Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort

Background

FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population.

Methodology

2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination.

Principal Findings

The FLG null variants were associated with AD (OR = 2.01, CI: 1.20–3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12–2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24–3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07–3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07–4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58–2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6).

Conclusions/Significance

In a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment.     

Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10⁻⁸) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P _combined = 2.3×10⁻¹⁰, odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10⁻¹⁰, OR = 1.52, and DPB1*0901: P = 2.0×10⁻⁷, OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.     

Evidence for more than one Parkinson's disease-associated variant within the HLA region

Parkinson''s disease (PD) was recently found to be associated with HLA in a genome-wide association study (GWAS). Follow-up GWAS''s replicated the PD-HLA association but their top hits differ. Do the different hits tag the same locus or is there more than one PD-associated variant within HLA? We show that the top GWAS hits are not correlated with each other (0.00≤r²≤0.15). Using our GWAS (2000 cases, 1986 controls) we conducted step-wise conditional analysis on 107 SNPs with P<10⁻³ for PD-association; 103 dropped-out, four remained significant. Each SNP, when conditioned on the other three, yielded P_SNP1 = 5×10⁻⁴, P_SNP2 = 5×10⁻⁴, P_SNP3 = 4×10⁻³ and P_SNP4 = 0.025. The four SNPs were not correlated (0.01≤r²≤0.20). Haplotype analysis (excluding rare SNP2) revealed increasing PD risk with increasing risk alleles from OR = 1.27, P = 5×10⁻³ for one risk allele to OR = 1.65, P = 4×10⁻⁸ for three. Using additional 843 cases and 856 controls we replicated the independent effects of SNP1 (P_{conditioned-on-SNP4} = 0.04) and SNP4 (P_{conditioned-on-SNP1} = 0.04); SNP2 and SNP3 could not be replicated. In pooled GWAS and replication, SNP1 had OR_{conditioned-on-SNP4} = 1.23, P_{conditioned-on-SNP4} = 6×10⁻⁷; SNP4 had OR_{conditioned-on-SNP1} = 1.18, P_{conditioned-on-SNP1} = 3×10⁻³; and the haplotype with both risk alleles had OR = 1.48, P = 2×10⁻¹². Genotypic OR increased with the number of risk alleles an individual possessed up to OR = 1.94, P = 2×10⁻¹¹ for individuals who were homozygous for the risk allele at both SNP1 and SNP4. SNP1 is a variant in HLA-DRA and is associated with HLA-DRA, DRB5 and DQA2 gene expression. SNP4 is correlated (r² = 0.95) with variants that are associated with HLA-DQA2 expression, and with the top HLA SNP from the IPDGC GWAS (r² = 0.60). Our findings suggest more than one PD-HLA association; either different alleles of the same gene, or separate loci.     

Association analysis of single nucleotide polymorphisms at five loci: comparison between atopic dermatitis and asthma in the Chinese Han population

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10⁻⁴, OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P _correction = 3.60×10⁻¹⁰, OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P _correction = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.     

GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹⁹) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻⁸), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻⁴; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.     

Determinants of Allergic Rhinitis in Young Children with Asthma

Background

In the preschool period, allergic rhinitis (AR) is infrequent and thus under-diagnosed. However, recent works have highlighted the occurrence of AR in toddlers although the causes of AR in this young population remain unknown. The objective of this study was to identify determinants of AR in young children with asthma.

Methods

We carried out a case-control study of 227 children with active asthma and enrolled in the Trousseau Asthma Program. AR and other allergic diseases (asthma, food allergy and eczema) were diagnosed by medical doctors using standardized questionnaires. Parental history of AR and asthma, biological markers of atopy (total IgE, blood eosinophilia, allergic sensitization towards food and aeroallergens) and environmental parameters were also collected.

Results

Forty one of the children (18.1%) had AR. By univariate logistic regression analysis, AR was mainly associated with peanut sensitization (OR = 6.75; p = 0.002); food allergy (OR = 4.31; p = 0.026); mold exposure (OR = 3.81 p<0.01) and parental history of AR (OR = 1.42; p = 0.046). Due to the strong link between food allergy and peanut sensitization three models of multivariate logistic regression were performed and confirmed that AR is associated with peanut sensitization but also food allergy and mold exposure. A random forest analysis was also performed to explain AR. The results reinforced the logistic analysis that peanut sensitization and mold exposure were the principal determinants of AR.

Conclusions & Clinical Relevance

These results stress the importance of investigating AR in young children with asthma to potentially diagnose a particularly severe allergic asthmatic phenotype. Moreover, these data evoke the hypothesis that peanut could be an aeroallergen.     

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci

Crohn''s disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.     

A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10⁻¹², odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10⁻¹⁴, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10⁻⁹, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) (P = 6.54×10⁻⁸), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis.     

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10⁻¹², OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10⁻⁶, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10⁻⁷, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10⁻⁶¹, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10⁻⁷⁶, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10⁻²¹, OR = 0.55) and ATA (P = 1.14×10⁻⁸, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.     

Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI≥30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10⁻⁹, OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10⁻⁸, OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10⁻¹⁴. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10⁻¹⁶. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.     

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10⁻¹⁵) and controls (OR = 0.53, p = 2×10⁻⁵). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10⁻⁵). The German dataset confirmed these findings (OR = 0.54, p = 1×10⁻⁴ and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.     

Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson''s disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP''s main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P_2df = 10⁻⁶, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10⁻⁷) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: OR_Replication = 0.59, P_Replication = 10⁻³; OR_Pooled = 0.51, P_Pooled = 7×10⁻⁸. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10⁻³), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10⁻¹³). Imputation revealed a block of SNPs that achieved P_2df<5×10⁻⁸ in GWAIS, and OR = 0.41, P = 3×10⁻⁸ in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.     

ABCC5, a Gene That Influences the Anterior Chamber Depth,Is Associated with Primary Angle Closure Glaucoma

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10⁻⁹). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10⁻⁹; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.     

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.     

Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men

Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR)  = 1.30, p = 7.98×10⁻⁴), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10⁻⁶). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs—rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)—showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development.     

Hsa-miR-196a2 Rs11614913 polymorphism contributes to cancer susceptibility: evidence from 15 case-control studies

Background

MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results.

Methodology/Principal Findings

We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR = 1.18, 95% CI = 1.03–1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR = 1.11, 95%CI = 1.01–1.23, P _{heterogeneity} = 0.210) and lung cancer risk (OR = 1.25, 95%CI = 1.06–1.46, P _{heterogeneity} = 0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR = 1.24, 95% CI = 1.07–1.43, P _{heterogeneity} = 0.006).

Conclusions

These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers.     

Association between CD209 -336A/G and -871A/G Polymorphisms and Susceptibility of Tuberculosis: A Meta-Analysis

Background

The association between CD209 promoter polymorphisms (-336A/G, -871A/G) and tuberculosis (TB) risk has been widely reported, but results of previous studies remain controversial and ambiguous. To assess the association between CD209 polymorphisms and TB risk, a meta-analysis was performed.

Methods

Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, we identified outcome data from all articles estimating the association between CD209 polymorphisms and TB risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.

Results

A total of 14 studies with 3,610 cases and 3,539 controls were identified. There was no significant association between CD209 -336A/G polymorphism and TB risk (OR = 1.04, 95% CI = 0.91–1.19 for G vs. A; OR = 1.13, 95% CI = 0.84–1.53 for GG vs. AA; OR = 1.04, 95% CI = 0.87–1.24 for GG+AG vs. AA; OR = 1.11, 95% CI = 0.88–1.39 for GG vs. AG+AA). However, the significant association was revealed for Asians in GG vs. AA (OR = 2.48, 95% CI = 1.46–4.22, P = 0.0008) and GG vs. AG+AA (OR = 2.10, 95% CI = 1.33–3.32, P = 0.001). For the CD209 -871A/G polymorphism, lack of an association was also found (OR = 0.81, 95% CI = 0.70–0.95 for G vs. A; OR = 1.00, 95% CI = 0.52–1.93 for GG vs. AA; OR = 0.73, 95% CI = 0.60–0.89 for GG+AG vs. AA; OR = 1.09, 95% CI = 0.57–2.10 for GG vs. AG+AA).

Conclusion

The present meta-analysis suggested that CD209 promoter polymorphisms (-336A/G, -871A/G) were unlikely to substantially contribute to TB susceptibility. However, the GG genotype of CD209 -336A/G polymorphism might be a genetic risk factor that increases TB susceptibility for Asians in GG vs. AA and GG vs. AG+AA.