Community-acquired infections and their association with myeloid malignancies

Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown. Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n = 8489), CML (n = 3626) diagnosed 1992–2005; MDS (n = 3072) and MPNs (n = 2001) diagnosed 2001–2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality. Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14–1.26], 1.25 [95% CI: 1.16–1.36]), influenza (ORs 1.16 [95% CI: 1.07–1.25], 1.29 [95% CI: 1.16–1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06–1.21], 1.22 [95% CI: 1.11–1.35]), pneumonia (ORs 1.28 [95% CI: 1.21–1.36], 1.52 [95% CI: 1.40–1.66]), sinusitis (ORs 1.23 [95% CI: 1.16–1.30], 1.25 [95% CI: 1.15–1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07–1.18], 1.26 [95% CI: 1.17–1.36]). Cellulitis (OR 1.51 [95% CI: 1.39–1.64]), herpes zoster (OR 1.31 [95% CI: 1.14–1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17–1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12–1.31]), pneumonia (OR 1.49 [95% CI: 1.37–1.62]), sinusitis (OR 1.19 [95% CI: 1.09–1.29]) and cellulitis (OR 1.43 [95% CI: 1.32–1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21–1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded. Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.     

Associations of Genetic Variants in the PSCA,MUC1 and PLCE1 Genes with Stomach Cancer Susceptibility in a Chinese Population

BackgroundSeveral genetic variants including PSCA rs2294008 C>T and rs2976392 G>A, MUC1 rs4072037 T>C, and PLCE1 rs2274223 A>G have shown significant association with stomach cancer risk in the previous genome-wide association studies (GWASs).MethodsTo evaluate associations of these SNPs in the Han Chinese, an independent hospital based case-control study was performed by genotyping these four polymorphisms in a total of 692 stomach cancer cases and 774 healthy controls acquired by using frequency matching for age and gender. False-positive report probability (FPRP) analysis was also performed to validate all statistically significant findings.ResultsIn the current study, significant association with stomach cancer susceptibility was observed for all the four polymorphisms of interest. Specifically, a significant increased stomach cancer risk was associated with PSCA rs2294008 (CT vs. CC: adjusted OR = 1.37, 95% CI = 1.07–1.74, and CT/TT vs.CC: adjusted OR = 1.30, 95% CI = 1.03–1.63), PSCA rs2976392 (AG vs. GG: adjusted OR = 1.30, 95% CI = 1.02–1.65, and AG/AA vs. GG: adjusted OR = 1.26, 95% CI = 1.00–1.59), or PLCE1 rs2274223 (AG vs. AA: adjusted OR = 1.48, 95% CI = 1.15–1.90, and AG/GG vs. AA: adjusted OR = 1.45, 95% CI = 1.14–1.84), respectively. In contrast, MUC1 rs4072037 was shown to decrease the cancer risk (CT vs. TT: adjusted OR = 0.77, 95% CI = 0.60–0.98). Patients with more than one risk genotypes had significant increased risk to develop stomach cancer (adjusted OR = 1.30, 95% CI = 1.03–1.64), when compared with those having 0–1 risk genotypes. Stratified analysis indicated that the increased risk was more pronounced in younger subjects, men, ever smokers, smokers with pack years ≤ 27, patients with high BMI, or non-cardia stomach cancer.ConclusionsThis study substantiated the associations between four previous reported genetic variants and stomach cancer susceptibility in an independent Han Chinese population. Further studies with larger sample size and different ethnicities are warranted to validate our findings.     

The Increased Risk for Autoimmune Diseases in Patients with Eating Disorders

Objective

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.

Methods

Patients (N = 2342) treated at the Eating Disorder Unit of Helsinki University Central Hospital between 1995 and 2010 were compared with general population controls (N = 9368) matched for age, sex, and place of residence. Data of 30 autoimmune diseases from the Hospital Discharge Register from 1969 to 2010 were analyzed using conditional and Poisson regression models.

Results

Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease (OR 1.7, 95% CI 1.5–2.0, P<0.001). The increase in endocrinological diseases (OR 2.4, 95% CI 1.8–3.2, P<0.001) was explained by type 1 diabetes, whereas Crohn''s disease contributed most to the risk of gastroenterological diseases (OR 1.8, 95% CI 1.4–2.5, P<0.001). Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment (OR 1.5, 95% CI 1.1–2.1, P = 0.02) and at the end of the follow-up (OR 1.4, 95% CI 1.1–1.8, P = 0.01).

Conclusions

We observed an association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our findings support the link between immune-mediated mechanisms and development of eating disorders. Future studies are needed to further explore the risk of autoimmune diseases and immunological mechanisms in individuals with eating disorders and their family members.     

Prevalence and Risk Factors of Chronic Otitis Media: The Korean National Health and Nutrition Examination Survey 2010–2012

BackgroundThe performance of nationwide studies of chronic otitis media (COM) in adults has been insufficient in Korea. We evaluated the prevalence and risk factors of COM in Korea.MethodsThis study was conducted using data from the fifth Korean National Health and Nutrition Examination Survey (n = 23,621). After excluding the subjects under 20 year old and suffered from cancers, 16,063 patients were evaluated for COM. Participants underwent a medical interview, physical examination, endoscopic examination, and blood and urine test. COM was diagnosed by trained residents in the Department of Otorhinolaryngology using an ear, nose, and throat questionnaire and otoendoscopy findings. Data on the presence and absence of COM were collected. Multivariate logistic regression analyses were performed to identify its risk factors.ResultsOf the 16,063 participants aged above 20 year old, the weighted prevalence of COM was 3.8%. In the multivariate analyses, the following factors showed high odds ratios (ORs) for COM: pulmonary tuberculosis (adjusted OR, 1.78; 95% confidence interval [CI], 1.06-3.01), chronic rhinosinusitis (adjusted OR, 1.87; 95% CI, 1.17-2.98), mild hearing impairment (adjusted OR, 1.95; 95% CI, 1.34-2.85), moderate hearing impairment (adjusted OR, 4.00; 95% CI, 2.21-7.22), tinnitus (adjusted OR, 1.82; 95% CI, 1.34-2.49), increased hearing thresholds in pure tone audiometry in the right ear (adjusted OR, 1.02; 95% CI, 1.01-1.03), and left ear (adjusted OR, 1.03; 95% CI, 1.02-1.04). The following factors showed low odds ratios for COM: hepatitis B (adjusted OR, 0.28; 95% CI, 0.08-0.94) and rhinitis (adjusted OR, 0.60; 95% CI, 0.42-0.88). In addition, high levels of vitamin D, lead, and cadmium, EQ-5D index; and low red blood cell counts were associated with development of COM (Student’s t-test, P < 0.01).ConclusionsOur population-based study showed that COM is not rare in Korea, and its development may be associated with various host and environmental factors. Further research on its relationships and the pathogenesis are needed.     

Association between the Polymorphism rs3217927 of CCND2 and the Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population

CyclinD proteins, the ultimate recipients of mitogenic and oncogenic signals, play a crucial role in cell-cycle regulation. CyclinD2, one of the cyclinD family, is overexpressed in T-acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia and involved in the pathogenesis of leukemias. Recent reports indicated that CCND2 polymorphisms are associated with human cancer risk, thusly we hypothesized that CCND2 gene polymorphisms may contribute to childhood ALL susceptibility. We selected the polymorphism rs3217927 located in the 3′UTR region of CCND2 to assess its associations with childhood ALL risk in a case-control study. A significant difference was found in the genotype distributions of rs3217927 polymorphism between cases and controls (P = 0.019) and homozygous GG genotype may be an increased risk factor for childhood ALL (adjusted OR  =  1.84, 95% CI  =  1.14 —2.99). Furthermore, this increased risk was more pronounced with GG genotype among high-risk ALL (adjusted OR  = 1.95, 95% CI  =  1.04–3.67), low-risk ALL (adjusted OR  =  2.09, 95% CI  =  1.13–3.87), B-phenotype ALL patients (adjusted OR  =  1.78, 95% CI  =  1.08–2.95) and T-phenotype ALL patients (adjusted OR  =  2.87, 95% CI  =  1.16–7.13). Our results provide evidence that CCND2 polymorphism rs3217927 may be involved in the etiology of childhood ALL, and the GG genotype of rs3217927 may modulate the genetic susceptibility to childhood ALL in the Chinese population. Further functional studies and investigations in larger populations should be conducted to validate our findings.     

Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification

The purpose of this overview is to discuss the changes in the 2008 WHO classification of myeloid neoplasms, with exclusion of acute myeloid leukaemia. Specific mutations or rearrangements leading to constitutive activation of growth factor receptors or cytoplasmic tyrosine kinases are now recognised as recurrent genetic events characterising the group of myeloproliferative neoplasms (MPN). A newly introduced subgroup consists of patients with persistent eosinophilia and myeloid or lymphoid proliferations harbouring specific genetic changes involving platelet-derived growth factor receptors alpha and beta (PDGFRA and PDGFRB) or fibroblast growth factor receptor 1 (FGFR1). The clinical relevance of recognising myeloid neoplasms with aberrant tyrosine kinase activity is based in novel treatment options with tyrosine kinase inhibitors. The myelodysplastic syndromes (MDS) without increased blasts are further divided into subtypes of refractory cytopaenias with unilineage dysplasia. A new provisional entity is refractory cytopaenia of childhood. Down syndrome- and therapy-related myeloid neoplasms, including MDS, were moved to the section of acute myeloid leukaemia and related precursor neoplasms.     

Interactions among Candidate Genes Selected by Meta-Analyses Resulting in Higher Risk of Ischemic Stroke in a Chinese Population

Ischemic stroke (IS) is a multifactorial disorder caused by both genetic and environmental factors. The combined effects of multiple susceptibility genes might result in a higher risk for IS than a single gene. Therefore, we investigated whether interactions among multiple susceptibility genes were associated with an increased risk of IS by evaluating gene polymorphisms identified in previous meta-analyses, including methylenetetrahydrofolate reductase (MTHFR) C677T, beta fibrinogen (FGB, β-FG) A455G and T148C, apolipoprotein E (APOE) ε2–4, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), and endothelial nitric oxide synthase (eNOS) G894T. In order to examine these interactions, 712 patients with IS and 774 controls in a Chinese Han population were genotyped using the SNaPshot method, and multifactor dimensionality reduction analysis was used to detect potential interactions among the candidate genes. The results of this study found that ACE I/D and β-FG T148C were significant synergistic contributors to IS. In particular, the ACE DD + β-FG 148CC, ACE DD + β-FG 148CT, and ACE ID + β-FG 148CC genotype combinations resulted in higher risk of IS. After adjusting for potential confounding IS risk factors (age, gender, family history of IS, hypertension history and history of diabetes mellitus) using a logistic analysis, a significant correlation between the genotype combinations and IS patients persisted (overall stroke: adjusted odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.22–2.02, P < 0.001, large artery atherosclerosis subtype: adjusted OR = 1.50, 95% CI: 1.08–2.07, P = 0.016, small-artery occlusion subtype: adjusted OR = 2.04, 95% CI: 1.43–2.91, P < 0.001). The results of this study indicate that the ACE I/D and β-FG T148C combination may result in significantly higher risk of IS in this Chinese population.     

A Meta-Analysis of the Relationship between Cigarette Smoking and Incidence of Myelodysplastic Syndromes

Background

In recent years, epidemiologic studies have reported controversial results relating cigarette smoking to myelodysplastic syndromes (MDS) risk. A meta-analysis was performed to assess such potential relationship between cigarette smoking and incidence of MDS.

Methods

A search of literature published before October 2012 for observational studies evaluating the association between cigarette smoking and MDS, returned 123 articles and of these, 14 were selected for this study. The outcomes from these studies were calculated and reported as odds ratios (OR). Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the I² index and source of heterogeneity was detected by sensitivity analyses. Finally, publication bias was assessed through visual inspection of funnel plots and Egger’s test.

Results

The pooled OR of developing MDS in ever-smokers was 1.45 (95% CI, 1.25 to 1.68) versus non-smokers. Current and former smokers had increased risks of MDS, with ORs of 1.81 (95% CI, 1.24 to 2.66) and 1.67 (95% CI, 1.42 to 1.96), respectively. In subset analyses, ever-smokers had increased risks of developing MDS if they were living in the United States, or in Europe, female in gender, had refractory anemia (RA)/RA with ringed sideroblasts (RARS) or RA with excess blasts (RAEB)/RAEB in transformation (RAEBt), respectively. Our results demonstrated that the association was stronger in individuals who smoked ≥20 cigarettes/day (OR, 1.62; 95% CI, 1.03 to 2.55) versus those who smoked <20 cigarettes/day (OR, 1.36; 95% CI, 1.13 to 1.64). Moreover, individuals who smoked more than 20 pack-years had increased MDS risk (OR, 1.94; 95% CI, 1.29 to 2.92).

Conclusion

Our outcomes show that smoking increases the risk of developing MDS in ever-smokers who are current or former smokers. We also demonstrate here that positive association between cigarette smoking and risk of MDS exists, and occurs in a dose-dependent manner.     

Stevens-Johnson Syndrome Associated with Drugs and Vaccines in Children: A Case-Control Study

Objective

Stevens-Johnson Syndrome (SJS) is one of the most severe muco-cutaneous diseases and its occurrence is often attributed to drug use. The aim of the present study is to quantify the risk of SJS in association with drug and vaccine use in children.

Methods

A multicenter surveillance of children hospitalized through the emergency departments for acute conditions of interest is currently ongoing in Italy. Cases with a diagnosis of SJS were retrieved from all admissions. Parents were interviewed on child’s use of drugs and vaccines preceding the onset of symptoms that led to the hospitalization. We compared the use of drugs and vaccines in cases with the corresponding use in a control group of children hospitalized for acute neurological conditions.

Results

Twenty-nine children with a diagnosis of SJS and 1,362 with neurological disorders were hospitalized between 1^st November 1999 and 31^st October 2012. Cases were more frequently exposed to drugs (79% vs 58% in the control group; adjusted OR 2.4; 95% CI 1.0–6.1). Anticonvulsants presented the highest adjusted OR: 26.8 (95% CI 8.4–86.0). Significantly elevated risks were also estimated for antibiotics use (adjusted OR 3.3; 95% CI 1.5–7.2), corticosteroids (adjusted OR 4.2; 95% CI 1.8–9.9) and paracetamol (adjusted OR 3.2; 95% CI 1.5–6.9). No increased risk was estimated for vaccines (adjusted OR: 0.9; 95% CI 0.3–2.8).

Discussion

Our study provides additional evidence on the etiologic role of drugs and vaccines in the occurrence of SJS in children.     

Non-steroidal anti-inflammatory drug use and cervical cancer risk: A case-control study using the Clinical Practice Research Datalink

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have many anticarcinogenic properties via the inhibition of cyclooxygenase 2 (COX-2). Only one study, a cohort study examining risk of all cancers, investigated their role in cervical cancer with inconsistent findings between non-aspirin NSAIDs and aspirin. The aim of this study was to further investigate NSAID/aspirin use and cervical cancer risk. Methods: Using the United Kingdom Clinical Practice Research Datalink, 724 women diagnosed with cervical cancer between 1 January, 1995 and December 2010 were compared to 3479 women (without cervical cancer) matched on year of birth and general practice. Conditional logistic regression analysis adjusted for smoking, sexually transmitted infections, HRT and contraceptive use, was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for cervical cancer risk among users of any oral NSAIDs, non-aspirin NSAIDs and aspirin, as assessed from primary care prescribing data. Results: Excluding the year prior to diagnosis, there was no association in adjusted analyses between ever vs. never use of an NSAID (OR 0.92, 95% CI 0.77–1.09), non-aspirin NSAID (OR 0.95, 95% CI 0.80–1.13) or low-dose aspirin (OR 1.07, 0.80–1.44) and cervical cancer risk. In analysis of daily defined doses, there was no association with cervical cancer risk comparing the highest users to non-users of NSAIDs (OR 0.98, 95% CI 0.69–1.39) or non-aspirin NSAIDs (OR 1.00, 95% CI 0.70–1.43) or low-dose aspirin (OR 1.04, 95% CI 0.59–1.81). Conclusion: This large historical cohort study found no evidence of an association between non-aspirin NSAID or aspirin use and cervical cancer risk.     

Association of the vascular endothelial growth factor (VEGF-1154G>A) polymorphism in patients with colorectal cancer

Angiogenesis plays a pivotal role in the development of colon cancer during the promotion and metastasis of tumor growth. Vascular endothelial growth factor (VEGF) is known to be a potent angiogenic factor. This hospital-based case-control study was carried out to decide where there existed an association between the VEGF-1154G>A polymorphism and the susceptibility to colon cancer. DNA samples taken from 278 colon cancer patients and 226 healthy controls were studied using with real-time PCR for VEGF-1154G>A polymorphism. Genotype frequencies of the VEGF-1154G>A polymorphism were significantly different between patient and control groups (adjusted OR=2.735, 95% CI=1.243?6.015 for AA vs. GG genotype). In addition, upon stratification by gender and age, the frequencies of the A allele-bearing genotypes significantly increased the risk for development of colon cancer in men and patients younger than 55 years (in men, adjusted OR=3.375, 95% CI=1.062?10.717, and in <55 years, adjusted OR=4.908, 95% CI=1.294?18.617). Also, upon stratification of patients with proximal and distal colon cancer individually, the association only showed these significant patterns in distal colon cancer. This study provides evidence that VEGF-1154G>A polymorphism, at least in Koreans, might be associated with risks of the colon cancer, particularly in males.     

Seroprevalence and Potential Risk Factors for Brucella Spp. Infection in Traditional Cattle,Sheep and Goats Reared in Urban,Periurban and Rural Areas of Niger

Introduction

In Niamey, Niger, interactions within the interface between animals, humans and the environment induce a potential risk of brucellosis transmission between animals and from animals to humans. Currently, little is known about the transmission of Brucella in this context.

Results

5,192 animals from 681 herds were included in the study. Serum samples and hygroma fluids were collected. A household survey enabled to identify the risk factors for transmission of brucellosis. The true adjusted herd-level prevalence of brucellosis ranged between 11.2% and 17.2% and the true adjusted animal-population level prevalence was 1.3% (95% CI: 0.9–1.8%) based on indirect ELISA test for Brucella antibodies. Animals aged of 1–4 years were found to be more susceptible than animals less than 1 year old (Odds ratio [OR] of 2.7; 95% CI: 1.43–5.28). For cattle, the odds of brucellosis seropositivity were higher in rural compared to the periurban areas (OR of 2.8; 95% CI: 1.48–5.17) whereas for small ruminants the risk of seropositivity appeared to be higher in urban compared to periurban areas (OR of 5.5; 95% CI: 1.48–20.38). At herd level, the risk of transmission was increased by transhumance (OR of 5.4; 95% CI: 2.84–10.41), the occurrence of abortions (OR of 3.0; 95% CI: 1.40–6.41), and for herds having more than 50 animals (OR of 11.0; 95% CI: 3.75–32.46). Brucella abortus biovar 3 was isolated from the hygromas.

Conclusion

brucellosis in Niger is a serious problem among cattle especially in the rural areas around Niamey and among sheep in the urban areas of Niamey. The seroprevalence varies across strata and animal species with important risk factors including herd size, abortion and transhumance at herd level and age at animal population level. For effective control of brucellosis, an integrated approach seems appropriate involving all stakeholders working in public and animal health.     

Potentially Functional Polymorphism in IL-23 Receptor and Risk of Acute Myeloid Leukemia in a Chinese Population

The interleukin-23 (IL-23) and its receptor (IL-23R) mediate the direct antitumor activities in human hematologic malignancies including pediatric acute leukemia. Two potentially functional genetic variants (IL-23R rs1884444 T>G and rs6682925 T>C) have been found to contribute to solid cancer susceptibility. In this study, we conducted a case-control study including 545 acute myeloid leukemia (AML) patients and 1,146 cancer-free controls in a Chinese population to assess the association between these two SNPs and the risk of AML. We found that IL-23R rs1884444 TG/GG and rs6682925 TC/CC variant genotypes were associated with significantly increased risk of AML [rs1884444: adjusted odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.01–1.62; rs6682925: adjusted OR = 1.30, 95%CI = 1.01–1.67], compared to their corresponding wild-type homozygotes, respectively. These findings indicated that genetic variants in IL-23R may contribute to AML risk in our Chinese population.     

Copy Number Variation of GSTT1 and GSTM1 and the Risk of Prostate Cancer in a Caribbean Population of African Descent

Background

Deletions of the glutathione S-transferase genes M1 and T1 (GSTM1 and GSTT1) have been studied as potential risk factors for prostate cancer. Conflicting results have been obtained. Moreover, most such studies could not discriminate heterozygous from homozygous carriers of the non-deleted alleles.

Objective

We investigated whether copy number variation (CNV) of the GSTM1 and/or GSTT1 genes contribute to the risk of prostate cancer in the Caribbean population of African descent of Guadeloupe.

Methods

In a population-based case-control study, we compared 629 prostate cancer patients and 622 control subjects. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Exact copy numbers of GSTM1 and GSTT1 were determined by real-time PCR.

Results

A higher copy number of GSTM1 was marginally associated with prostate cancer risk. Men with 2 and 3 or more GSTT1 genes were at higher risk of prostate cancer (OR: 1.55, 95% CI: 1.11–2.16 and OR: 4.89, 95% CI: 1.71–13.99, respectively; P_trend<0.001). Men with 3, 4 and 5 or more copies of both GSTM1 and GSTT1 genes were at higher risk of prostate cancer (OR: 2.18, 95% CI: 1.21–3.91, OR: 3.24, 95% CI: 1.63–6.46, and OR: 5.77, 95% CI: 1.40–23.84, respectively; P_trend<0.001).

Conclusions

Copy number of GSTT1 and combined GSTM1/GSTT1 appear to be associated with prostate cancer risk in our population study with gene dose relationship. Our results support the hypothesis that variations in copy number of GSTT1 modulate the risk of prostate cancer.     

Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population

Previous investigations indicated that histamine receptor H4 (HRH4) played important roles in many aspects of breast cancer pathogenesis, and that the polymorphisms of HRH4 gene may result in expression and functional changes of HRH4 proteins. However, the relationship between polymorphisms of HRH4 and breast cancer risk and malignant degree is unclear. In the present study, we conducted a case–control investigation among 185 Chinese Han breast cancer patients and 199 ethnicity-matched health controls. Four tag-SNPs (i.e. rs623590, rs16940762, rs11662595 and rs1421125) of HRH4 were genotyped and association analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. We found that the T allele of rs623590 had a decreased risk of breast cancer (adjusted OR, 0.667; 95% CI, 0.486–0.913; P = 0.012) while the A allele of rs1421125 had an increased risk (adjusted OR, 1.653; 95% CI, 1.139–2.397; P = 0.008). Further haplotype analysis showed that the CAA haplotype of rs623590–rs11662595–rs1421125 was more frequent among patients with breast cancer (adjusted OR, 1.856; 95% CI, 1.236–2.787; P = 0.003). Additionally, polymorphisms of rs623590 and rs11662595 were also correlated with clinical stages, lymph node involvement, and HER2 status. These findings indicated that the variants of rs623590, rs11662595 and rs1421125 genotypes of HRH4 gene were significantly associated with the risk and malignant degree of breast cancer in Chinese Han populations, which may provide us novel insight into the pathogenesis of breast cancer although further studies with larger participants worldwide are still needed for conclusion validation.     

ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis

IntroductionAnkylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese.MethodsFour ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters.ResultsThe SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10^-5, OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10^-5, OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10^-4, OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10^-3, OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10^-3, OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10^-3, OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P <0.00001, OR 1.38, 95% CI: 1.12 to 1.58) in Taiwanese.ConclusionsThis study provides the first evidence of ERAP1 SNPs involving syndesmophyte formation. The interactions between ERAP1 SNPs and HLA-B27 play critical roles in pMHC I pathway processing contributing to the pathogenesis of AS in multiple populations.     

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto''s thyroiditis), as well as autoimmune hyperthyroidism (Graves'' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10⁻⁸) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10⁻⁸), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10⁻⁶), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10⁻⁴). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves'' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10⁻⁷ and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10⁻⁵). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10⁻³). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.     

Early pregnancy azathioprine use and pregnancy outcomes

BACKGROUND: Azathioprine (AZA) is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation. Previous studies have demonstrated potential risks. METHODS: The Swedish Medical Birth Register was used to identify 476 women who reported the use of AZA in early pregnancy. The effect of AZA exposure on pregnancy outcomes was studied after adjustment for maternal characteristics that could act as confounders. RESULTS: The most common indication for AZA use was IBD. The rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98–2.04). An association between early pregnancy AZA exposure and ventricular/atrial septal defects was found (adjusted OR: 3.18, 95% CI: 1.45–6.04). Exposed infants were also more likely to be preterm, to weigh <2500 gm, and to be small for gestational age compared to all infants born. This effect remained for preterm birth and low birth weight when infants of women with IBD but without AZA exposure were used as a comparison group. A trend toward an increased risk of congenital malformations was found among infants of women with IBD using AZA compared to women with IBD not using AZA (adjusted OR: 1.42, 95% CI: 0.93–2.18). CONCLUSIONS: Infants exposed to AZA in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects. There is also an increased risk of growth restriction and preterm delivery. These associations may be confounded by the severity of maternal illness. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Depression remission after six months of collaborative care management: role of initial severity of depression in outcome

Aim The impact of initial severity of depression on the rate of remission has not been well studied. The hypothesis for this study was that increased depression severity would have an inverse relationship on clinical remission at six months while in collaborative care management.Participants The study cohort was 1128 primary care patients from a south-eastern Minnesota practice and was a longitudinal retrospective chart review analysis.Results Clinical remission at six months was less likely in the severe depression group at 29.6% compared with 36.9% in the moderately severe group and 45.6% in the moderate depression group (P < 0.001). Multivariate analysis of a sub-group demonstrated that increased initial anxiety symptoms (odds ratio [OR] 0.9645, 95% confidence interval [CI] 0.9345–0.9954, P = 0.0248) and an abnormal screening for bipolar disorder (OR 0.4856, 95% CI 0.2659–0.8868, P = 0.0187) predicted not achieving remission at six months. A patient with severe depression was significantly less likely to achieve remission at six months (OR 0.6040, 95% CI 0.3803–0.9592, P = 0.0327) compared with moderate depression, but not moderately severe depression (P = 0.2324). There was no statistical difference in the adjusted means of the PHQ-9 score for those patients who were in remission at six months. However, in the unremitted patients, the six-month PHQ-9 score was significantly increased by initial depression severity when controlling for all other variables.Conclusion Multivariate analysis in our study demonstrated that patients with severe depression have a decreased OR for remission at six months compared with moderate depression. Also, there was a significant increase in the six-month PHQ-9 score for those unremitted patients in the severe vs. moderate depression groups.