Effective Detection of Human Leukocyte Antigen Risk Alleles in Celiac Disease Using Tag Single Nucleotide Polymorphisms

Background: The HLA genes, located in the MHC region on chromosome 6p21.3, play an important role in many autoimmune disorders, such as celiac disease (CD), type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis, psoriasis and others. Known HLA variants that confer risk to CD, for example, include DQA1*05/DQB1*02 (DQ2.5) and DQA1*03/DQB1*0302 (DQ8). To diagnose the majority of CD patients and to study disease susceptibility and progression, typing these strongly associated HLA risk factors is of utmost importance. However, current genotyping methods for HLA risk factors involve many reactions, and are complicated and expensive. We sought a simple experimental approach using tagging SNPs that predict the CD-associated HLA risk factors. Methodology: Our tagging approach exploits linkage disequilibrium between single nucleotide polymorphism (SNPs) and the CD-associated HLA risk factors DQ2.5 and DQ8 that indicate direct risk, and DQA1*0201/DQB1*0202 (DQ2.2) and DQA1*0505/DQB1*0301 (DQ7) that attribute to the risk of DQ2.5 to CD. To evaluate the predictive power of this approach, we performed an empirical comparison of the predicted DQ types, based on these six tag SNPs, with those executed with current validated laboratory typing methods of the HLA-DQA1 and -DQB1 genes in three large cohorts. The results were validated in three European celiac populations. Conclusion: Using this method, only six SNPs were needed to predict the risk types carried by >95% of CD patients. We determined that for this tagging approach the sensitivity was >0.991, specificity >0.996 and the predictive value >0.948. Our results show that this tag SNP method is very accurate and provides an excellent basis for population screening for CD. This method is broadly applicable in European populations

Composition of Human Skin Microbiota Affects Attractiveness to Malaria Mosquitoes

The African malaria mosquito Anopheles gambiae sensu stricto continues to play an important role in malaria transmission, which is aggravated by its high degree of anthropophily, making it among the foremost vectors of this disease. In the current study we set out to unravel the strong association between this mosquito species and human beings, as it is determined by odorant cues derived from the human skin. Microbial communities on the skin play key roles in the production of human body odour. We demonstrate that the composition of the skin microbiota affects the degree of attractiveness of human beings to this mosquito species. Bacterial plate counts and 16S rRNA sequencing revealed that individuals that are highly attractive to An. gambiae s.s. have a significantly higher abundance, but lower diversity of bacteria on their skin than individuals that are poorly attractive. Bacterial genera that are correlated with the relative degree of attractiveness to mosquitoes were identified. The discovery of the connection between skin microbial populations and attractiveness to mosquitoes may lead to the development of new mosquito attractants and personalized methods for protection against vectors of malaria and other infectious diseases

Paternal HLA-C is a risk factor in unexplained recurrent miscarriage

PROBLEM: HLA-C is the only classical HLA-I antigen expressed on trophoblast. We hypothesized that the alloimmune response to paternal HLA-C plays a role in unexplained recurrent miscarriage. METHOD OF STUDY: In a case-control design, we included 100 women with at least three unexplained consecutive miscarriages along with their partners and children. For the first control group, we included 90 women with an uneventful singleton pregnancy without pregnancy complications in their history along with their children. The second control group consisted of 425 families. HLA-C*07 and HLA-C*17 frequencies, which are the most immunogenic HLA-C antigens, along with HLA-C mismatches, and the presence of specific HLA antibodies in the mother were determined. RESULTS: HLA-C and HLA-C*07 mismatches were significantly increased in couples with recurrent miscarriage compared to control subjects (P = .016, P = .008, respectively). The incidence of child-specific HLA-C*07/HLA-C*17 antibodies was increased in women with recurrent miscarriage (P = .007). CONCLUSION: The results show that HLA-C incompatibility between couples is significantly associated with unexplained recurrent miscarriage

Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients

Background: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. Methods: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. Results: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. Conclusion: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

\u3cp\u3eWe aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort. 525 NT1 patients and 1272 HLA-DQB1*06:02-positive healthy controls were included. Because of the discussion that has arisen on the existence of sporadic and post-H1N1 NT1, HLA-DQB1-associations in pre- and post-H1N1 NT1 patients were compared. The associations between HLA-DQB1 alleles and NT1 were not significantly different between pre- and post-H1N1 NT1 patients. Both HLA-DQB1-associations with pre- and -post H1N1 NT1 reported in recent smaller studies were replicated. Our findings combine the results of studies in pre- and post-H1N1 NT1 and argue against considering post-H1N1 NT1 as a different entity.\u3c/p\u3

Venous and arterial thrombosis in dialysis patients

Whether the risk of both venous and arterial thrombosis is increased in dialysis patients as compared to the general population is unknown. In addition, it is unknown which subgroups are at highest risk. Furthermore, it is unknown whether having a history of venous thrombosis or arterial thrombosis prior to dialysis treatment increases mortality risk. A total of 455 dialysis patients were followed for objectively verified symptomatic thrombotic events between January 1997 and June 2009. The incidence rates in dialysis patients as compared to the general population was 5.6-fold (95% CI 3.1-8.9) increased for venous thrombosis, 11.9-fold (95% CI 9.3-14.9) increased for myocardial infarction, and 8.4-fold (95% CI 5.7-11.5) increased for ischaemic stroke. The combination of haemodialysis, lowest tertile of albumin, history of venous thrombosis, and malignancy was associated with subsequent venous thrombosis. Increased age, renal vascular disease, diabetes, high cholesterol levels, history of venous thrombosis, and history of arterial thrombosis were associated with subsequent arterial thrombosis. The all-cause mortality risk was 1.9-fold (95% CI 1.1-3.3) increased for patients with a history of venous thrombosis and 1.9-fold (95% CI 1.4-2.6) increased for patients with a history of arterial thrombosis. A potential limitation of this study was that in some risk categories associations with venous thrombosis did not reach statistical significance due to small numbers. In conclusion, dialysis patients have clearly elevated risks of venous thrombosis and arterial thrombosis and occurrence of venous thrombosis or arterial thrombosis prior to the start of dialysis is associated with an increased mortality ris

The MY09B gene is a strong risk factor for developing refractory Celiac disease

Background & Aims: Celiac disease (CD) is associated with HLA-DQ2 and HLA-DQ8 and has been linked to genetic variants in the MY09B gene on chromosome 19. HLA-DQ2 homozygosity is associated with complications of CD such as refractory celiac disease type II (RCD II) and enteropathy-associated T-cell lymphoma (EATL). We investigated whether MY09B also predisposes to RCD II and EATL. Methods: Genotyping of ATY09B and molecular HLA-DQ2 typing were performed on 62 RCD II and EATL patients, 421 uncomplicated CD patients, and 1624 controls. Results: One single nucleotide polymorphism in MY09B showed a significantly different allele distribution in RCD II and EATL patients compared with controls (P = .00002). The rs7259292 T allele was significantly more frequent in RCD II and EATL patients compared with CD patients (P = .0003; odds ratio [OR], 3.61; 95% confidence interval [CI], 1.78-7.31). The frequency of the haplotype carrying the T allele of this single nucleotide polymorphism was significantly increased in RCD II and EATL patients (11%), compared with controls (2%) and CD patients (3%) (OR, 6.76; 95% CI, 3.40-13.46; P = 2.27E-09 and OR, 4.22; 95% CI, 1.95-9.11; P = .0001, respectively). Both MY09B rs7259292 and HLA-DQ2 homozygosiry increase the risk for RCD II and EATL to a similar extent when compared with uncomplicated CD patients (OR, 4.3; 95% CI, 1.9-9.8 and OR, 5.4; 95% Cl, 3.0-9.6, respectively), but there was no evidence for any interaction between these 2 risk factors. Conclusions: We show that both MY09B and HLA-DQ2 homozygosity might be involved in the prognosis of CD and the chance of developing RCD II and EATL

Reserve requirements and double Bertrand competition among banks

The paper considers a model of double Bertrand competition among banks, in which banks compete for deposits as well as loans. It is shown that the introduction of reserve requirements can have an effect on the existence and efficiency properties of Nash equilibria of this model. This provides a new rationale for imposing reserve requirements on banks.