Association of glucokinase regulatory protein polymorphism with type 2 diabetes and fasting plasma glucose: a meta-analysis

Glucokinase regulatory protein (GCKR) which binds to glucokinase (GCK) in the nucleus and inhibits its activity in the presence of fructose-6-phosphate is critical for glucose metabolism. In the past few years, a number of case–control studies have been carried out to investigate the relationship between the GCKR polymorphism and type 2 diabetes (T2D) since it was first identified to be associated with fasting plasma glucose levels, insulin resistance through genome-wide association approach. After that, a number of studies reported that the rs780094 polymorphism in GCKR has been implicated in T2D risk. However, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 19 studies involving a total of 298,977 subjects for GCKR rs780094 to evaluate its effect on genetic susceptibility for T2D. In a combined analysis, the summary per-allele odds ratio for T2D of the rs780094 polymorphism was 1.11 (95 % CI: 1.07–1.14, P < 10^?5). Significant results were also observed using dominant (OR = 1.18, 95 % CI: 1.05–1.34, P < 10^?5) or recessive genetic model (OR = 1.20, 95 % CI: 1.12–1.28, P < 10^?5). Significant results were found in Asians and Caucasians when stratified by ethnicity. Besides, the polymorphism was found to be significantly associated with increased fasting plasma glucose level. There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. This meta-analysis suggests that the rs780094 polymorphism in GCKR is associated with elevated T2D risk, but these associations vary in different ethnic populations.     

Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis

Pathogenesis and genetic factors influencing predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. To date, many case–control studies have been carried out to investigate the relationship between the NAT2 polymorphisms and ATDH, but the results have been inconsistent. To investigate this inconsistency, a meta-analysis was performed. Databases including PubMed, Web of Science, EMBASE and CNKI were searched to find relevant studies. A total of 26 case–control studies, involving 1,198 cases and 2,921 controls were included. Overall, we found significant association between slow acetylator genotype of NAT2 and ATDH (OR = 3.10, 95 % CI: 2.47–3.88, P < 10^?5). Significant results were also found in East Asians, South Asians, Brazilians and Middle Eastern when stratified by ethnicity. However, no significant associations were found for Caucasians. This meta-analysis demonstrated that the slow acetylator genotype of NAT2 is a risk factor associated with increased ATDH susceptibility, but these associations vary in different ethnic populations.     

Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change

Background

Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.

Methods and Findings

We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16–39 y; 51% women; mean ± standard deviation BMI 24±4 kg/m²). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%–183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87%±3%; R ² = 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160%±2%; R ² = 0.92).

Conclusions

Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors'' Summary     

Association Between Serum Zinc Levels and the Risk of Parkinson’s Disease: a Meta-Analysis

Recent studies have found that the serum zinc levels were associated with the risk of Parkinson’s disease (PD), but the results were inconsistent. Thus, we conducted a meta-analysis to summarize the evidence from observational studies between them. Pertinent studies were identified by a search in PubMed, Embase, and Web of science up to July, 10, 2016. Standardized mean difference (SMD) and 95% confidence intervals (CI) with random-effect model was used to combine the results. Subgroup analysis and meta-regression were also conducted. Publication bias was estimated using Begg’s regression asymmetry test. A total of 11 articles involving 822 PD patients and 777 healthy controls were included in the meta-analysis. Our meta-analysis results revealed that the serum zinc levels in PD patients were significantly lower than those in health controls (SMD = ?0.779, 95%CI = [?1.323, ?0.234], P < 0.001). The association was also significant oriental studies (SMD = ?1.601, 95%CI = [?2.398, ?0.805], P < 0.001). No publication bias was found. The current study indicated that serum zinc levels in PD patients were significantly lower than those in healthy controls.     

Role of RASSF1A promoter methylation in the pathogenesis of hepatocellular carcinoma: a meta-analysis of 21 cohort studies

We carried out the current meta-analysis aiming to comprehensively assess the potential role of RASSF1A aberrant promoter methylation in the pathogenesis of hepatocellular carcinoma (HCC). A range of electronic databases were searched: Web of Science (1945–2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966–2013), EMBASE (1980–2013), CINAHL (1982–2013) and the Chinese Biomedical Database (CBM) (1982–2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude risk difference (RD) with their 95 % confidence interval (95 % CI) was calculated. In the present meta-analysis, 21 clinical cohort studies with a total of 1,205 HCC patients were included. The results of our meta-analysis illustrated that the frequency of RASSF1A promoter methylation in cancer tissues were significantly higher than those of normal, adjacent and benign tissues (cancer tissues vs. normal tissues: RD = 0.63, 95 % CI 0.53–0.73, P < 0.001; cancer tissues vs. adjacent tissues: RD = 0.43, 95 % CI 0.33–0.53, P < 0.001; cancer tissues vs. benign tissues: RD = 0.48, 95 % CI 038–0.58, P < 0.001; respectively). Further subgroup by ethnicity demonstrated that RASSF1A aberrant promoter methylation was correlated with the pathogenesis of HCC among both Asians and Caucasians (all P < 0.05). The current meta-analysis suggests that RASSF1A aberrant promoter methylation may be implicated in the pathogenesis of HCC. Thus, detection of RASSF1A promoter methylation may be a helpful and valuable biomarker for diagnosis and prognosis of HCC.     

A functional polymorphism,rs28493229, in <Emphasis Type="Italic">ITPKC</Emphasis> and risk of Kawasaki disease: an integrated meta-analysis

Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case–control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case–control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34?1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P _{heterogeneity} = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.     

Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR–RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with “Luminal A” breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = ?0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.     

Salivary metabolite signatures of children with and without dental caries lesions

A metabolomic approach was used to analyze endogenous metabolites and to correlate with a specific biological state. The analysis of salivary metabolites is a growing area of investigation with potential for basic and clinical applications. Analyses of children’s saliva in different dentitions and with or without caries could potentially reveal a specific profile related to oral disease risk. Nuclear Magnetic Resonance (NMR) is well suited for mixture analysis followed by Principal Component Analysis combined with Linear Regression (PCA-LR) statistics and was used to identify differences in the salivary metabolites. The classificatory analysis was performed using PCA-LR based on 1,000 cross-validation bootstrap runs from both classifiers in order to increase the data information from a small sample size. The PCA-LR presented a statistically good classificatory performance for children with and without caries with an accuracy of 90.11 % (P < 0.001), 89.61 % sensitivity (P < 0.001), and 90.82 % specificity (P < 0.001). Children with caries lesions presented higher levels of several metabolites, including lactate, fatty acid, acetate and n-butyrate. Saliva from subjects with different dentition stages was also analyzed. Although the salivary samples were poorly classified, permanent dentition presented increased levels of acetate, saccharides and propionate. The NMR data and PCA-LR were able to classify saliva from children with or without caries, with performance indexes comparable to the partial least-squares regression discriminant analysis (PLS-DA) results also performed. Our data also showed similar salivary metabolite profiles for healthy subjects despite the differences in their oral hygiene habits, socioeconomic status and food intake.     

Role of p16 gene promoter methylation in gastric carcinogenesis: a meta-analysis

This meta-analysis was performed to evaluate the relationships between promoter DNA methylation in tumor suppressor gene p16 and gastric carcinogenesis. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated. Forty-seven clinical cohort studies that met all inclusion criteria were included in this meta-analysis. A total of 2,813 gastric cancer (GC) patients were assessed. Our meta-analysis results revealed that the frequencies of p16 promoter methylation in the GC tissues were higher than those of normal and adjacent tissues (Normal: OR = 23.04, 95 % CI = 13.55–39.15, P < 0.001; Adjacent: OR = 4.42, 95 % CI = 1.66–11.76, P = 0.003; respectively). Furthermore, we observed significant associations of p16 promoter methylation with TNM stage, histologic grade, invasive grade, lymph node metastasis of GC (TNM stage: OR = 3.60, 95 % CI: 2.17–5.98, P < 0.001; Histologic grade: OR = 2.63, 95 % CI: 1.55–4.45, P < 0.001; Invasive grade: OR = 3.44, 95 % CI: 1.68–7.06, P = 0.001; Lymph node metastasis: OR = 2.68, 95 % CI: 1.66–4.32, P < 0.001; respectively). However, there were no correlations of p16 promoter methylation with the TNM stage and Helicobacter pylori (HP) infection of GC (Tumor size: OR = 0.76, 95 % CI: 0.14–4.07, P = 0.746; HP infection: OR = 1.31, 95 % CI: 0.75–2.27, P = 0.342; respectively). Our findings provide empirical evidence that p16 promoter methylation may play an important role in gastric carcinogenesis. Thus, p16 promoter methylation may be a promising potential biomarker for the early diagnosis of GC.     

Investigation of genetic risk factors for chronic adult diseases for association with preterm birth

Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case–control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P < 0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10^–219). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.     

Metabolic heritability at birth: implications for chronic disease research

Recent genome-wide association studies of the adult human metabolome have identified genetic variants associated with relative levels of several acylcarnitines, which are important clinical correlates for chronic conditions such as type 2 diabetes and obesity. We have previously shown that these same metabolite levels are highly heritable at birth; however, no studies to our knowledge have examined genetic associations with these metabolites measured at birth. Here, we examine, in 743 newborns, 58 single nucleotide polymorphisms (SNPs) in 11 candidate genes previously associated with differing relative levels of short-chain acylcarnitines in adults. Six SNPs (rs2066938, rs3916, rs3794215, rs555404, rs558314, rs1799958) in the short-chain acyl-CoA dehydrogenase gene (ACADS) were associated with neonatal C4 levels. Most significant was the G allele of rs2066938, which was associated with significantly higher levels of C4 (P = 1.5 × 10^?29). This SNP explains 25 % of the variation in neonatal C4 levels, which is similar to the variation previously reported in adult C4 levels. There were also significant (P < 1 × 10^?4) associations between neonatal levels of C5-OH and SNPs in the solute carrier family 22 genes (SLC22A4 and SLC22A5) and the 3-methylcrotonyl-CoA carboxylase 1 gene (MCCC1). We have replicated, in newborns, SNP associations between metabolic traits and the ACADS and SLC22A4 genes observed in adults. This research has important implications not only for the identification of rare inborn errors of metabolism but also for personalized medicine and early detection of later life risks for chronic conditions.     

Targeted metabolomics profiles are strongly correlated with nutritional patterns in women

Nutrition plays an important role in human metabolism and health. Metabolomics is a promising tool for clinical, genetic and nutritional studies. A key question is to what extent metabolomic profiles reflect nutritional patterns in an epidemiological setting. We assessed the relationship between metabolomic profiles and nutritional intake in women from a large cross-sectional community study. Food frequency questionnaires (FFQs) were applied to 1,003 women from the TwinsUK cohort with targeted metabolomic analyses of serum samples using the Biocrates Absolute-IDQ? Kit p150 (163 metabolites). We analyzed seven nutritional parameters: coffee intake, garlic intake and nutritional scores derived from the FFQs summarizing fruit and vegetable intake, alcohol intake, meat intake, hypo-caloric dieting and a “traditional English” diet. We studied the correlation between metabolite levels and dietary intake patterns in the larger population and identified for each trait between 14 and 20 independent monozygotic twins pairs discordant for nutritional intake and replicated results in this set. Results from both analyses were then meta-analyzed. For the metabolites associated with nutritional patterns, we calculated heritability using structural equation modelling. 42 metabolite nutrient intake associations were statistically significant in the discovery samples (Bonferroni P < 4 × 10^?5) and 11 metabolite nutrient intake associations remained significant after validation. We found the strongest associations for fruit and vegetables intake and a glycerophospholipid (Phosphatidylcholine diacyl C38:6, P = 1.39 × 10^?9) and a sphingolipid (Sphingomyeline C26:1, P = 6.95 × 10^?13). We also found significant associations for coffee (confirming a previous association with C10 reported in an independent study), garlic intake and hypo-caloric dieting. Using the twin study design we find that two thirds the metabolites associated with nutritional patterns have a significant genetic contribution, and the remaining third are solely environmentally determined. Our data confirm the value of metabolomic studies for nutritional epidemiologic research.     

Is high prevalence of vitamin D deficiency a correlate for attention deficit hyperactivity disorder?

The aim of the study was to determine the association between vitamin D and attention deficit hyperactivity disorder (ADHD), and difference in the level of vitamin D in ADHD children and control. This a case–control study carried out in school health and primary health care clinics. A total of 1,331 children and adolescents who were diagnosed with ADHD based on clinical criteria and standardized questionnaires were enrolled in this study and were matched with 1,331 controls, aged 5–18 years old. Data on body mass index (BMI), clinical biochemistry variables including serum 25-hydroxyvitamin D were collected. The study found significant association between ADHD and vitamin D deficiency after adjusting for BMI and sex (adj. OR 1.54; 95 % CI 1.32–1.81; P < 0.001). Majority of the ADHD children were in the age group 5–10 years (40.7 %), followed by 11–13 years (38.4 %). The proportion of BMI <85th percentile was significantly over represented in ADHD group as compared to healthy control (87.8 vs. 83 %; P < 0.001, respectively), while on the other hand, BMI >95th percentile was over represented in the control than ADHD group (7.6 vs. 4.6 %; P < 0.001, respectively). Mean values of vitamin D (ng/mL) were significantly lower in ADHD children (16.6 ± 7.8) than in healthy children (23.5 ± 9.0) (P < 0.001). There was significant correlation between vitamin D deficiency and age (r = ?0.191, P = 0.001); calcium (r = 0.272, P = 0.001); phosphorous (r = 0.284, P = 0.001); magnesium (r = 0.292, P = 0.001); and BMI (r = 0.498, P = 0.001) in ADHD children. The vitamin D deficiency was higher in ADHD children compared to healthy children.     

The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis

Monocyte differentiation antigen CD14 is considered an important cell-activating mediator of inflammatory responses that may result in atherosclerosis, coronary heart disease (CHD), thrombus formation, and myocardial infarction (MI). A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with CHD. To investigate this inconsistency, we performed a meta-analysis of 28 studies involving a total of 13,335 CHD cases and 7,979 controls for C-260T of the CD14 gene to evaluate the effect of CD14 on genetic susceptibility for CHD. An overall random effects odds ratio of 1.24 (95 % CI: 1.12–1.36, P < 10^?5) was found for T allele. Significant results were also observed using dominant (OR = 1.34, 95 % CI: 1.17–1.54, P < 10^?4) or recessive genetic model (OR = 1.25, 95 % CI: 1.10–1.41, P = 0.0004). There was strong evidence of heterogeneity (P < 10^?5), which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant results were found in East Asians; whereas no significant associations were found among Caucasians and other ethnic populations in all genetic models. In the stratified analysis according to sample size, CHD endpoints, and HWE status, significantly increased risks for the polymorphism were found in all genetic models. In conclusion, our results indicate that the CD14 C-260T polymorphism is a risk factor of CHD, especially in East Asians. However, additional very large-scale studies are warranted to confirm our results.     

Obesity-related metabolite profiles of black women spanning the epidemiologic transition

In developed countries, specific metabolites have been associated with obesity and metabolic diseases, e.g. type 2 diabetes. It is unknown whether a similar profile persists across populations of African-origin, at increased risk for obesity and related diseases. In a cross-sectional study of normal-weight and obese black women (33.3 ± 6.3 years) from the US (N = 69, 65 % obese), South Africa (SA, N = 97, 49 % obese) and Ghana (N = 82, 33 % obese) serum metabolite profiles were characterized via gas chromatography-time of flight/mass spectrometry. In US and SA women, BMI correlated with branched-chain and aromatic amino acids, as well as dopamine and aminoadipic acid. The relationship between BMI and lipid metabolites differed by site; BMI correlated positively with palmitoleic acid (16:1) in the US; negatively with stearic acid (18:0) in SA, and positively with arachidonic acid (20:4) in Ghana. BMI was also positively associated with sugar-related metabolites in the US; i.e. uric acid, and mannitol, and with glucosamine, glucoronic acid and mannitol in SA. While we identified a common amino acid metabolite profile associated with obesity in black women from the US and SA, we also found site-specific obesity-related metabolites suggesting that the local environment is a key moderator of obesity.     

Obesity Modulates the Immune Response to Oxidized LDL in Hypertensive Patients

Obesity and hypertension have been recognized as inflammatory diseases capable of activating the immune system, thus contributing to an increased cardiovascular risk. However, the link between adaptive immunity, obesity, and hypertension is poorly understood. We investigated the relationship of the body mass index (BMI) on the inflammatory, vascular, and immune responses in patients with hypertension naïve of anti-hypertensive treatment. Hypertensive patients (N = 88) were divided into three groups: normal weight (NW), overweight (OW), and obese (OB) subjects. Anti-oxidized LDL autoantibodies (anti-oxLDL Abs), anti-ApoB-D peptide (anti-ApoB-D) Abs, interleukin (IL)-8 and IL-10, flow-mediated dilation (FMD) of the brachial artery, and 24-h ambulatory blood pressure monitoring (ABPM) were assessed. OB patients presented lower levels of anti-oxLDL Abs and IL-10, higher levels of IL-8, and impaired FMD, when compared to NW and OW (P < 0.05), without differences between groups regarding anti-ApoB-D Abs. After adjusting for age, systolic and diastolic blood pressure, anti-oxLDL Abs were inversely correlated with BMI and waist circumference (r = ?0.24, P = 0.02 and r = ?0.25, P = 0.02, respectively), whereas ApoB-D correlated with 24-h ABPM (r = 0.22, P = 0.05 for systolic, and r = 0.29, P = 0.01 for diastolic blood pressure). Regression analyses showed inverse associations of anti-oxLDL Abs with BMI (β = ?0.05, P = 0.01) and waist circumference (β = ?0.01, P = 0.02); anti-ApoB-D Abs were associated with systolic and diastolic 24-h ABPM (β = 0.96, P = 0.04; β = 1.02, P = 0.005, for systolic and diastolic 24-h ABPM, respectively). Among hypertensive patients, obesity modulates the immune and inflammatory milieu, determining an unfavorable balance of cytokines and reduction in titers of anti-oxLDL Abs. Twenty-four hour ABPM is associated with titers of anti-ApoB-D Abs.     

Genetic association of lipid metabolism related SNPs with myocardial infarction in the Pakistani population

Myocardial infarction (MI) is the major cardiovascular disease. This can be caused by mutual interaction of environmental and genetic factors. The current study was designed to investigate the role of lipid metabolism related genetic polymorphisms with the onset of MI in Punjabi population of Pakistan. A total of 384 subjects was studied from April 2011 to July 2012. To determine the genetic associations with MI, the single nucleotide polymorphisms (SNPs) were genotyped by sequencing, as well as one label extension method. Out of eight SNPs in four candidate genes, seven genetic variants were significantly (P < 0.05) associated with elevated risk of MI. In current study two SNPs rs662799 risk allele G (P = 0.03) and rs3135506 risk allele C (P = 0.05) of APOA5 were found to be associated with significant higher risk of triglyceride levels, irrespective of age, sex, obesity, diabetes, hypertension and smoking. Gene variants (rs1558861, rs662799 and rs10750097) in APOA5 showed almost complete linkage disequilibrium and their minor allele frequencies (0.34, 0.28, and 0.41 respectively) were more prevalent (P < 0.05) in cases than controls. We further revealed risk haplotypes (C-T-G-A, G-C-A-G; P = 0.001) and protective haplotypes (G-T-A-G, C-C-G-A; P = 0.005) between these four SNPs for the progression of MI. Current study confirms the correlation between lipid metabolism related SNPs with MI and supports the role of APOA5 in raising plasma triglyceride levels in Pakistanis. However further studies are needed for delineating the role of these SNPs.     

Common genetic variants (rs4779584 and rs10318) at 15q13.3 contributes to colorectal adenoma and colorectal cancer susceptibility: evidence based on 22 studies

Several genome-wide association studies on colorectal cancer (CRC) have reported similar findings of a new susceptibility locus, 15q13.3. After that, a number of studies have reported that the rs4779584 and rs10318 polymorphisms at chromosome 15q13.3 have been implicated in CRC and colorectal adenoma (CRA) risk; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 22 studies involving a total of 48,468 CRC cases, 4,189 CRA cases, and 85,105 controls for the two polymorphisms to evaluate its effect on genetic susceptibility for CRC/CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio (OR) of rs4779584-T variant for CRC was 1.13 (95 % CI 1.09–1.16, P < 10^?5) and 1.15 (95 % CI 1.04–1.28, P = 0.006) for CRA. After stratified by ethnicity, significantly increased CRC risks were found for rs4779584 polymorphism among East Asians and Caucasians, while no significant associations were detected among African American and other ethnic populations. A meta-analysis of studies on the rs10318 polymorphism also showed significant overall association with CRC, yielding a per-allele OR of 1.13 (95 % CI 1.02–1.24, P = 0.02). In the subgroup analysis by ethnicity, significantly increased CRC risks were found in Caucasians; whereas no significant associations were found among East Asians and African Americans. This meta-analysis demonstrated that the rs4779584 and rs10318 polymorphism at 15q13.3 is a risk factor associated with increased CRC/CRA susceptibility, but these associations vary in different ethnic populations.     

Genetic polymorphisms in VDR,ESR1 and ESR2 genes may contribute to susceptibility to Parkinson’s disease: a meta-analysis

We conducted this meta-analysis of relevant case–control studies to investigate the relationships between genetic polymorphisms in VDR, ESR1 and ESR2 genes to the susceptibility of Parkinson’s disease (PD). A search on electronic databases without any language restrictions was conducted: MEDLINE (1966–2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980–2013), CINAHL (1982–2013), Web of Science (1945–2013) and the Chinese Biomedical Database (1982–2013). Meta-analysis was performed using the STATA statistical software. Crude odds ratio (OR) with their 95 % confidence interval (95 % CI) was calculated. Fourteen case–control studies with a total of 3,689 PD patients and 4,627 healthy subjects were included in our meta-analysis. The results of our meta-analysis demonstrated that the VDR genetic polymorphisms might be closely related to increased risks of PD (allele model: OR = 1.18, 95 % CI 1.09–1.29, P < 0.001; dominant model: OR = 1.37, 95 % CI 1.16–1.63, P < 0.001; respectively), especially for the polymorphisms rs7976091 and rs10735810. Our findings also illustrated that ESR1 genetic polymorphisms might increase the risk of PD (allele model: OR = 1.56, 95 % CI 1.17–2.07, P = 0.002; recessive model: OR = 1.93, 95 % CI 1.33–2.80, P < 0.001; homozygous model: OR = 1.35, 95 % CI 1.02–1.79, P = 0.038; heterozygous model: OR = 2.04, 95 % CI 1.36–3.07, P = 0.001; respectively), especially for the polymorphisms rs2234693 and rs9340799. Furthermore, we found significant correlations of ESR2 genetic polymorphisms with the risk of PD (allele model: OR = 1.78, 95 % CI 1.19–2.67, P = 0.005; recessive model: OR = 1.93, 95 % CI 1.15–3.27, P = 0.014; homozygous model: OR = 1.77, 95 % CI 1.09–2.89, P = 0.022; heterozygous model: OR = 1.88, 95 % CI 1.08–3.27, P = 0.025; respectively), especially for the rs1256049 polymorphism. Our meta-analysis suggests that genetic polymorphisms in VDR, ESR1 and ESR2 genes may contribute to increased risks for PD.     

Common genetic variants on 3q28 contribute to non-small cell lung cancer susceptibility: evidence from 10 case-control studies

The association between common variations (rs10937405, rs4488809) on 3q28 and lung cancer has been widely evaluated in various ethnic groups, since it was first identified through genome-wide association approach. However, the results have been inconclusive. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis. The random-effects model was applied, addressing heterogeneity and publication bias. A total of 10 articles involving 36,221 cases and 58,108 controls were included. Overall, the summary per-allele OR of 1.19 (95 % CI 1.14–1.25, P < 10^?5) and 1.17 (95 % CI 1.10–1.23, P < 10^?5) was found for the rs10937405 and rs4488809 polymorphisms, respectively. Significant results were also observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. Significant results were found in East Asians when stratified by ethnicity, whereas no significant associations were found among Caucasians. After stratifying by sample size, study design, control source and sex, significant associations were also obtained. In addition, our data indicate that these polymorphisms are involved in lung cancer susceptibility and confer its effect primarily in lung adenocarcinoma when stratified by histological subtype. Furthermore, significant associations were also detected both never-smokers and smokers for these polymorphisms. In conclusion, this meta-analysis demonstrated that rs10937405 and rs4488809 are a risk factor associated with increased non-small cell lung cancer susceptibility, particularly for East Asian populations.