A genetic association study of single nucleotide polymorphisms in FGFR1OP2/wit3.0 and long-term atrophy of edentulous mandible

Background

After dental extraction, the external surface of alveolar bone undergoes resorption at various rates, and a group of patients develop excessive jawbone atrophy. Oral mucosa overlying the atrophied jawbone is unusually thin; therefore, we have hypothesized that excessive jawbone atrophy may be associated with abnormal oral mucosa contraction. FGFR1OP2/wit3.0, a cytoskeleton molecule initially identified in oral wound fibroblasts, has been shown to induce oral mucosa contraction after dental extraction. This study examined the genetic association between single nucleotide polymorphisms (SNPs) of FGFR1OP2/wit3.0 and excessive atrophy of edentulous mandible.

Methods and Findings

First, the expression of FGFR1OP2/wit3.0 was determined in gingival tissues of 8 subjects before and after dental extraction. In situ hybridization revealed that all subject increased FGFR1OP2/wit3.0 expression in the post-operative oral mucosa tissues; however, significantly high levels of FGFR1OP2/wit3.0 were observed in 3 out of 8 subjects. In a separate study, 20 long-term edentulous subjects (66.4±9.4 years) were recruited. Tag-SNPs in the FGFR1OP2/wit3.0 allele were determined by Taqman-based polymerase chain reaction. The mandibular bone height was determined following the American College of Prosthodontists (ACP) protocol. Subjects with minor allele of rs840869 or rs859024 were found in the highly atrophied group by the ACP classification (Chi square test, p = 0.0384 and p = 0.0565, respectively; Fisher''s Exact, p = 0.0515 and p = 0.2604, respectively). The linear regression analysis indicated a suggestive association between rs859024 and the decreased bone heights (Mann-Whitney, p = 0.06). The average bone height of the subjects with rs840869 or rs859024 minor alleles (10.6±3.2 mm and 9.6±3.2 mm, respectively) was significantly smaller than that of those subjects with the major alleles (14.2±4.5 mm, p<0.05).

Conclusions

The patients with the minor allele of rs840869 or rs859024 were associated with excessive atrophy of edentulous mandible. This study may provide the basis for a genetic marker identifying susceptible individuals to develop jawbone atrophy after dental extraction.     

Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies

Hypothesis

Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans.

Methods

Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals.

Results

Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC_C-Peptide/AUC_Glc ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMI×rs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI≤25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC_Ins/AUC_Glc (TT: 226±7, XG: 246±9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71–1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers.

Conclusions

The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.     

Several polymorphisms of KCNQ1 gene are associated with plasma lipid levels in general Chinese populations

Background

Potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) is thought to be an important candidate gene of diabetes. Several single nucleotide polymorphisms (SNPs) in a 40-kb linkage disequilibrium (LD) block in its intron 15 have been identified to be associated with diabetes in East Asian populations in recent genome-wide association studies. The aim of this study was to investigate whether KCNQ1 polymorphisms influence the levels of the metabolic phenotypes in general Chinese populations.

Methodology/Principal Findings

We investigated the associations of two SNPs (rs2237892 and rs2237895) in the aforementioned 40-kb LD block, a missense variant rs12720449 (P448R) in exon 10, and a synonymous variant rs1057128 (S546S) in exon 13 with metabolic phenotypes in a Uyghur population (n = 478) and replicated these associations in a Han population (n = 2,485). We found that rs2237892-T allele was significantly associated with decreased triglyceride levels (p_combined = 0.001). The minor G allele of the rs12720449, with sharp difference of the allelic frequency between European and East Asian populations (0.2% versus 14%, respectively), was associated with a lower triglyceride levels than G allele in Uyghur subjects (p = 0.004), in Han subjects (p = 0.052), and in subjects of meta-analysis (p_combined = 0.001). Moreover, the minor A allele of the rs1057128 was also associated with decreased triglyceride levels in meta-analysis (p_combined = 0.010).

Conclusions

To the best of our knowledge, this is the first report associating a missense mutation of KCNQ1, rs12720449, with triglyceride levels. Rs2237892, representing the 40-kb LD block, is also associated with triglyceride levels in Han population. Further studies are required to replicate these findings in other East Asian populations.     

The TT Genotype of the STAT4 rs7574865 Polymorphism Is Associated with High Disease Activity and Disability in Patients with Early Arthritis

Background

The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis.

Methodology and Results

We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5′ allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01–0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = −0.27 [−0.56– −0.01], p = 0.042; TT genotype = −0.68 [−1.64– −0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype.

Conclusions

Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.     

Impact of genetic variation in SORCS1 on memory retention

Objective

We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory.

Methods

We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses.

Results

Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = −0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002ConclusionsVariation in intron 1 in SORCS1 is associated with memory changes in AD.     

Associations of type 2 diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese

Background

Previous studies have identified that variants in peroxisome proliferator-activated receptor PPAR-δ (PPARD), a target gene of vitamin D, were significantly associated with fasting glucose and insulin sensitivity in European populations. This current study sought to determine (1) whether the genetic associations of PPARD variants with type 2 diabetes and its related traits could be replicated in Chinese Han population, and (2) whether the associations would be modified by the effect of vitamin D status.

Methods and Findings

We genotyped 9 tag single nucleotide polymorphisms (SNPs) that cover the gene of PPARD (rs2267664, rs6902123, rs3798343, rs2267665, rs2267668, rs2016520, rs2299869, rs1053049, and rs9658056) and tested their associations with type 2 diabetes risk and its related traits, including fasting glucose, insulin and HbA1c in 3,210 Chinese Hans. Among the 9 PPARD tag SNPs, rs6902123 was significantly associated with risk of type 2 diabetes (odds ratio 1.75 [95%CI 1.22–2.53]; P = 0.0025) and combined type 2 diabetes and impaired fasting glucose (IFG) (odds ratio 1.47 [95%CI 1.12–1.92]; P = 0.0054). The minor C allele of rs6902123 was associated with increased levels of fasting glucose (P = 0.0316) and HbA1c (P = 0.0180). In addition, we observed that vitamin D modified the effect of rs6902123 on HbA1c (P for interaction = 0.0347).

Conclusions/Significance

Our findings demonstrate that common variants in PPARD contribute to the risk of type 2 diabetes in Chinese Hans, and provided suggestive evidence of interaction between 25(OH)D levels and PPARD-rs6902123 on HbA1c.     

P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1

Context

Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.

Objectives

To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.

Design

Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.

Participants

Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).

Results

P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10⁻⁹). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45–0.49, p = 0.003–0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.

Conclusions

Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.     

Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study

Background

Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD.

Methodology/Principal Findings

We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11–1.45, P = 3.4×10⁻⁴) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11–1.48, P = 7.9×10⁻⁴). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01–1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P<0.05).

Conclusions/Significance

Two novel genetic variants, one in the cardiac sodium channel gene SCN5A and another at 4q25 previously associated with atrial fibrillation, are associated with SCD.     

The NOD2 single nucleotide polymorphisms rs2066843 and rs2076756 are novel and common Crohn's disease susceptibility gene variants

Background

The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences.

Methodology/Principal Findings

Genomic DNA from 2700 Caucasians including 812 patients with Crohn''s disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10⁻⁵, OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10⁻⁶; OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values <10⁻¹⁰. The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D''>0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10⁻¹⁶) and behaviour (p = 0.02) were significantly associated with the need for surgery.

Conclusion/Significance

The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.     

A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers

Background and Aims

Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.

Methods

Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).

Results

The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).

Conclusions

A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.     

Variation in the FFAR1 gene modifies BMI, body composition and beta-cell function in overweight subjects: an exploratory analysis

Background

FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids.

Methodology/Principal Findings

For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m² higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI-increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six.

Conclusions/Significance

Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function.     

Potentially functional variants of PLCE1 identified by GWASs contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population

Background

Recent genome-wide association studies (GWAS) have found a single nucleotide polymorphism (SNP, rs2274223 A>G) in PLCE1 to be associated with risk of gastric adenocarcinoma. In the present study, we validated this finding and also explored the risk associated with another unreported potentially functional SNP (rs11187870 G>C) of PLCE1 in a hospital-based case-control study of 1059 patients with pathologically confirmed gastric adenocarcinoma and 1240 frequency-matched healthy controls.

Methodology/Principal Findings

We determined genotypes of these two SNPs by the Taqman assay and used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that a significant higher gastric adenocarcinoma risk was associated with rs2274223 variant G allele (adjusted OR = 1.35, 95% CI = 1.14–1.60 for AG+GG vs. AA) and rs11187870 variant C allele (adjusted OR = 1.26, 95% CI = 1.05–1.50 for CG+CC vs. GG). We also found that the number of combined risk alleles (i.e., rs2274223G and rs11187870C) was associated with risk of gastric adenocarcinoma in an allele-dose effect manner (P _trend = 0.0002). Stratification analysis indicated that the combined effect of rs2274223G and rs11187870C variant alleles was more evident in subgroups of males, non-smokers, non-drinkers and patients with gastric cardia adenocarcinoma. Further real-time PCR results showed that expression levels of PLCE1 mRNA were significantly lower in tumors than in adjacent noncancerous tissues (0.019±0.002 vs. 0.008±0.001, P<0.05).

Conclusions/Significances

Our results further confirmed that genetic variations in PLCE1 may contribute to gastric adenocarcinoma risk in an eastern Chinese population.     

Effect of genetic variation in STXBP5 and STX2 on von Willebrand factor and bleeding phenotype in type 1 von Willebrand disease patients

Background

In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients.

Methods

In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score.

Results

In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = −0.04 IU/mL per allele, [95%CI −0.07;−0.001], p = 0.04) and VWF:CB activity (β = −0.12 IU/mL per allele, [95%CI −0.17;−0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = −0.03 IU/mL per allele [95% CI −0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02).

Conclusions

Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.     

The SNP rs3128965 of HLA-DPB1 as a Genetic Marker of the AERD Phenotype

Background

Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.

Methods

A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.

Results

The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively).

Conclusions

This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.     

Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome

Background

Corticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients.

Methods

A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402) were genotyped. Subjects'' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale.

Results

The TT genotype of rs7209436 (P = 0.01) and rs242924 (P = 0.02) was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms) and the T allele of rs7209436 (P = 0.008), T allele of rs242924 (P = 0.019), A allele of rs110402 (P = 0.047), and TAT haplocopies (P = 0.048). Negative emotion was not associated with the examined CRH-R1 SNPs.

Conclusion

These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.     

Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study

Background

CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer.

Methods

In the discovery phase, a total of 580 SNPs within +/−5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results.

Results

24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19–2.06], OR = 0.61, [95% CI: 0.43–0.87], OR = 0.59, [95% CI: 0.54–0.76], respectively).

Conclusions

Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis.     

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children

Background

The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

Methods and Findings

All studies identified to have data on the FTO rs9939609 variant (or any proxy [r ²>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p _interaction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.

Conclusions

The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors'' Summary