Early gene expression changes with rush immunotherapy

Background

Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.

Objective

To test for associations between variants in TSLP, TSLP -related genes, and AR in children with asthma.

Methods

We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.

Results

Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10^-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.

Conclusions

TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.     

Genome-wide association study in Han Chinese identifies three novel loci for human height

Human height is a complex genetic trait with high heritability but discovery efforts in Asian populations are limited. We carried out a meta-analysis of genome-wide association studies (GWAS) for height in 6,534 subjects with in silico replication of 1,881 subjects in Han Chinese. We identified three novel loci reaching the genome-wide significance threshold (P < 5 × 10^?8), which mapped in or near ZNF638 (rs12612930, P = 2.02 × 10^?10), MAML2 (rs11021504, P = 7.81 × 10^?9), and C18orf12 (rs11082671, P = 1.87 × 10^?8). We also confirmed two loci previously reported in European populations including CS (rs3816804, P = 2.63 × 10^?9) and CYP19A1 (rs3751599, P = 4.80 × 10^?10). In addition, we provided evidence supporting 35 SNPs identified by previous GWAS (P < 0.05). Our study provides new insights into the genetic determination of biological regulation of human height.     

Association of IL10 Polymorphisms and Leprosy: A Meta-Analysis

Leprosy is a chronic infectious disease that depends on the interplay of several factors. Single nucleotide polymorphisms (SNPs) in host immune related genes have been consistently suggested as participants in susceptibility towards disease. Interleukin-10 (IL-10) is a crucial immunomodulatory cytokine in mycobacterial pathogenesis and especially the -819C>T SNP (rs1800871) has been tested in several case-control studies indicating association with leprosy risk, although a recent consensus estimate is still missing. In this study, we evaluated the association of the -819C>T SNP and leprosy in two new Brazilian family-based populations. Then, we performed meta-analysis for this polymorphism summarizing published studies including these Brazilian family-based groups. Finally, we also retrieved published studies for other distal and proximal IL10 polymorphisms: -3575 T>A (rs1800890), -2849 G>A (rs6703630), -2763 C>A (rs6693899), -1082 G>A (rs1800896) and -592 C>A (rs1800872). Results from meta-analysis supported a significant susceptibility association for the -819T allele, with pooled Odds Ratio of 1.22 (CI = 1.11–1.34) and P-value = 3x10^–5 confirming previous data. This result remained unaltered after inclusion of the Brazilian family-based groups (OR = 1.2, CI = 1.10–1.31, P-value = 2x10^–5). Also, meta-analysis confirmed association of -592 A allele and leprosy outcome (OR = 1.24, CI = 1.03–1.50, P-value = 0.02). In support of this, linkage disequilibrium analysis in 1000 genomes AFR, EUR, ASN and AMR populations pointed to r² = 1.0 between the -592C>A and -819C>T SNPs. We found no evidence of association for the other IL10 polymorphisms analyzed for leprosy outcome. Our results reinforce the role of the -819C>T as a tag SNP (rs1800871) and its association with leprosy susceptibility.     

Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10^-09; rs12008279—OR 1.56, P = 1.53 x 10^-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10^-09; rs6622126—OR 1.75, P = 4.04x10^-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10^-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10^-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.     

Fine Mapping of the Body Fat QTL on Human Chromosome 1q43

IntroductionEvidence for linkage and association of obesity-related quantitative traits to chromosome 1q43 has been reported in the Quebec Family Study (QFS) and in populations of Caribbean Hispanic ancestries yet no specific candidate locus has been replicated to date.MethodsUsing a set of 1,902 single nucleotide polymorphisms (SNPs) genotyped in 525 African American (AA) and 391 European American (EA) women enrolled in the NIEHS uterine fibroid study (NIEHS-UFS), we generated a fine association map for the body mass index (BMI) across a 2.3 megabase-long interval delimited by RGS7 (regulator of G-protein signaling 7) and PLD5 (Phospholipase D, member 5). Multivariable-adjusted linear regression models were fitted to the data to evaluate the association in race-stratified analyses and meta-analysis.ResultsThe strongest associations were observed in a recessive genetic model and peaked in the 3’ end of RGS7 at intronic rs261802 variant in the AA group (p = 1.0 x 10⁻⁴) and in meta-analysis of AA and EA samples (p = 9.0 x 10⁻⁵). In the EA group, moderate associations peaked at rs6429264 (p = 2.0 x 10⁻³) in the 2 Kb upstream sequence of RGS7. In the reference populations for the European ancestry in the 1,000 genomes project, rs6429264 occurs in strong linkage disequilibrium (D’ = 0.94) with rs1341467, the strongest candidate SNP for total body fat in QFS that failed genotyping in the present study. Additionally we report moderate associations at the 3’ end of PLD5 in meta-analysis (3.2 x 10⁻⁴ ≤ p ≤ 5.8 x 10⁻⁴).ConclusionWe report replication data suggesting that RGS7, a gene abundantly expressed in the brain, might be a putative body fat QTL on human chromosome 1q43. Future genetic and functional studies are required to substantiate our observations and to potentially link them to the neurobehavioral phenotypes associated with the RGS7 region.     

Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large,International Pediatric Cohort

Objectives

There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study.

Methods

A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses.

Results

We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10⁻⁴>P>5.8x10⁻⁶). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10⁻⁴). A SNP near PKIA (rs117128341, P = 6.5x10⁻⁸, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10⁻⁷, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10⁻⁶, HR = 0.76 and LPP, P = 2.8x10⁻⁵, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10⁻⁴); non-HLA genes are therefore involved in development of tTGA.

Conclusions

In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.     

Inference of Super-exponential Human Population Growth via Efficient Computation of the Site Frequency Spectrum for Generalized Models

The site frequency spectrum (SFS) and other genetic summary statistics are at the heart of many population genetic studies. Previous studies have shown that human populations have undergone a recent epoch of fast growth in effective population size. These studies assumed that growth is exponential, and the ensuing models leave an excess amount of extremely rare variants. This suggests that human populations might have experienced a recent growth with speed faster than exponential. Recent studies have introduced a generalized growth model where the growth speed can be faster or slower than exponential. However, only simulation approaches were available for obtaining summary statistics under such generalized models. In this study, we provide expressions to accurately and efficiently evaluate the SFS and other summary statistics under generalized models, which we further implement in a publicly available software. Investigating the power to infer deviation of growth from being exponential, we observed that adequate sample sizes facilitate accurate inference; e.g., a sample of 3000 individuals with the amount of data expected from exome sequencing allows observing and accurately estimating growth with speed deviating by ≥10% from that of exponential. Applying our inference framework to data from the NHLBI Exome Sequencing Project, we found that a model with a generalized growth epoch fits the observed SFS significantly better than the equivalent model with exponential growth (P-value = 3.85 × 10^?6). The estimated growth speed significantly deviates from exponential (P-value  ? 10^?12), with the best-fit estimate being of growth speed 12% faster than exponential.     

Association of SNP Rs9943582 in APLNR with Left Ventricle Systolic Dysfunction in Patients with Coronary Artery Disease in a Chinese Han GeneID Population

Heart failure affects 1–2% of the adult population worldwide and coronary artery disease (CAD) is the underlying etiology of heart failure in 70% of the patients. The pathway of apelin and its apelin receptor (APJ) was implicated in the pathogenesis of heart failure in animal models, but a similar role in humans is unknown. We studied a functional variant, rs9943582 (-154G/A), at the 5’-untranslated region, that was associated with decreased expression of the APJ receptor gene (APLNR) in a population consisting of 1,751 CAD cases and 1,022 controls. Variant rs9943582 was not associated with CAD, but among CAD patients, it showed significant association with left ventricular systolic dysfunction (431 CAD patients with left ventricular systolic dysfunction (LV ejection fraction or LVEF< 40%) versus 1,046 CAD patients without LV systolic dysfunction (LVEF>50%) (P-adj = 6.71×10^-5, OR = 1.43, 95% CI, 1.20–1.70). Moreover, rs9943582 also showed significant association with quantitative echocardiographic parameters, including left ventricular end-diastolic diameter (effect size: increased 1.67±0.43 mm per risk allele A, P = 1.15×10^-4), left atrial size (effect size: increased 2.12±0.61 mm per risk allele A, P = 9.56×10^-4) and LVEF (effect size: decreased 2.59±0.32 percent per risk allele A, P = 7.50×10^-15). Our findings demonstrate that allele A of rs9943582 was significantly associated with left ventricular systolic dysfunction, left ventricular end-diastolic diameter, the left atrial diameter and LVEF in the CAD population, which suggests an important role of the apelin/APJ system in the pathology of heart failure associated with ischemic heart disease.     

RXRA introne polymorphism and ABO blood groups in chronic heart failure

Retinoic X receptor alpha (RXRA), a member of nuclear receptor superfamily, plays a key role in development, metabolism, glucose homeostasis, and intestinal cholesterol balance. The aim of this study was to examine an association of RXR alpha introne 5 A(39526)AA polymorphism and ABO blood groups with chronic heart failure (CHF) in the Czech population. A total of 238 patients with chronic heart failure and a control group of 246 subjects were included in the study. The RXR alpha gene polymorphism and ABO blood groups were detected by PCR and RFLP methods. Significant differences in distributions of RXRA A(39526)AA alleles and genotypes between CHF patients and controls were observed (P_g=0.03, P_a=0.02). The RXRA gene polymorphism differences of within blood group A between CHF patients and controls were highly significant in genotype distributions (P_g=0.002) and in allele frequency comparisons (P_a=0.0001). The prevalence of AA allele in CHF patients with A blood group was four-fold lower than in controls with the same blood group (OR=0.24; P_corr=0.0001). A highly significant association of RXRA introne single-nucleotide insertion polymorphism and A blood group in chronic heart failure was observed. Our results suggest close linkage between RXRA A(39526)AA polymorphism and ABO blood groups.     

Total and Differential Leukocyte Counts in Relation to Incidence of Diabetes Mellitus: A Prospective Population-Based Cohort Study

Objective

High concentrations of leukocytes in blood have been associated with diabetes mellitus. This prospective study aimed to explore whether total and differential leukocyte counts are associated with incidence of diabetes. A missense variant R262W in the SH2B3 (SH2B adaptor protein 3) gene, coding for a protein that negatively regulates hematopoietic cell proliferation, was also studied in relation to incidence of diabetes.

Methods and Results

Leukocyte count and its subtypes (neutrophils, lymphocytes and mixed cells) were analyzed in 26,667 men and women, 45–73 years old, from the population-based Malmö Diet and Cancer study. Information about the R262W polymorphism (rs3184504) in SH2B3 was genotyped in 24,489 subjects. Incidence of diabetes was studied during a mean follow-up of 14 years. Cox proportional hazards regression was used to examine incidence of diabetes by total and differential leukocyte counts. Mendelian randomization analysis using R262W as an instrumental variable was performed with two-stage least squares regression. A total of 2,946 subjects developed diabetes during the follow-up period. After taking several possible confounders into account, concentrations of total leukocyte count, neutrophils and lymphocytes were all significantly associated with incidence of diabetes. The adjusted hazard ratios (95% confidence interval; quartile 4 vs quartile 1) were 1.37 (1.22–1.53) for total leukocytes, 1.33 (1.19–1.49) for neutrophils and 1.29 (1.15–1.44) for lymphocytes. The R262W polymorphism was strongly associated with leukocytes (0.11x10⁹ cells/l per T allele, p = 1.14 x10^-12), lymphocytes (p = 4.3 x10^-16), neutrophils (p = 8.0 x10^-6) and mixed cells (p = 3.0 x10^-6). However, there was no significant association between R262W and fasting glucose, HbA_1c or incidence of diabetes.

Conclusions

Concentrations of total leukocytes, neutrophils and lymphocytes are associated with incidence of diabetes. However, the lack of association with the R262W polymorphism suggests that the associations may not be causal, although limitations in statistical power and balancing pleiotropic effects cannot be excluded.     

A GWAS Study on Liver Function Test Using eMERGE Network Participants

Introduction

Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations.

Methods

The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC).

Results

Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10^-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10⁻⁸ spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10^-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10^-117) and rs111741722 (p = 5.41x10^-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10^-15).

Conclusions

Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.     

Analysis of clusterin gene (CLU/APOJ) polymorphism in Alzheimer’s disease patients and in normal cohorts from Russian populations

Mutations in three genes PSEN1, PSEN2, and APP are known to be a cause of familial forms of Alzheimer’s disease (AD). APOE gene polymorphism is a strong risk genetic factor for AD. We have evaluated allele and genotype frequency distribution of rs11136000 polymorphism in the clusterin (CLU) gene (or apolipoprotein J, APOJ) in the samples from three Russian populations and in AD patients. Genome-wide association studies in samples from several European populations have recently revealed the highly significant association of CLU gene with AD (p = 8.5 × 10^?10). We found no differences in allele and genotype frequencies of rs11136000 between the populations from the Moscow, Ural, and Siberia regions. The allele frequencies are close to those in European populations. The genetic association analysis in cohort of AD patients and normal individuals (>500 individuals in each group) revealed no significant association of the rs11136000 polymorphism in CLU gene with Alzheimer’s disease in Russian populations. Although our results showed that the CLU gene polymorphism rs11136000 is likely not a major genetic factor for the common form of Alzheimer’s disease, the data do not rule out the possibility of a modest effect of CLU and interaction between CLU and APOE genotypes in etiology of Alzheimer’s disease.     

Relationship between atorvastatin dose and the harm caused by torcetrapib

Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confined to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were significantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confined to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib.     

Impact of IL28B,APOH and ITPA Polymorphisms on Efficacy and Safety of TVR- or BOC-Based Triple Therapy in Treatment-Experienced HCV-1 Patients with Compensated Cirrhosis from the ANRS CO20-CUPIC Study

Background

Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1.

Patients and Methods

A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model.

Results

None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50–3.70], P = 2x10^-4). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82–8.92], P = 8x10^-4). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10^-5).

Conclusion

Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.     

Quantitative Assessment of the Effect of KCNJ11 Gene Polymorphism on the Risk of Type 2 Diabetes

To clarify the role of potassium inwardly-rectifying-channel, subfamily-J, member 11 (KCNJ11) variation in susceptibility to type 2 diabetes (T2D), we performed a systematic meta-analysis to investigate the association between the KCNJ11 E23K polymorphism (rs5219) and the T2D in different genetic models. Databases including PubMed, Medline, EMBASE, and ISI Web of Science were searched to identify relevant studies. A total of 48 published studies involving 56,349 T2D cases, 81,800 controls, and 483 family trios were included in this meta-analysis. Overall, the E23K polymorphism was significantly associated with increased T2D risk with per-allele odds ratio (OR) of 1.12 (95% CI: 1.09–1.16; P<10⁻⁵). The summary OR for T2D was 1.09 (95% CI: 1.03–1.14; P<10⁻⁵), and 1.26 (95% CI: 1.17–1.35; P<10⁻⁵), for heterozygous and homozygous, respectively. Similar results were also detected under dominant and recessive genetic models. When stratified by ethnicity, significantly increased risks were found for the polymorphism in Caucasians and East Asians. However, no such associations were detected among Indian and other ethnic populations. Significant associations were also observed in the stratified analyses according to different mean BMI of cases and sample size. Although significant between study heterogeneity was identified, meta-regression analysis suggested that the BMI of controls significantly correlated with the magnitude of the genetic effect. The current meta-analysis demonstrated that a modest but statistically significant effect of the 23K allele of rs5219 polymorphism in susceptibility to T2D. But the contribution of its genetic variants to the epidemic of T2D in Indian and other ethnic populations appears to be relatively low.     

Assessment of gene–nutrient interactions on inflammatory status of the elderly with the use of a zinc diet score — ZINCAGE study

Although zinc plays an important role in health status of the elderly, their dietary habits in relation to zinc intake are not well documented. The main objective of the current study was the assessment of dietary zinc intake in European old populations and the investigation of its impact on plasma zinc and inflammatory cytokines concentrations, in relation to genetic markers. Within the ZINCAGE study, 819 healthy old Europeans (≥60 years old) were recruited. Plasma zinc, interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured. Genotype data were obtained for the ?174G/C polymorphism in the IL-6 gene. Dietary data were collected with a food frequency questionnaire and were used to calculate a zinc diet score. Zinc score was validated using additional dietary data (24-h recalls), in a subsample of 105 subjects. Zinc score was different among most of the European centres (P<.001), while an age-dependent decline was documented (P=4.4×10^?12). Plasma zinc concentrations were significantly correlated with the zinc score (standardized β=0.144, P=8.8×10^?5). The minor allele frequency for the ?174G/C polymorphism was f(C) 0.31. There was a significant interaction of zinc diet score and GG (?174G/C) genotype on higher plasma IL-6 levels (β±S.E.=0.014±0.0, P=.008). The main finding of our study was the detection of gene–nutrient and biochemical–nutrient interactions in a multiethnic cohort based on a common dietary assessment tool.     

A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS)

Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (n_max = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10^-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, P_DOM = 1.62x10^-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, P_DOM = 1.00x10^-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10^-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (n_max = 4156) and the strongest signal was rs1471880 (P_DOM = 8.38x10^-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.     

High pyrethroid-resistance intensity in Culex quinquefasciatus (Say) (Diptera: Culicidae) populations from Jigawa,North-West,Nigeria

This study examined pyrethroid resistance intensity and mechanisms in Culex quinquefasciatus (Say) (Diptera: Culicidae) populations from Jigawa, North-West Nigeria. Resistance statuses to permethrin, lambda-cyhalothrin and alphacypermethrin were determined with both WHO and CDC resistance bioassays. Synergist assay was conducted by pre-exposing the populations to Piperonyl butoxide (PBO) using the WHO method. Resistance intensities to 2x, 5x and 10x of diagnostic concentrations were determined with the CDC bottle method. Species analysis and presence of knockdown mutation (Leu-Phe) were done using Polymerase Chain Reaction (PCR). Results showed that Cx. quinquefasciatus was the only Culex spp. present and “Kdr-west” mutation was not detected in all analyzed samples. Using WHO method, Cx. quinquefasciatus resistance to permethrin was detected in Dutse (12.2%) and Kafin-Hausa (77.78%). Lambda-cyhalothrin resistance was recorded only in Kafin-Hausa (83.95%) with resistance suspected in Ringim (90%). Resistance to alphacypermethrin was recorded in all locations. Pre-exposure to PBO led to 100% mortality to alphacypermethrin and lambda-cyhalothrin in Ringim while mortality to permethrin and alphacypermethrin in Dutse increased from 12.2% to 97.5% and 64.37% to 79.52% respectively. Using CDC bottle bioassay, resistance was also recorded in all populations and the result shows a significant positive correlation (R² = 0.728, p = 0.026) with the result from the WHO bioassay. Results of resistance intensity revealed a very high level of resistance in Kafin-Hausa with susceptibility to lambda-cyhalothrin and alphacypermethrin not achieved at 10x of diagnostic doses. Resistance intensity was also high in Dutse with susceptibility to all insecticides not achieved at 5x of diagnostic doses. Widespread and high intensity of resistance in Cx. quinquefasciatus from North-West Nigeria is a major threat to the control of diseases transmitted by Culex and other mosquito species. It is a challenge that needs to be adequately addressed so as to prevent the failure of pyrethroid-based vector control tools.