Investigation of the Relationship Between Prostate Cancer and MSMB and NCOA4 Genetic Variants and Protein Expression

Two genome‐wide association studies (GWAS) identified the β‐microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow‐up studies demonstrate that the variant allele directly affects expression of the MSMB‐encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population‐based study of 1,323 cases and 1,268 age‐matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.     

Polymorphisms in interleukin‐1 receptor‐associated kinase 4 are associated with total serum IgE

Background: Serum immunoglobulin E (IgE) level is recognized to be under strong genetic control, but the causal and susceptibility genes remain to be identified. We sought to investigate the association between single nucleotide polymorphisms (SNPs) in the Toll‐like receptor (TLR) signaling pathway and total serum IgE level. Methods: A population of 206 patients with severe chronic rhinosinusitis (CRS) was used. Precise phenotyping of patients was accomplished by means of a questionnaire and clinical examination. Blood was drawn for measurement of total serum IgE, as well as DNA extraction. A maximally informative set of SNPs in the TLR1, 2, 3, 4, 6, 9, 10, CD14, MD2, MyD88, IRAK4, and TRAF6 genes were selected and genotyped. Significant findings were replicated in a second independent population of 956 subjects from 227 families with asthma. Results: A total of 97 out of 104 SNPs were successfully genotyped. Three SNPs in IRAK4– rs1461567, rs4251513, and rs4251559 – were associated with total serum IgE levels (P < 0.004). In the replication sample, the same SNPs as well as the same orientation of the risk allele were associated with IgE levels (P < 0.031). Conclusions: These results demonstrate a clear association between polymorphisms in the IRAK4 gene and serum IgE levels in patients with CRS and asthma. IRAK4 may be important in the regulation of IgE levels in patients with inflammatory diseases of the airways.     

The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility

Background: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl‐LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB₄ in airway disease. LTA₄ hydrolase and 5‐lipoxygenase activating protein have key roles in LTB₄ production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB₄ production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Methods: Three hundred and forty‐one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper‐responsiveness, FEV₁) were undertaken using the Family Based Association Test. Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042–0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41–3.32). Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB₄ in disease pathogenesis.     

Lack of association between CTLA-4 and PDCD1 polymorphisms and acute rejection in German liver transplant recipients

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs −1772T > C (rs733618), −1661A > G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G > A (rs11568821), 7209C > T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population.     

The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos

Background Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of arachidonate 5‐lipoxygenase‐activating protein (ALOX5AP) and leukotriene A₄ hydrolase (LTA4H) in asthma have been inconclusive. Objective To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans. Methods The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single‐nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analysed for associations with asthma and asthma‐related phenotypes in 687 parent–child trios of Mexican and Puerto Rican origin. Results In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P=0.007 and 0.05, respectively). Among the Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (odds ratio=0.78, P=0.02) and baseline lung function (P=0.018) in Puerto Ricans. A gene–gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P=0.003, in the combined sample). Conclusion Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations. Cite this as: M. Via, A. De Giacomo, H. Corvol, C. Eng, M. A. Seibold, C. Gillett, J. Galanter, S. Sen, H. Tcheurekdjian, R. Chapela, J. R. Rodríguez‐Santana, W. Rodríguez‐Cintrón, S. Thyne, P. C. Avila, S. Choudhry and E. González Burchard on behalf of the Genetics of Asthma in Latino Americans (GALA) Study, Clinical & Experimental Allergy, 2010 (40) 582–589.     

Two polymorphisms in the TIM‐4 gene are associated with asthma in a Chinese Han population

The gene family of the T cell immunoglobulin and mucin domain (TIM) proteins encodes cell surface receptors that are involved in the regulation of Th1‐ and Th2‐cell‐mediated immunity. TIM‐1 gene has been found to be associated with asthma in several populations. TIM‐4, the natural ligand for TIM‐1, may influence the susceptility to asthma.To investigate the association of the TIM‐4 gene polymorphisms with asthma in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TIM‐4 gene, rs6882076, rs12658558 and rs4702747, were genotyped in 551 unrelated asthma patients and 549 healthy controls. We found that two SNPs of the TIM‐4 gene, rs6882076 and rs4702747, were associated with asthma susceptibility in our study population (with P‐values = 0.009 and 0.005 respectively). No association was observed between asthma and rs12658558. Our results suggest that TIM‐4 gene polymorphisms are associated with asthma in a Chinese Han population.     

Association of G-protein-coupled receptor 154 with asthma and total IgE in a population of the Caribbean coast of Colombia

Background G protein‐coupled receptor 154 was described as an asthma susceptibility gene by positional cloning. It has been subsequently associated with asthma and other inflammatory diseases in several populations with different ethnic origin. Replication of associations adds reliability to these findings. Objective To analyze the association of G protein‐coupled receptor 154 with asthma and total and mite‐specific IgE levels in a population of the Caribbean Coast of Colombia. Methods We genotyped seven single nucleotide proteins (SNPs) in GPR154 in 475 asthmatics, 394 controls and 116 families from Cartagena, Colombia using either SnaPshot or TaqMan. Total and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus were determined by ELISA. Hardy–Weinberg equilibrium was assessed and case–control and family‐based analyses were performed to evaluate the association between the SNPs and their haplotypes and asthma and IgE. Association analyses in the case–control dataset were corrected by population stratification using 52 ancestry informative markers. Results Allelic distribution was similar to that described in other populations. Two SNPs were associated with the same direction of the effect in both datasets. Allele A of Hopo546333 was protective for asthma (case–control OR: 0.42; 95% CI: 0.17–0.99, P=0.042; P=0.043; families Z score=?2,236; P=0.025). Similarly, allele C of rs740347 conferred low risk for asthma (OR: 0.44; 95% CI: 0.28–0.70, P=0.00017; P_c=0.00037) and total IgE (OR: 0.29; 95% CI: 0.09–0.88, P=0.015; P_c=0.030) in the case–control study and families (Z score=?3.207, P=0.0013; Z score=?3.182, P=0.0014, respectively). Haplotype CCAGGT was associated with total IgE (OR: 1.76; 95% CI: 1.14–2.71, P=0.006, P_c=0.007) in the case–controls group and CGCGGT with both phenotypes (P=0.044 and P=0.032, respectively) in families. Neither SNPs nor haplotypes were associated with levels of mite‐specific IgE. Conclusions Our findings in a sample of asthmatics from Colombia suggest a relevant role of G protein‐coupled receptor 154 in the pathogenesis of asthma and allergy.     

Genetic effects of adiponectin single nucleotide polymorphisms on the clustering of metabolic risk factors in young Korean adults

Little is known if lifestyle-related risk factors modulate the adiponectin genetic effects on its outcome phenotypes. The aims of the study were to investigate whether the association between the adiponectin gene two SNPs (+45T>G, rs2241766 and +276G>T, rs1501299) and a clustering of metabolic risk factors is modified by both cardiorespiratory fitness (CRF) and insulin resistance in a study sample of 1,622 young Korean adults (941 men and 681 women, mean age 22.9 ± 2.4 years). The clustering of metabolic risk factors was defined as a sum of Z scores for waist circumference (WC), blood pressure (BP), triacylglycerols (TAG), high-density lipoprotein cholesterol, and fasting glucose. With respect to SNP +45T>G, the TT genotype had significantly higher values for BMI, WC, systolic BP, TAG, insulin, and a clustered risk score than did the TG+GG genotype. The genetic effect of SNP +45 on the clustered risk score remained significant even after controlling for age, sex, and smoking (P = 0.019). However, the genetic impact was no longer significant when additionally controlling for CRF (P = 0.097) and fasting insulin (P = 0.181), respectively. With respect to SNP +276G>T, the GT+TT genotypes had significantly higher values for BMI and TAG than did the TT genotype. In summary, the present findings suggest that the SNPs at position +45 and +276 are associated with several of metabolic risk factors; however, the genetic effect of SNP +45T/G variant on the clustered risk score is modulated by both CRF and insulin resistance.     

Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A₁>A₂, rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital‐based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A₁GCG and A₂CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A₁GCG), the haplotype A₂CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07–1.82), while the four other haplotypes A₁CCG (OR, 0.60; 95% CI, 0.45–0.79), A₂GCG (OR, 0.53; 95% CI, 0.35–0.81), A₁GTG (OR, 0.31; 95% CI, 0.15–0.64), and A₁GCA (OR, 0.19; 95% CI, 0.07–0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population. Hum Mutat 0, 1–9, 2009. © 2009 Wiley‐Liss, Inc.     

Vascular Endothelial Growth Factor Gene Polymorphisms May Predict the Risk of Acute Graft-versus-Host Disease following Allogeneic Transplantation: Preventive Effect of Vascular Endothelial Growth Factor Gene on Acute Graft-versus-Host Disease

Microvessel injury is associated with the development of graft-versus-host disease (GVHD), whereas high levels of posttransplantation vascular endothelial growth factor (VEGF) have a protective effect on severe acute GVHD (aGVHD) and transplantation-related mortality. The current study aimed to determine the impact of VEGFA gene single-nucleotide polymorphisms (SNPs) on the risk of aGVHD after allogeneic stem cell transplantation (SCT). Using polymerase chain reaction and restriction fragment length polymorphism, 4 VEGFA SNPs— -2578 C>A (rs699947), -460 T>C (rs833061), +405 G>C (rs2010963), and +936 C>T (rs3025039)—were analyzed in 98 recipients. Strong linkage disequilibrium was noted among loci -2578, -460, and +405, but not among these loci and locus +936. Accordingly, 4 haplotypes were generated based on the genotypes of -2578, -460, and +405: CTC (47.9%), CTG (26.7%), ACG (24.2%), and CCC (1.0%). The group with low VEGF production (ie, +936CT genotype and 2 copies of the ACG haplotype) had a higher incidence of aGVHD. Significant associations were found between the risk of grade 2-4 aGVHD and the +936 CT (P = .006), -2578 AA (P = .003), and -460 CC (P = .002) genotypes and the ACG haplotype (P = .003). No association between the VEGFA SNPs and chronic GVHD was observed. The VEGFA SNPs might predict a lower risk of aGVHD. Our findings suggest that VEGF may have a protective role in the pathogenesis of aGVHD.     

Genetic polymorphisms of the T-cell coreceptors CD28 and CTLA-4 in Afro- and Euro-Brazilians

CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are two receptors that have complementary functions in control of T-cell activation. Polymorphisms of their genes, CD28 and CTLA4, might confer differential susceptibility to diseases resulting from unbalanced or inefficient immune responses. Thus far, little is known about the CD28 polymorphism in populations and even for CTLA4 just one or two single nucleotide polymorphisms (SNPs) are usually analysed. To assess the allelic and haplotypic diversity and linkage disequilibrium in the Brazilian population, two samples differing according to predominant ancestry – African or European – have been analysed for seven SNPs, CD28 −372(G>A), and int3 17(T>C); CTLA4 −1722(T>C), −1577(G>A) −318(C>T), 49(A>G), 6230(G>A) also named CT60, and three microsatellites, CD28 (CAA)n, CTLA4 (AT)n and D2S72 (CA)n. The two population strata show little differentiation, the only significant differences being the allele frequencies of the CTLA4 −1577(G>A) SNP and the CTLA4 (AT)n microsatellite (P = 0.018 and P = 0.007, respectively). Linkage disequilibrium is high, especially between the CTLA4 polymorphisms. However, low r² values indicate that none of the markers is a tag SNP in these populations. These results provide valuable information for optimal selection of markers for use in future association studies. We conclude that disease association studies and functional studies addressing the possible consequences of polymorphisms of the 2q33 genomic region should consider haplotypic data besides analysis of individual polymorphisms.     

Combined effect of tumour necrosis factor-α and interleukin-13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma

Background TNF‐α and IL‐13, two pivotal pro‐inflammatory cytokines, are increased in asthmatic airways and may be linked to asthma susceptibility and/or bronchial hyperresponsiveness (BHR). Objective We investigated the association between the TNF‐α?308G/A polymorphism and asthma susceptibility or asthma‐related phenotypes in Korean children with asthma, and tested for a combined effect with IL‐13 polymorphisms. Methods Asthmatic children (n=719) and non‐atopic healthy control children (n=243) were evaluated for asthma phenotypes including total serum IgE and BHR to methacholine. Genotypes were determined by PCR‐restriction fragment length polymorphism analysis. Results The allele frequency of TNF‐α?308A in asthmatics (14.1%) was higher than that in control children [8.7%, odds ratio (OR) 1.72, 95% confidence interval (CI) 1.05–2.82]. Significantly lower PC₂₀ values were found in asthmatic children carrying one or two copies of the TNF‐α risk allele (?308A) vs. those homozygous for the common allele (P=0.026). Combined analysis revealed that atopic asthmatic children co‐inherited the risk alleles of TNF‐α?308G/A and IL‐13 +2044G/A more frequently than control children (aOR 1.91, 95% CI 1.00–3.65), and asthmatic children co‐inheriting both risk alleles had significantly lower PC₂₀ values vs. asthmatic children homozygous for the common alleles (P=0.024). Conclusion The TNF‐α promoter polymorphism (?308G/A) may be associated with asthma susceptibility and BHR in Korean children with asthma. In addition, there appears to be a synergistic effect between the TNF‐α promoter polymorphism and an IL‐13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.     

Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation

NOX enzymes are reactive oxygen species (ROS)‐generating NADPH oxidases. Several members of the NOX family depend on the p22^phox subunit, encoded by the CYBA gene. CYBA is highly polymorphic, and has been widely studied as a potential risk factor for various diseases, with conflicting results. In the present study, we used Epstein‐Barr (EBV)‐transformed B‐lymphocytes from 50 healthy unrelated individuals to analyze their CYBA mRNA sequence and NOX2‐dependent ROS generation. Seven single‐nucleotide polymorphisms (SNPs) were identified (five previously described, two novel). The combination of these SNPs yielded 11 distinct haplotypes, which could be grouped into seven haplogroups (A–G). Haplogroup C (c.214T>C, c.521T>C, and c.^*24G>A) showed a significantly lower ROS generation, as compared to the most frequent haplogroup, A. CYBA variants from the seven haplogroups were transduced into p22^phox‐deficient B‐lymphocytes. The haplogroup C variant showed significantly lower ROS production. c.214T>C and c.521T>C lead to nonsynonymous codon changes, while c.^*24G>A lies within the 3′UTR. Using a luciferase/3′UTR construct, we showed that the ^*24A allele led to decreased reporter gene activity. These results help to unravel the complex nature of how genetic variations in CYBA influence NOX2 activity, and indicate that haplotypes, rather than individual SNPs, define the effect on ROS generation. Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

CRP and FCGR2A genes have an epistatic effect on carotid artery intima‐media thickness: the Cardiovascular Risk in Young Finns Study

The role of the inflammatory mediator C‐reactive protein (CRP) in atherosclerosis is recognized although its specific functions are not entirely clear. CRP binds to the Fcγ receptor2A (FcγR2A) and its polymorphism, FCGR2A (Arg131His), strongly influences the binding. We wanted to evaluate the CRP‐mediated proatherogenic process on early atherosclerosis and investigated whether CRP and FCGR2A show an interactive effect on carotid intima‐media thickness (IMT). Polymorphisms of FCGR2A (Arg131His) and CRP (–717A > G, –286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped and their effects on IMT were analyzed in 2260 young adults participating in the Cardiovascular Risk in Young Finns Study. CRP haplotypes were constructed based on the CRP polymorphisms. The FCGR2A(Arg131His) polymorphism did not have an independent effect on IMT but a significant gene‐gene interaction, epistasis, between FCGR2A and CRP genetics on IMT was found. The epistatic effect was seen in men at haplotype and genotypic level; both CRP haplotype GCGCG (–717, –286, +1059, +1444 and +1846) and CRP–717A > G polymorphism interacted with FCGR2A(Arg131His) on IMT. After adjustment with classical risk factors the P‐values for interaction were P = 0.013 and P = 0.010, respectively. No associations were observed in women. In conclusion, this study showed that the effect of CRP genetics on early atherosclerotic changes is modulated by the FCGR2A genetics.     

IL33 and IL1RL1 variants are associated with asthma and atopy in a Brazilian population

Atopic asthma is a chronic inflammatory disease in airways resulting from genetic and environmental factors, characterized by production of the Th2 cytokines interleukin‐4 (IL‐4), interleukin‐5 (IL‐5) and interleukin‐13 (IL‐13). Interleukin‐33 (IL‐33) appears to be a potent inducer of Th2 immune response. This occurs when IL‐33 binds and activates its receptor, the membrane ST2 (ST2L) in mast cells, dendritic cells, basophils, eosinophils, innate lymphoids and Th2 cells, leading to the release of these cytokines and intensifying allergic inflammation. Polymorphisms in the IL33 and IL1RL1 can act as protective or risk factors for asthma and/or allergy in humans. No study was conducted to replicate such findings in a European and African descendent mixed population. DNA was extracted from peripheral blood from 1223 subjects, and the samples were genotyped using Illumina 2.5 Human Omni Beadchip. We tested for possible associations between SNPs in the IL33 and ST2 with asthma and allergy markers such as specific IgE (sIgE), IL‐5 and IL‐13 production and skin prick test (SPT). Logistics regressions were performed using PLINK software 1.07. The analyses were adjusted for sex, age, helminth infection and ancestry markers. The G allele of IL33 SNP rs12551256 was negatively associated with asthma (OR 0.71, 95% CI: 0.53–0.94, P = 0.017). In contrast, the A allele of IL1RL1 rs1041973 was positively associated with IL‐5 production (OR 1.36, 95% CI: 1.09–1.84, P = 0.044), sIgE levels (OR 1.40, 95% CI: 1.07–1.84, P = 0.013) and positive SPT (OR 1.48, 95% CI: 1.08–2.03, P = 0.014), for Blomia tropicalis mite. The same allele, in atopic subjects, was associated with decreased production of soluble ST2 (sST2) (P < 0.05). Moreover, expression quantitative trait loci (eQTL) analysis suggests that rs1041973 and rs873022 regulate the expression of IL1RL1 gene. This latest SNP, rs873022, the T allele, was also associated with a lower production of sST2 in plasma of Brazilians. The genetic risk score for rs1041973 and rs16924161 demonstrated a higher risk for SPT positivity against B. tropicalis, the greater the number of risk alleles for both SNPs. Our findings demonstrate a robust association of genetic variants in IL1RL1 and IL33 SNPs with allergy markers and asthma.     

Asthma and IL‐4 receptor alpha gene variants

Linkage of allergy to chromosome 16 has been described in several studies, together with a positive association with interleukin 4 receptor α gene variants. Our aim was to replicate these findings in a sample of German and Swedish families recruited through sib‐pairs affected by bronchial asthma. None of the markers showed linkage with the main phenotype of asthma or with total serum IgE. Seropositivity to D. pteronyssinus showed borderline significance in a region flanking the IL4Rα location. Single nucleotide polymorphisms (SNPs) leading to the protein exchanges I50V, E375A, C406R, S478P and Q551R in the IL‐4 receptor α were examined for allele sharing in sibs with asthma. Multiple regression analysis was performed for association with total serum IgE and specific IgE. Allele sharing of IL4Rα SNPs in asthmatic children was not significantly increased for any of the examined SNPs except for the intracytoplasmatic polymorphism 551R (0.79 vs. 0.84 expected, P = 0.044). The variants 50V, 478P and 551R were associated with slightly increased, and 375A and 406R with decreased total IgE levels, all at a non‐significant level. None of the examined IL4Rα variants were correlated to asthma severity. In summary, a single gene effect of IL4Rα variants or any other gene on chromosome 16 could not be shown in this selected population of children with asthma. As there could be interactions with multiple genetic and environmental factors, IL4Rα could still be involved in asthma pathogenesis.     

FcεRIα gene (FCER1A) promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients

Two promoter polymorphisms of the high-affinity IgE receptor α-subunit (FcεRIα) gene (FCER1A), −66T>C (rs2251746) and −315C>T (rs2427827), were analysed in Japanese atopic dermatitis subjects. Patients with the −315CT/TT genotype tended to have higher total serum IgE levels, while the proportion of −315CT/TT genotype or the −315T allele was significantly higher in those with highly elevated total serum IgE concentrations.     

SIRT1 gene polymorphisms are associated with nondiabetic type 1 cardiorenal syndrome

Type 1 cardiorenal syndrome (CRS1) is characterized by acute cardiac disease (e.g., acute heart failure [AHF]), leading to acute kidney injury. Sirtuin 1 (SIRT1), an NAD⁺‐dependent deacylase, has been found to be associated with CRS1. To confirm whether a correlation exists between SIRT1 variants and the risk of CRS1, the association between the prevalence of CRS1 and single‐nucleotide polymorphisms (SNPs) within the SIRT1 gene was investigated in AHF patients. A total of 316 Chinese AHF participants (158 patients with CRS1 and 158 age‐ and sex‐matched controls) were recruited for the present observational study to investigate the association between nine common SIRT1 SNPs (i.e., rs7895833 G > A, rs10509291 T > A, rs3740051 A > G, rs932658 A > C, rs33957861 C > T, rs7069102 C > G, rs2273773 T > C, rs3818292 A > G, and rs1467568 A > G) and the susceptibility to CRS1. Significant differences in genotype distribution between the control and CRS1 groups were found for rs7895833 and rs1467568. After applying a Bonferroni adjustment, the A allele of rs7895833 was still found to be protective (p = 0.001; odds ratio [OR] = 0.77) against CRS1 in this study population. The AA genotype of rs7895833 and the GA genotype of rs1467568 were associated with a significantly reduced risk of CRS1 (OR = 0.23 and 0.49, respectively). rs7895833 and rs1467568 were further analyzed as a haplotype, and the GA haplotype (rs7895833‐rs1467568) exhibited a significant association with CRS1 (p = 0.008), while the AA haplotype showed a significant protective effect (p = 0.022). Our study showed that SIRT1 rs7895833 and rs1467568 polymorphisms had a significant effect on the risk of developing CRS1 in a population in China.