APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica

Genetic variation in the APOC3 and APOA5 genes has been associated with plasma triglyceride concentrations and may affect the risk of myocardial infarction (MI). To assess whether APOC3/A5 haplotypes are associated with risk of MI, we examined three single-nucleotide polymorphisms (SNPs) in APOC3 (3238C>G, -455T>C, and -482C>T) and six SNPs in the APOA5 gene (-1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C) in incident cases (n = 1,703) of a first nonfatal MI matched for gender, age, and area of residence with population-based controls (n = 1,703). Conditional logistic regression models, adjusted for potential environmental confounders, were used for analysis. The common APOC3*222 haplotype was more frequent in cases than in controls (17.4% and 13.7%, respectively, P < 0.001) and was associated with increased risk of MI [odds ratio (OR) = 1.27; 95% confidence interval (95% CI), 1.09, 1.48] compared with APOC3*111 wild-type haplotype. This association was independent of the APOA5 SNPs. Although the APOC3 3238G, APOA5 -1131C, APOA5 c.-3G, and APOA5 c.1259C alleles were associated with higher triglyceride plasma concentrations, these effects could not explain the associations with MI in this population. In summary, this study supports the hypothesis that haplotypes in the APOC3 gene but not in the APOA5 gene increase susceptibility to MI.     

Mitochondrial DNA 10609T Promotes Hypoxia-Induced Increase of Intracellular ROS and Is a Risk Factor of High Altitude Polycythemia

Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson’s chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95%CI: 1.020–2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95%CI: 1.250–5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor.     

Interactions of Environmental Factors and APOA1-APOC3-APOA4-APOA5 Gene Cluster Gene Polymorphisms with Metabolic Syndrome

Objective

The present study investigated the prevalence and risk factors for Metabolic syndrome. We evaluated the association between single nucleotide polymorphisms (SNPs) in the apolipoprotein APOA1/C3/A4/A5 gene cluster and the MetS risk and analyzed the interactions of environmental factors and APOA1/C3/A4/A5 gene cluster polymorphisms with MetS.

Methods

A study on the prevalence and risk factors for MetS was conducted using data from a large cross-sectional survey representative of the population of Jilin Province situated in northeastern China. A total of 16,831 participations were randomly chosen by multistage stratified cluster sampling of residents aged from 18 to 79 years in all nine administrative areas of the province. Environmental factors associated with MetS were examined using univariate and multivariate logistic regression analyses based on the weighted sample data. A sub-sample of 1813 survey subjects who met the criteria for MetS patients and 2037 controls from this case-control study were used to evaluate the association between SNPs and MetS risk. Genomic DNA was extracted from peripheral blood lymphocytes, and SNP genotyping was determined by MALDI-TOF-MS. The associations between SNPs and MetS were examined using a case-control study design. The interactions of environmental factors and APOA1/C3/A4/A5 gene cluster polymorphisms with MetS were assessed using multivariate logistic regression analysis.

Results

The overall adjusted prevalence of MetS was 32.86% in Jilin province. The prevalence of MetS in men was 36.64%, which was significantly higher than the prevalence in women (29.66%). MetS was more common in urban areas (33.86%) than in rural areas (31.80%). The prevalence of MetS significantly increased with age (OR = 8.621, 95%CI = 6.594–11.272). Mental labor (OR = 1.098, 95%CI = 1.008–1.195), current smoking (OR = 1.259, 95%CI = 1.108–1.429), excess salt intake (OR = 1.252, 95%CI = 1.149–1.363), and a fruit and dairy intake less than 2 servings a week were positively associated with MetS (P<0.05). A family history of diabetes (OR = 1.630, 95%CI = 1.484–1.791), cardiovascular disease or cerebral diseases (OR = 1.297, 95%CI = 1.211–1.389) was associated with MetS. APOA1 rs670, APOA5 rs662799 and rs651821 revealed significant differences in genotype distributions between the MetS patients and control subjects. The minor alleles of APOA1 rs670, APOA5 rs662799 and rs651821, and APOA5 rs2075291 were associated with MetS (P<0.0016). APOA1 rs5072 and APOC3 rs5128, APOA5 rs651821 and rs662799 were in strong linkage disequilibrium to each other with r² greater than 0.8. Five haplotypes were associated with an increased risk of MetS (OR = 1.23, 1.58, 1.80, 1.90, and 1.98). When we investigated the interactions of environmental factors and APOA1/C3/A4/A5 gene cluster gene polymorphisms, we found that APOA5 rs662799 had interactions with tobacco use and alcohol consumption (P_GE<0.05).

Conclusions

There was a high prevalence of MetS in the northeast of China. Male gender, increasing age, mental labor, family history of diabetes, cardiovascular disease or cerebral diseases, current smoking, excess salt intake, fruit and dairy intake less than 2 servings a week, and drinking were associated with MetS. The APOA1/C3/A4/A5 gene cluster was associated with MetS in the Han Chinese. APOA5 rs662799 had interactions with the environmental factors associated with MetS.     

Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11

Members of the apolipoprotein gene cluster (APOA1/C3/A4/A5) on human chromosome 11q23 play an important role in lipid metabolism. Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. The close genomic locations of these two genes as well as their functional similarity have hindered efforts to define whether each gene independently influences human triglyceride concentrations. In this study, we examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. We identified a total of five common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein gene in the cluster by a region of significantly increased recombination. Furthermore, one previously identified triglyceride risk haplotype of APOA5 (APOA5*3) showed no association with three APOC3 SNPs previously associated with triglyceride concentrations, in contrast to the other risk haplotype (APOA5*2), which was associated with all three minor APOC3 SNP alleles. These results highlight the complex genetic relationship between APOA5 and APOC3 and support the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans.     

Positive Association between APOA5 rs662799 Polymorphism and Coronary Heart Disease: A Case-Control Study and Meta-Analysis

Objective

Apolipoprotein A5 (APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism.

Methods

We collected 1,521 samples (783 CHD patients and 738 controls) for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software.

Results

Significant differences were observed between CHD cases and controls at the level of both genotype (χ² = 8.964, df = 2, P = 0.011) and allele (χ² = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089–1.492). A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (χ² = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088–1.628). An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001).

Conclusion

Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD.     

The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.     

Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men

The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.     

Innate Immunity and Non-Hodgkin’s Lymphoma (NHL) Related Genes in a Nested Case-Control Study for Gastric Cancer Risk

Objective

Genetic variants regulating the host immune system may contribute to the susceptibility for the development of gastric cancer. Little is known about the role of the innate immunity- and non-Hodgkin’s lymphoma (NHL)-related genes for gastric cancer risk. This nested case-control study was conducted to identify candidate genes for gastric cancer risk for future studies.

Methods

In the Discovery phase, 3,072 SNPs in 203 innate immunity- and 264 NHL-related genes using the Illumine GoldenGateTM OPA Panel were analyzed in 42 matched case-control sets selected from the Korean Multi-center Cancer Cohort (KMCC). Six significant SNPs in four innate immunity (DEFA6, DEFB1, JAK3, and ACAA1) and 11 SNPs in nine NHL-related genes (INSL3, CHMP7, BCL2L11, TNFRSF8, RAD50, CASP7, CHUK, CD79B, and CLDN9) with a permutated p-value <0.01 were re-genotyped in the Replication phase among 386 cases and 348 controls. Odds ratios (ORs) for gastric cancer risk were estimated adjusting for age, smoking status, and H. pylori and CagA sero-positivity. Summarized ORs in the total study population (428 cases and 390 controls) are presented using pooled- and meta-analyses.

Results

Four SNPs had no heterogeneity across the phases: in the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio (OR) for gastric cancer (95% CIs = 1.1–1.6; and 1.1–1.5, respectively). INSL3 rs10421916 and rs11088680 had both a 0.8-fold decreased OR for gastric cancer (95% CIs = 0.7–0.97; and 0.7–0.9, respectively).

Conclusions

Our findings suggest that certain variants in the innate immunity and NHL-related genes affect the gastric cancer risk, perhaps by modulating infection-inflammation-immunity mechanisms that remain to be defined.     

Association between APOC1 Polymorphism and Alzheimer’s Disease: A Case-Control Study and Meta-Analysis

Background

Previous association studies examining the relationship between the APOC1 polymorphism and susceptibility to Alzheimer’s disease (AD) have shown conflicting results, and it is not clear if an APOC1 variant acts as a genetic risk factor in AD etiology across multiple populations.

Methods

To confirm the risk association between APOC1 and AD, we designed a case-control study and also performed a meta-analysis of previously published studies.

Results

Seventy-nine patients with AD and one hundred fifty-six unrelated controls were included in case-control study. No association was found between the variation of APOC1 and AD in stage 1 of our study. However, our meta-analysis pooled a total of 2092 AD patients and 2685 controls. The APOC1 rs11568822 polymorphism was associated with increased AD risk in Caucasians, Asians and Caribbean Hispanics, but not in African Americans. APOE ε4 carriers harboring the APOC1 insertion allele, were more prevalent in AD patients than controls (χ² = 119.46, OR = 2.79, 95% CI = 2.31–3.36, P<0.01).

Conclusions

The APOC1 insertion allele, in combination with APOE ε4, likely serves as a potential risk factor for developing AD.     

Prediction of genetic risk for dyslipidemia

The purpose of the present study was to identify genetic variants that confer susceptibility to dyslipidemia. A total of 5213 individuals from two independent populations were examined: Subject panel A comprised 3794 individuals who visited participating hospitals; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined. The chi(2) test and multivariable logistic regression analysis revealed that seven polymorphisms of APOA5, APOC3, APOA1, ACAT2, and LPL were significantly associated with hypertriglyceridemia, six polymorphisms of APOA5, LIPC, and CYP3A4 with low HDL-cholesterol, and three polymorphisms of APOE and CCR2 with high LDL-cholesterol in subject panel A. For validation of these associations, the same polymorphisms were examined in subject panel B. Six polymorphisms of APOA5, APOC3, APOA1, and LPL were again significantly associated with hypertriglyceridemia, three polymorphisms of APOA5 with low HDL-cholesterol, and two polymorphisms of APOE with high LDL-cholesterol. Serum triglyceride, HDL-cholesterol, and LDL-cholesterol concentrations differed significantly among genotypes of these corresponding polymorphisms in both subject panels. These results indicate that polymorphisms of APOA5, APOC3, APOA1, and LPL are determinants of hypertriglyceridemia and that those of APOA5 and APOE are determinants of low HDL-cholesterol and high LDL-cholesterol, respectively, in Japanese individuals.     

Apolipoprotein C3 Polymorphisms,Cognitive Function and Diabetes in Caribbean Origin Hispanics

Background

Apolipoprotein C3 (APOC3) modulates triglyceride metabolism through inhibition of lipoprotein lipase, but is itself regulated by insulin, so that APOC3 represents a potential mechanism by which glucose metabolism may affect lipid metabolism. Unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. Associations between apolipoprotein C3 (APOC3) gene polymorphisms and impaired lipid and glucose metabolism are well-established, but potential connections between APOC3 polymorphisms, cognitive decline and diabetes deserve further attention.

Methods

We examined whether APOC3 single nucleotide polymorphisms (SNPs) m482 (rs2854117) and 3u386 (rs5128) were related to cognitive measures, whether the associations between cognitive differences and genotype were related to metabolic differences, and how diabetes status affected these associations. Study subjects were Hispanics of Caribbean origin (n = 991, aged 45–74) living in the Boston metropolitan area.

Results

Cognitive and metabolic measures differed substantially by type II diabetes status. In multivariate regression models, APOC3 m482 AA subjects with diabetes exhibited lower executive function (P = 0.009), Stroop color naming score (P = 0.014) and Stroop color-word score (P = 0.022) compared to AG/GG subjects. APOC3 m482 AA subjects with diabetes exhibited significantly higher glucose (P = 0.032) and total cholesterol (P = 0.028) compared to AG/GG subjects. APOC3 3u386 GC/GG subjects with diabetes exhibited significantly higher triglyceride (P = 0.004), total cholesterol (P = 0.003) and glucose (P = 0.016) compared to CC subjects.

Conclusions

In summary, we identified significant associations between APOC3 polymorphisms, impaired cognition and metabolic dysregulation in Caribbean Hispanics with diabetes. Further research investigating these relationships in other populations is warranted.     

Decreased Galectin-9 and Increased Tim-3 Expression Are Related to Poor Prognosis in Gastric Cancer

Introduction

Galectin-9 (Gal-9) induces adhesion and aggregation of certain cell types and inhibits the metastasis of tumor cells. T-cell immunoglobulin–and mucin domain-3–containing molecule 3 (TIM-3) plays a pivotal role in immune regulation. The aim of this study is to investigate Gal-9 and TIM-3 alterations in gastric cancer and their prognostic values.

Methods

Gal-9 and Tim-3 expression was evaluated using a tissue microarray immunohistochemistry method in 305 gastric cancers, of which 84 had paired adjacent normal samples. Cell lines SGC-7901, BGC-823, MGC-803, MKN45 and GES-1 were also stained. Correlations were analyzed between expression levels of Gal-9 and Tim-3 protein and tumor parameters or clinical outcomes.

Results

Gal-9 and Tim-3 stained positive on tumor cells in 86.2% (263/305), and 60.0% (183/305) patients with gastric cancer, respectively. Gal-9 expression was significantly higher in cancer than in normal mucosa (P<0.001). Reduced Gal-9 expression was associated with lymph-vascular invasion, lymph node metastasis, distant metastasis and worse TNM staging (P = 0.034, P = 0.009, P = 0.002 and P = 0.043, respectively). In contrast, Tim-3 expression was significantly lower in cancer than in control mucosa (P<0.001). Patients with lymph-vascular invasion had higher expression levels of Tim-3 (P<0.001). Moreover, multivariate analysis shows that both high Gal-9 expression and low Tim-3 expression were significantly associated with long overall survival (P = 0.002, P = 0.010, respectively); the combination of Gal-9 and Tim-3 expression was an independent prognostic predictor for patients with gastric cancer (RR: 0.43; 95%CI: 0.20–0.93). H.pylori infection status was not associated with Gal-9 and Tim-3 expression (P = 0.102, P = 0.565).

Conclusion

The results suggest that expression of Gal-9 and Tim-3 in tumor cells may be a potential, independent prognostic factor for patients with gastric cancer. Gal-9 and TIM-3 may play an important part in the gastric carcinogenesis.     

Identification of Restricted Subsets of Mature microRNA Abnormally Expressed in Inactive Colonic Mucosa of Patients with Inflammatory Bowel Disease

Background

Ulcerative Colitis (UC) and Crohn''s Disease (CD) are two chronic Inflammatory Bowel Diseases (IBD) affecting the intestinal mucosa. Current understanding of IBD pathogenesis points out the interplay of genetic events and environmental cues in the dysregulated immune response. We hypothesized that dysregulated microRNA (miRNA) expression may contribute to IBD pathogenesis. miRNAs are small, non-coding RNAs which prevent protein synthesis through translational suppression or mRNAs degradation, and regulate several physiological processes.

Methodology/Findings

Expression of mature miRNAs was studied by Q-PCR in inactive colonic mucosa of patients with UC (8), CD (8) and expressed relative to that observed in healthy controls (10). Only miRNAs with highly altered expression (>5 or <0.2 -fold relative to control) were considered when Q-PCR data were analyzed. Two subsets of 14 (UC) and 23 (CD) miRNAs with highly altered expression (5.2->100 -fold and 0.05–0.19 -fold for over- and under- expression, respectively; 0.001<p≤0.05) were identified in quiescent colonic mucosa, 8 being commonly dysregulated in non-inflamed UC and CD (mir-26a,-29a,-29b,-30c,-126*,-127-3p,-196a,-324-3p). Several miRNA genes with dysregulated expression co-localize with acknowledged IBD-susceptibility loci while others, (eg. clustered on 14q32.31), map on chromosomal regions not previously recognized as IBD-susceptibility loci. In addition, in silico clustering analysis identified 5 miRNAs (mir-26a,-29b,-126*,-127-3p,-324-3p) that share coordinated dysregulation of expression both in quiescent and in inflamed colonic mucosa of IBD patients. Six miRNAs displayed significantly distinct alteration of expression in non-inflamed colonic biopsies of UC and CD patients (mir-196b,-199a-3p,-199b-5p,-320a,-150,-223).

Conclusions/Significance

Our study supports miRNAs as crucial players in the onset and/or relapse of inflammation from quiescent mucosal tissues in IBD patients. It allows speculating a role for miRNAs as contributors to IBD susceptibility and suggests that some of the miRNA with altered expression in the quiescent mucosa of IBD patients may define miRNA signatures for UC and CD and help develop new diagnostic biomarkers.     

TLR9 Promoter Polymorphism Is Associated with Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

Objective

Genetic polymorphisms of Toll-like receptors (TLRs) may influence the effects of H. pylori infection and play important roles in gastric carcinogenesis. The aim of this study was to determine whether the polymorphisms of TLR4 and TLR9 are associated with susceptibility to gastric carcinoma and its prognosis.

Methods

This study consisted of 314 patients with gastric cancer and 314 healthy controls. The polymorphisms were assessed using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis. Survival was analyzed by Kaplan–Meier survival curves.

Results

No variant genotypes of TLR4+896A/G, TLR4+1196C/T, or TLR9 -1237T/C were detected. For TLR9 -1486 T/C, multiple logistic regression analyses revealed that compared with the TT homozygote, patients with both the TC variant (adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.04–2.10) and the CC variant (adjusted OR = 1.63, 95% CI = 1.01–2.64) had higher risks of gastric cancer. Further stratification analyses revealed that an increased risk of gastric cancer associated with C carriers was evident among females (adjusted OR = 1.84, 95%CI = 1.02–3.33), in younger subjects aged less than 60 years old (adjusted OR = 1.86, 95%CI = 1.15–3.00), and subjects with H. pylori infection (adjusted OR = 1.53, 95% CI = 1.03–2.27). We also observed a significant association between C carriers and noncardia gastric cancer (adjusted OR = 1.51, 95% CI = 1.03–2.20). In addition, we demonstrated that the C carrier genotype and H. pylori infection may have a synergistic effect and conferred an OR of 2.44 for developing gastric cancer. TLR9 -1486C was also identified as an independent marker of poor survival of carcinoma.

Conclusions

Our results suggest that TLR9 -1486C carriers are associated with an increased risk and poor prognosis of gastric carcinoma in the Chinese population.     

Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia

During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del, p.Leu253Pro, and p.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia.     

A 346 Case Analysis for Laparoscopic Spleen-Preserving No.10 Lymph Node Dissection for Proximal Gastric Cancer: A Single Center Study

Purpose

This study was designed to formulate a model that efficiently predicts splenic hilar lymph node metastasis (SHLNM) in patients with proximal gastric cancer and to assess indications for laparoscopic spleen-preserving no.10 lymph node dissection (LSPNo.10LND) based on this model.

Methods

Patients (N = 346) with proximal gastric cancer who underwent LSPNo.10LND from January 2010 to October 2013 were prospectively enrolled and retrospectively evaluated. Groups of patients with and without SHLNM were compared, and independent risk factors for SHLNM determined. An optimal predictive model of SHLNM in patients with proximal gastric cancer was well established.

Results

Of the 346 patients with proximal gastric cancer, only 35 (10.1%) were diagnosed with SHLNM. Depth of invasion, tumor location and metastases to No.7 and No.11 lymph nodes (LNs) were independent risk factors for SHLNM (p<0.0001 each). A model involving depth of invasion, tumor location and metastasis to No.7 and 11 LNs yielded a lowest Akaike’s information criterion (AIC) of −913.535 and a highest area under the ROC curve (AUC) of 0.897(95%CI:0.851–0.944). Stratification analysis showed no SHLNMs in the absence of serosal invasion of the lesser curvature and metastases at No.7 and No.11 LNs (T2-3∶0/87, 95% CI: 0.00–4.15).

Conclusions

A model including depth of invasion, tumor location and metastases at No.7 and No.11 LNs was found optimal for predicting SHLNM for proximal gastric cancers. LSPNo.10LND may be avoided when tumors on the lesser curvature did not show serosal invasion or metastases at No.7 and No.11 LNs.     

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fluxes through the RCT pathway in patients with low plasma high density lipoprotein cholesterol (HDL-c) due to mutations in APOA1. Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 ± 19 mg/dl) and seven unaffected controls (mean HDL-c: 54 ± 11 mg/dl, P < 0.0001) received a 20 h infusion of ¹³C₂-cholesterol (¹³C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a three-compartment SAAM-II model, tissue cholesterol efflux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 ± 0.8 mg/kg/h versus 5.7 ± 0.7 mg/kg/h in controls, P = 0.02). Fecal ¹³C recovery and sterol excretion 7 days postinfusion did not differ significantly between carriers and controls: 21.3 ± 20% versus 13.3 ± 6.3% (P = 0.33), and 2,015 ± 1,431 mg/day versus 1456 ± 404 mg/day (P = 0.43), respectively. TCE is reduced in carriers of mutations in APOA1, suggesting that HDL contributes to efflux of tissue cholesterol in humans. The residual TCE and unaffected fecal sterol excretion in our severely affected carriers suggest, however, that non-HDL pathways contribute to RCT significantly.     

Genetic Associations with Diabetes: Meta-Analyses of 10 Candidate Polymorphisms

Aims

The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility.

Methods

Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes.

Results

A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01), IL2RA rs11594656 (OR = 0.86, 95% CI = 0.82–0.91, P<0.00001), and CLEC16A rs725613 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01). APOA5 −1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, OR = 1.27, 95% CI = 1.03–1.57, P = 0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C.

Conclusion

Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 −1131T/C are risky factors of T1D and T2D, respectively.