controls.</p> <p>Methods</p> <p>We studied four common polymorphisms in <it>ABCA1 </it>gene: G/A-L158L, G/A-R219K, G/A-G316G and G/A-R1587K in 400 Caucasian ischaemic stroke patients and 487 controls. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay.</p> <p>Results</p> <p>Genotype and allele frequencies of all polymorphisms were similar in cases and controls, except for a modest difference in the <it>ABCA1 </it>R219K allele frequency (P-value = 0.05). Using the PHASE2 program, haplotype frequencies for the four loci (158, 219, 316, and 1587) were estimated in cases and controls. There was no significant difference in overall haplotypes arrangement in patients group compared to controls (p = 0.27). 2211 and 1211 haplotypes (1 = common allele, 2 = rare allele) were more frequent in cases (p = 0.05). Adjusted ORs indicated 40% and 46% excess risk of stroke for these haplotypes respectively. However, none of the adjusted ORs were statistically significant. Individuals who had R219K "22" genotype had a higher LDL level (p = 0.001).</p> <p>Conclusion</p> <p>Our study does not support a major role for the <it>ABCA1 </it>gene as a risk factor for ischaemic stroke. Some haplotypes may confer a minor amount of increased risk or protection. Polymorphisms in this gene may influence serum lipid profile.</p