Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

Introduction

The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans.

Methods

RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts.

Results

After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001.

Conclusions

The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.     

Swift block-updating EM and pseudo-EM procedures for Bayesian shrinkage analysis of quantitative trait loci

Introduction

Virtually all existing expectation-maximization (EM) algorithms for quantitative trait locus (QTL) mapping overlook the covariance structure of genetic effects, even though this information can help enhance the robustness of model-based inferences.

Results

Here, we propose fast EM and pseudo-EM-based procedures for Bayesian shrinkage analysis of QTLs, designed to accommodate the posterior covariance structure of genetic effects through a block-updating scheme. That is, updating all genetic effects simultaneously through many cycles of iterations.

Conclusion

Simulation results based on computer-generated and real-world marker data demonstrated the ability of our method to swiftly produce sensible results regarding the phenotype-to-genotype association. Our new method provides a robust and remarkably fast alternative to full Bayesian estimation in high-dimensional models where the computational burden associated with Markov chain Monte Carlo simulation is often unwieldy. The R code used to fit the model to the data is provided in the online supplementary material.     

Bayesian estimation of genetic parameters for growth,stem straightness,and survival in Eucalyptus globulus on an Andean Foothill site

Knowledge of the genetic variation of key economic traits in Eucalyptus globulus under cold conditions is crucial to the genetic improvement of environmental tolerances and other economic traits. A Bayesian analysis of genetic parameters for quantitative traits was carried out in 37 E. globulus open-pollinated families under cold conditions in southern Chile. The trial is located in the Andean foothills, in the Province of Bío-Bío. The Bayesian approach was performed using Gibbs sampling algorithm. Multi-trait linear and threshold models were fitted to phenotypic data (growth traits, survival, and stem straightness). Fifteen years after planting, height, diameter at breast height, and stem volume were found to be weakly to moderately heritable with Bayesian credible intervals (probability of 90 %): $ {\widehat{h}}^2 $ ?=?0.009–0.102, $ {\widehat{h}}^2 $ ?=?0.031–0.185, and $ {\widehat{h}}^2 $ ?=?0.045–0.205, respectively. Stem straightness was found to be weakly to moderately heritable ranging from 0.032 to 0.208 (Bayesian 90 % credible interval); posterior mode $ {\widehat{h}}^2 $ ?=?0.091. Tree survival at age of 15 years was high in the trial (84.8 %) with such heritability values ranging from 0.072 to 0.157. Survival was non-significantly genetically correlated to growth and stem straightness. Stem volume had the highest predicted genetic gains ranging from 17.9 to 23.7 % (selection rate of 15.8 and 8.3 %, respectively). The results of this study confirm the potential for selective breeding of this eucalypt in areas of southern Chile where cold is a significant constraint.     

Earth before life

Background

A recent study argued, based on data on functional genome size of major phyla, that there is evidence life may have originated significantly prior to the formation of the Earth.

Results

Here a more refined regression analysis is performed in which 1) measurement error is systematically taken into account, and 2) interval estimates (e.g., confidence or prediction intervals) are produced. It is shown that such models for which the interval estimate for the time origin of the genome includes the age of the Earth are consistent with observed data.

Conclusions

The appearance of life after the formation of the Earth is consistent with the data set under examination.

Reviewers

This article was reviewed by Yuri Wolf, Peter Gogarten, and Christoph Adami.     

Learning probabilistic models of hydrogen bond stability from molecular dynamics simulation trajectories

Background

The estimation of individual ancestry from genetic data has become essential to applied population genetics and genetic epidemiology. Software programs for calculating ancestry estimates have become essential tools in the geneticist's analytic arsenal.

Results

Here we describe four enhancements to ADMIXTURE, a high-performance tool for estimating individual ancestries and population allele frequencies from SNP (single nucleotide polymorphism) data. First, ADMIXTURE can be used to estimate the number of underlying populations through cross-validation. Second, individuals of known ancestry can be exploited in supervised learning to yield more precise ancestry estimates. Third, by penalizing small admixture coefficients for each individual, one can encourage model parsimony, often yielding more interpretable results for small datasets or datasets with large numbers of ancestral populations. Finally, by exploiting multiple processors, large datasets can be analyzed even more rapidly.

Conclusions

The enhancements we have described make ADMIXTURE a more accurate, efficient, and versatile tool for ancestry estimation.     

Risk of herpes zoster in patients prescribed inhaled corticosteroids: a cohort study

Background

Childhood asthma prevalence is widely measured by parental proxy report of physician-diagnosed asthma in questionnaires. Our objective was to validate this measure in a North American population.

Methods

The 2884 study participants were a subsample of 5619 school children aged 5 to 9 years from 231 schools participating in the Toronto Child Health Evaluation Questionnaire study in 2006. We compared agreement between "questionnaire diagnosis" and a previously validated "health claims data diagnosis". Sensitivity, specificity and kappa were calculated for the questionnaire diagnosis using the health claims diagnosis as the reference standard.

Results

Prevalence of asthma was 15.7% by questionnaire and 21.4% by health claims data. Questionnaire diagnosis was insensitive (59.0%) but specific (95.9%) for asthma. When children with asthma-related symptoms were excluded, the sensitivity increased (83.6%), and specificity remained high (93.6%).

Conclusions

Our results show that parental report of asthma by questionnaire has low sensitivity but high specificity as an asthma prevalence measure. In addition, children with "asthma-related symptoms" may represent a large fraction of under-diagnosed asthma and they should be excluded from the inception cohort for risk factor studies.     

Delimitation of lymphatic filariasis transmission risk areas: a geo-environmental approach

Background

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) depends upon Mass Drug Administration (MDA) to interrupt transmission. Therefore, delimitation of transmission risk areas is an important step, and hence we attempted to define a geo-environmental risk model (GERM) for determining the areas of potential transmission of lymphatic filariasis.

Methods

A range of geo-environmental variables has been selected, and customized on GIS platform to develop GERM for identifying the areas of filariasis transmission in terms of "risk" and "non-risk". The model was validated through a 'ground truth study' following standard procedure using GIS tools for sampling and Immuno-chromotographic Test (ICT) for screening the individuals.

Results

A map for filariasis transmission was created and stratified into different spatial entities, "risk' and "non-risk", depending on Filariasis Transmission Risk Index (FTRI). The model estimation corroborated well with the ground (observed) data.

Conclusion

The geo-environmental risk model developed on GIS platform is useful for spatial delimitation purpose on a macro scale.     

Immunohistochemical diagnosis of abdominal and lymph node tuberculosis by detecting Mycobacterium tuberculosis complex specific antigen MPT64

Background

Epstein-Barr virus has been proved to be associated with many of the human malignancy including gastric carcinoma, one of the most important human malignancies in the world. There has been no study about the presence of EBV in gastric adenocarcinoma in Iran.

Methods

We examined the presence of EBV in 273 formalin fixed paraffin-embedded cases of gastric carcinoma from Cancer institute of Tehran University, from 1969 to 2004. In situ hybridization of EBV-encoded small RNA-1 (EBER-1) was conducted. The strain of positive cases was examined by means of polymerase chain reaction and/or restriction fragment length polymorphism analysis.

Results

We found 9 (3%; 95% CI = 1–5%) EBV positive cases. The gender difference was not statisticaly significant. The proportion of EBV-GC cases in diffuse type was higher than intestinal type (OR = 0.08; 95% CI = 0.002–0.64). EBV-GC cases had no relation with age, location and invasion. Six out of 9 EBV-GC cases were born during the period between 1928 and 1930. All 9 cases were Type A. Prototype F was seen in 6 out of 8 cases. Type "i" was found in 8 cases and type I in 1 case. XhoI+ and XhoI- polymorphism accounted 6 and 3 of the cases, respectively.

Conclusion

Our study is the first to describe the frequency of EBV-GC in Iran and the Middle East, highlighting a very low prevalence with specific clinicopathologic features. The predominance of EBV-GC birth year in a fixed period, suggests that EBV infection or other events at early childhood may be related to the development of EBV-GC later in the life. The predominance of the type "i" and XhoI+ cases are contradictory to other studies in Asia and is similar to what is reported from Latin American countries.     

Can molecular cell biology explain chromosome motions?

Background

Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering "molecular cell biology" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.

Results

Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.

Conclusion

We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply.     

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care

Background

Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common.

Methods

The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms.

Results

The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS.

Conclusion

The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.     

Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients

Background

Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations.

Methods

Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland.

Results

No association was found in any of the populations studied.

Conclusion

Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.     

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

Background

Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.

Methods

From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.

Results

Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.

Conclusions

We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.     

A little help from my friends: caring for premature babies in a war zone

Background

Too much or too little milk production are common problems in a lactation consultant's practice. Whereas underproduction is widely discussed in the lactation literature, overabundant milk supply is not. In my practice I work with women who experience moderate to severe oversupply syndrome. In most cases the syndrome can be successfully treated with full removal of milk followed by unilateral breastfeeding ad lib with the same breast offered at every breastfeed in a certain time block ("block feeding").

Case presentations

Four cases of over-supply of breast milk are presented. The management and outcome of each case is described.

Conclusion

Overabundant milk supply is an often under-diagnosed condition in otherwise healthy lactating women. Full drainage and "block feeding" offer an adequate and userfriendly way to normalize milk production and treat symptoms in both mother and child.     

Bayesian QTL analyses using pedigreed families of an outcrossing species,with application to fruit firmness in apple

Key message

Proof of concept of Bayesian integrated QTL analyses across pedigree-related families from breeding programs of an outbreeding species. Results include QTL confidence intervals, individuals’ genotype probabilities and genomic breeding values.

Abstract

Bayesian QTL linkage mapping approaches offer the flexibility to study multiple full sib families with known pedigrees simultaneously. Such a joint analysis increases the probability of detecting these quantitative trait loci (QTL) and provide insight of the magnitude of QTL across different genetic backgrounds. Here, we present an improved Bayesian multi-QTL pedigree-based approach on an outcrossing species using progenies with different (complex) genetic relationships. Different modeling assumptions were studied in the QTL analyses, i.e., the a priori expected number of QTL varied and polygenic effects were considered. The inferences include number of QTL, additive QTL effect sizes and supporting credible intervals, posterior probabilities of QTL genotypes for all individuals in the dataset, and QTL-based as well as genome-wide breeding values. All these features have been implemented in the FlexQTL^? software. We analyzed fruit firmness in a large apple dataset that comprised 1,347 individuals forming 27 full sib families and their known ancestral pedigrees, with genotypes for 87 SSR markers on 17 chromosomes. We report strong or positive evidence for 14 QTL for fruit firmness on eight chromosomes, validating our approach as several of these QTL were reported previously, though dispersed over a series of studies based on single mapping populations. Interpretation of linked QTL was possible via individuals’ QTL genotypes. The correlation between the genomic breeding values and phenotypes was on average 90 %, but varied with the number of detected QTL in a family. The detailed posterior knowledge on QTL of potential parents is critical for the efficiency of marker-assisted breeding.     

The burden of atrial fibrillation in the Netherlands

Background

Atrial fibrillation (AF) is the most common sustained atrial arrhythmia and it is independently associated with an increased morbidity and mortality. As a result of the high prevalence of AF, the economic and clinical impact of the disease is substantial. This study describes the economic and clinical impact of AF in the Netherlands.

Methods

Epidemiological data on AF in the Netherlands were projected on population estimates of the Netherlands in 2009 and combined with data on the cost of AF and its interventions.

Results

Overall prevalence of AF in the Netherlands is 5.5% in the population over 55 years, corresponding to about 250,000 AF patients. The prevalence increases with age, and the mean age of AF patients is 69.3 years. Incidence of AF in the Netherlands varies with age, from 1188 new cases in the age group of 55 to 59 up to 7074 new cases in the age group 75 to 79. Total new cases amounts to 45,085 patients per year in the Netherlands. Total costs of AF in the Netherlands are € 583 million, of which the majority (70%) were accounted for by hospitalisations and in-hospital procedures. Pharmacotherapeutic management of AF totalled € 17 million in the Netherlands in 2009.

Discussion

AF is a serious disease with a high clinical and economic burden, especially due to hospitalisations as a result of cardiovascular events. The number of patients with AF in the Netherlands is considerable and will increase with the ageing population in the future.     

A simplified study of trans-mitral Doppler patterns

Background

Electrical fusion between left ventricular pacing and spontaneous right ventricular activation is considered the key to resynchronisation in sinus rhythm patients treated with single-site left ventricular pacing.

Aim

Use of QRS morphology to optimize device programming in patients with heart failure (HF), sinus rhythm (SR), left bundle branch block (LBBB), treated with single-site left ventricular pacing.

Methods and Results

We defined the "fusion band" (FB) as the range of AV intervals within which surface ECG showed an intermediate morphology between the native LBBB and the fully paced right bundle branch block patterns. Twenty-four patients were enrolled. Echo-derived parameters were collected in the FB and compared with the basal LBBB condition. Velocity time integral and ejection time did not improve significantly. Diastolic filling time, ejection fraction and myocardial performance index showed a statistically significant improvement in the FB. Interventricular delay and mitral regurgitation progressively and significantly decreased as AV delay shortened in the FB. The tissue Doppler asynchrony index (Ts-SD-12-ejection) showed a non significant decreasing trend in the FB. The indications provided by the tested parameters were mostly concordant in that part of the FB corresponding to the shortest AV intervals.

Conclusion

Using ECG criteria based on the FB may constitute an attractive option for a safe, simple and rapid optimization of resynchronization therapy in patients with HF, SR and LBBB.     

Analysis of IL-12 p40 subunit gene and IFN-γ G5644A polymorphisms in Idiopathic Pulmonary Fibrosis

Background

Genes encoding cytokine mediators are prime candidates for genetic analysis in conditions with T-helper (Th) cell disease driven imbalance. Idiopathic Pulmonary Fibrosis (IPF) is a predominantly Th2 mediated disease associated with a paucity of interferon-gamma (IFN-γ). The paucity of IFN-γ may favor the development of progressive fibrosis in IPF. Interleukin-12 (IL-12) plays a key role in inducing IFN-γ production. The aim of the current study was to assess whether the 1188 (A/C) 3'UTR single nucleotide polymorphism (SNP) in the IL-12 p40 subunit gene which was recently found to be functional and the 5644 (G/A) 3' UTR SNP of the IFN-γ gene were associated with susceptibility to IPF.

Methods

We investigated the allelic distribution in these loci in UK white Caucasoid subjects comprising 73 patients with IPF and 157 healthy controls. The SNPs were determined using the polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3'-end.

Results

Our results showed that these polymorphisms were distributed similarly in the IPF and control groups

Conclusion

We conclude that these two potentially important candidate gene single nucleotide polymorphisms are not associated with susceptibility to IPF.     

Development of a genetic linkage map for Pinus radiata and detection of pitch canker disease resistance associated QTLs

Key message

The heritability of genetic resistance of radiata pine against Fusarium circinatum was not clear. We demonstrated that there are at least 3 QTLs that could be involved in this resistance/susceptibility.

Abstract

A genetic linkage map was developed for Pinus radiata, using Amplified Fragment Length Polymorphism (AFLP), Inter-Simple Sequence Repeat (ISSR), Selective Amplification of Microsatellite Polymorphic Loci (SAMPL), and Simple Sequence Repeat (SSR) molecular markers, based on a two-way pseudo-testcross strategy, using 86 individuals of a F1 full-sib family and 787 molecular markers for genotyping. Linkage analysis generated a map of medium to high density for each parent, with 1,060 and 1,258 cM for parents XO and XP, respectively. A total of 458 markers were mapped on 12 linkage groups (LG) in XO and XP, which equals the number of haploid chromosomes present in P. radiata. Analysis of quantitative trait loci (QTL) for resistance against pitch canker disease caused by Fusarium circinatum was made using Bayesian Information Criterion (BIC). In the XO parental map, two groups (LG-1 and LG-9) showed high probabilities for one or more QTLs. Only one group (LG-9) in the XP parental map showed probability for one or more QTLs. The results indicate that resistance to pitch canker is inherited from both parents. These results provide the basis for further studies focused on structure, evolution, and function of the P. radiata genome.