Independent European Populations Research Articles

Evaluating the Efficacy of Type 2 Diabetes Polygenic Risk Scores in an Independent European Population.

Numerous type 2 diabetes (T2D) polygenic risk scores (PGSs) have been developed to predict individuals' predisposition to the disease. An independent assessment and verification of the best-performing PGS are warranted to allow for a rapid application of developed models. To date, only 3% of T2D PGSs have been evaluated. In this study, we assessed all (n = 102) presently published T2D PGSs in an independent cohort of 3718 individuals, which has not been included in the construction or fine-tuning of any T2D PGS so far. We further chose the best-performing PGS, assessed its performance across major population principal component analysis (PCA) clusters, and compared it with newly developed population-specific T2D PGS. Our findings revealed that 88% of the published PGSs were significantly associated with T2D; however, their performance was lower than what had been previously reported. We found a positive association of PGS improvement over the years (p-value = 8.01 × 10-4 with PGS002771 currently showing the best discriminatory power (area under the receiver operating characteristic (AUROC) = 0.669) and PGS003443 exhibiting the strongest association PGS003443 (odds ratio (OR) = 1.899). Further investigation revealed no difference in PGS performance across major population PCA clusters and when compared with newly developed population-specific PGS. Our findings revealed a positive trend in T2D PGS performance, consistently identifying high-T2D-risk individuals in an independent European population.

Kidney stone disease and cardiovascular events: a study on bidirectional causality based on mendelian randomization.

BackgroundKidney stone disease (KSD) has been reported to be associated with several cardiovascular diseases. However, the causality between the conditions remains unknown. In the study, we performed a study on bidirectional causality by two-sample Mendelian randomization (MR) to investigate the causality between KSD and cardiovascular diseases including coronary atherosclerosis, hypertension, and cardiomyopathy.MethodsIn the recent study, we performed a bidirectional two-sample MR study using available genome-wide association summary data from the online database MRBASE. We identified genetic variants associated with KSD in one European population from UK Biobank (version 2, n=462,933). Two phenotypes of samples were chosen from the population to define our genetic instrumental variables: (I) samples with the phenotype of kidney stone/ureter stone/bladder stone (ukb-b-8297), and (II) samples with the phenotype of kidney stone surgery/lithotripsy (ukb-b-13537). For cardiovascular diseases, we picked up another independent European population from FinnGen Biobank (n=93,421). We selected the exposure and outcome SNPs and then performed the two-sample MR using R package.ResultsAfter bidirectional causality by two-sample MR, we verified that genetic predisposition to KSD could increase the risk of coronary atherosclerosis (OR: 4.45×1037; SE=±7.80×1014, P for MR-Egger =0.024) and cardiomyopathy (OR: 5.35×1013; SE=±7.18×106, P for IVW=0.045 for finn-a-I9_CARDMYO, and OR: 3.60×1025; SE=±3.26×1012, P for IVW=0.041 for finn-a-I9_CARDMYOOTH) when we used ukb-b-13537 as exposure group. Furthermore, hypertension could increase the risk of KSD (OR: 1.001; SE=±1.00, P for IVW=0.003) when we used ukb-b-8297 as exposure group, without detected pleiotropy bias (P>0.05).ConclusionsWe confirmed KSD may trigger causal pathological processes including coronary atherosclerosis and cardiomyopathy. Furthermore, hypertension may causally affect KSD.

Risk of lower respiratory tract infections: a genome-wide association study with Mendelian randomization analysis in three independent European populations

ObjectiveLower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality worldwide. Few studies have previously investigated genetic susceptibility and potential risk factors for LRTI. MethodsWe used data from the UK Biobank, Trøndelag Health Study (HUNT), and FinnGen to conduct a genome-wide association study (GWAS). Cases were subjects hospitalized with LRTI, and controls were subjects with no such hospitalization. We conducted stratification and interaction analyses to evaluate whether the genetic effect of LRTI differed by sex or smoking. Mendelian randomization (MR) analyses were conducted to identify the unconfounded relationship between cardiometabolic risk factors and LRTI. ResultsA total of 25 320 cases and 575 294 controls were included. The 15q25.1 locus reached genome-wide significance in the meta-analysis (rs10519203: OR 0.94, p 3.87e-11). The protective effect of effect allele of rs10519203 was present among smokers (OR 0.90, 95%CI 0.87–0.92, p 1.38e-15) but not among never-smokers (OR 1.01, 95%CI 0.97–1.06, p 5.20e-01). In MR analyses, we found that increasing body mass index (OR 1.31, 95%CI 1.24–1.40, p 3.78e-18), lifetime smoking (OR 2.83, 95%CI 2.34–3.42, p 6.56e-27), and systolic blood pressure robustly increased the risk of LRTIs (OR 1.11, 95%CI 1.02–1.22, p 1.48e-02). ConclusionA region in 15q25.1 was strongly associated with LRTI susceptibility. Reduction in the prevalence of smoking, overweight, obesity, and hypertension may reduce the disease burden of LRTIs.

Self-rated health in individuals with and without disease is associated with multiple biomarkers representing multiple biological domains

Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual’s subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.

IgG glycan patterns are associated with type 2 diabetes in independent European populations

BackgroundType 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N-glycan patterns in type 2 diabetes with healthy subjects. MethodsIn the DiaGene study, a population-based case-control study, (1886 cases and 854 controls) 58 IgG glycan traits were analyzed. Findings were replicated in the population-based CROATIA-Korcula-CROATIA-Vis-ORCADES studies (162 cases and 3162 controls), and meta-analyzed. AUCs of ROC-curves were calculated using 10-fold cross-validation for clinical characteristics, IgG glycans and their combination. ResultsAfter correction for extensive clinical covariates, 5 IgG glycans and 13 derived traits significantly associated with type 2 diabetes in meta-analysis (after Bonferroni correction). Adding IgG glycans to age and sex increased the AUC from 0.542 to 0.734. Adding them to the extensive model did not substantially improve the AUC. The AUC for IgG glycans alone was 0.729. ConclusionsSeveral IgG glycans and traits firmly associate with type 2 diabetes, reflecting a pro-inflammatory and biologically-aged state. IgG glycans showed limited improvement of AUCs. However, IgG glycans showed good prediction alone, indicating they may capture information of combined covariates. The associations found may yield insights in type 2 diabetes pathophysiology. General significanceThis work shows that IgG glycomic changes have biomarker potential and may yield important insights into pathophysiology of complex public health diseases, illustrated here for the first time in type 2 diabetes.

Genetic variants in ALDH1B1 and alcohol dependence risk in a British and Irish population: A bioinformatic and genetic study.

Alcohol is metabolized in the liver via the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Polymorphisms in the genes encoding these enzymes, which are common in East Asian populations, can alter enzyme kinetics and hence the risk of alcohol dependence and its sequelae. One of the most important genetic variants, in this regards, is the single nucleotide polymorphism (SNP) rs671 in ALDH2, the gene encoding the primary acetaldehyde metabolizing enzyme ALDH2. However, the protective allele of rs671 is absent in most Europeans although ALDH1B1, which shares significant sequence homology with ALDH2, contains several, potentially functional, missense SNPs that do occur in European populations. The aims of this study were: (i) to use bioinformatic techniques to characterize the possible effects of selected variants in ALDH1B1 on protein structure and function; and, (ii) to genotype three missense and one stop-gain, protein-altering, non-synonymous SNPs in 1478 alcohol dependent cases and 1254 controls of matched British and Irish ancestry. No significant allelic associations were observed between the three missense SNPs and alcohol dependence risk. The minor allele frequency of rs142427338 (Gln378Ter) was higher in alcohol dependent cases than in controls (allelic P = 0.19, OR = 2.98, [0.62–14.37]) but as this SNP is very rare the study was likely underpowered to detect an association with alcohol dependence risk. This potential association will needs to be further evaluated in other large, independent European populations.

Rumination in migraine: Mediating effects of brooding and reflection between migraine and psychological distress

Objective: The relationship between migraine and psychological distress has been consistently reported in cross-sectional and longitudinal studies. We hypothesised that a stable tendency to perseverative thoughts such as rumination would mediate the relationship between migraine and psychological distress.Design and Main Outcomes Measures: Self-report questionnaires measuring depressive rumination, current psychological distress and migraine symptoms in two independent European population cohorts, recruited from Budapest (N = 1139) and Manchester (N = 2004), were used. Structural regression analysis within structural equation modelling was applied to test the mediational role of brooding and reflection, the components of rumination, between migraine and psychological distress. Sex, age and lifetime depression were controlled for in the analysis.Results: Migraine predicted higher brooding and reflection scores, and brooding proved to be a mediator between migraine and psychological distress in both samples, while reflection mediated the relationship significantly only in the Budapest sample.Conclusions: Elevated psychological distress in migraine is partially attributed to ruminative response style. Further studies are needed to expand our findings to clinical samples and to examine how rumination links to the adjustment to migraine.

Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis.

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10−49); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations – BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10−4 for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10−3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10−6). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.

Analysis of the role of interleukin 6 receptor haplotypes in the regulation of circulating levels of inflammatory biomarkers and risk of coronary heart disease.

Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T—block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C—block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation.

Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans

ObjectivesGenome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.MethodsA cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.ResultsSignificant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10−9).ConclusionsThis study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

Discovery, Validation and Characterization of Erbb4 and Nrg1 Haplotypes Using Data from Three Genome-Wide Association Studies of Schizophrenia

Schizophrenia is one of the most common and complex neuropsychiatric disorders, which is contributed both by genetic and environmental exposures. Recently, it is shown that NRG1-mediated ErbB4 signalling regulates many important cellular and molecular processes such as cellular growth, differentiation and death, particularly in myelin-producing cells, glia and neurons. Recent association studies have revealed genomic regions of NRG1 and ERBB4, which are significantly associated with risk of developing schizophrenia; however, inconsistencies exist in terms of validation of findings between distinct populations. In this study, we aim to validate the previously identified regions and to discover novel haplotypes of NRG1 and ERBB4 using logistic regression models and Haploview analyses in three independent datasets from GWAS conducted on European subjects, namely, CATIE, GAIN and nonGAIN. We identified a significant 6-kb block in ERBB4 between chromosome locations 212,156,823 and 212,162,848 in CATIE and GAIN datasets (p = 0.0206 and 0.0095, respectively). In NRG1, a significant 25-kb block, between 32,291,552 and 32,317,192, was associated with risk of schizophrenia in all CATIE, GAIN, and nonGAIN datasets (p = 0.0005, 0.0589, and 0.0143, respectively). Fine mapping and FastSNP analysis of genetic variation located within significantly associated regions proved the presence of binding sites for several transcription factors such as SRY, SOX5, CEPB, and ETS1. In this study, we have discovered and validated haplotypes of ERBB4 and NRG1 in three independent European populations. These findings suggest that these haplotypes play an important role in the development of schizophrenia by affecting transcription factor binding affinity.

NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis

Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of NIPA1 have been associated with a higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role of genetic variation in NIPA1 in ALS susceptibility and disease course is, however, not known. We sequenced the entire coding sequence of NIPA1 and genotyped a polyalanine repeat located in the first exon of NIPA1. A total of 2292 ALS patients and 2777 controls from three independent European populations were included. We identified two sequence variants that have a potentially damaging effect on NIPA1 protein function. Both variants were identified in ALS patients; no damaging variants were found in controls. Secondly, we found a significant effect of 'long' polyalanine repeat alleles on disease susceptibility: odds ratio = 1.71, P = 1.6 × 10(-4). Our analyses also revealed a significant effect of 'long' alleles on patient survival [hazard ratio (HR) = 1.60, P = 4.2 × 10(-4)] and on the age at onset of symptoms (HR = 1.37, P = 4.6 × 10(-3)). In patients carrying 'long' alleles, median survival was 3 months shorter than patients with 'normal' genotypes and onset of symptoms occurred 3.6 years earlier. Our data show that NIPA1 polyalanine repeat expansions are a common risk factor for ALS and modulate disease course.

High-Density SNP Mapping of the HLA Region Identifies Multiple Independent Susceptibility Loci Associated with Selective IgA Deficiency

Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10−57; OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10−17; OR = 4.28) and the DRB1*1501 (combined P = 2.24×10−35; OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.

Genome-wide association of anthropometric traits in African- and African-derived populations

Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations.

Variance of the SGK1 Gene Is Associated with Insulin Secretion in Different European Populations: Results from the TUEF, EUGENE2, and METSIM Studies

HypothesisSerum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans.MethodsThree independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals.ResultsCarriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUCC-Peptide/AUCGlc ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMI×rs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI≤25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUCIns/AUCGlc (TT: 226±7, XG: 246±9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71–1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers.ConclusionsThe rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

An Apolipoprotein A-I Gene Promoter Polymorphism Associated with Cognitive Decline, but Not with Alzheimer’s Disease

Background/Aims: Accumulating biological and epidemiological evidence suggests a close link between cholesterol metabolism and the pathophysiology of Alzheimer’s disease (AD). The observation that the use of statins reduces the risk of AD sustains this hypothesis. Apolipoprotein A-I (APOA1) is the major component of the high-density lipoproteins, particles involved in reverse cholesterol transport. Therefore, genetic polymorphisms in the gene encoding APOA1 might influence cholesterol metabolism and be a risk factor for AD. A previous study suggested an impact of a G→A polymorphism at position –75 bp in the APOA1 gene on the risk for early-onset AD and on the age at onset of the disease. We studied this polymorphism in 3 independent European population samples. Methods: Genotyping was conducted asdescribed in the previous study. Results: We were unable to show any impact of this polymorphism on the risk of AD. Conversely, subjects bearing the A allele of this polymorphism were at risk of cognitive decline. Conclusion: Our resultssuggest an impact of the G→A polymorphism at position –75 bp in the APOA1 gene on cognitive impairment, but not on the risk of AD.

A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema

IL-31 is a novel cytokine that, when overexpressed in transgenic mice, induces severe itching dermatitis resembling human eczema. We aimed to evaluate the importance of polymorphisms in the human IL-31 gene (IL31) in the genetic susceptibility to eczema. We sequenced the entire IL-31 gene, including the promoter region, and determined the haplotype structure. Single nucleotide polymorphisms tagging the main haplotypes were genotyped in 3 independent European populations comprising 690 affected families. An association analysis of IL31 gene variants with atopic and nonatopic eczema was performed. We found significant association of a common IL31 haplotype with the nonatopic type of eczema in all 3 study populations (combined P = 4.5 x 10(-5)). Analysis of PBMCs in healthy individuals revealed a strong induction IL31 mRNA expression on stimulation with anti-CD3 and anti-CD28 that was 3.8-fold higher in individuals homozygous for the risk haplotype (AA) in contrast to non-A haplotype carriers, suggesting that altered regulation of IL-31 gene expression is the disease-causing factor. Our results lend strong support to an important role of IL-31 in the pathogenesis of nonatopic eczema. This study presents the first genetic risk factor for the nonatopic type of eczema and indicates a primary role of IL-31-induced pruritus in the initiation of this disease, thus proposing a new target for the prevention and therapy of eczema.

Molecular analysis of estrogen receptor alpha gene AGATA haplotype and SNP12 in European populations: potential protective effect for cryptorchidism and lack of association with male infertility

A specific haplotype (AGATA) in the estrogen receptor alpha (ER1) gene was recently described as a new risk factor for cryptorchidism in the Japanese population. In this ethnic group, single-nucleotide polymorphism 12 (SNP12) was concluded to be the tag SNP for the AGATA haplotype. A large group of patients (total number=335) and controls (total number=567) of two Caucasian populations were analysed for the AGATA haplotype and SNP12 to verify whether this genetic variant and its tag SNP were associated with cryptorchidism or with severe spermatogenic failure. We confirm that SNP12 is the tag SNP for the AGATA haplotype also in Caucasians. However, in contrast with the Japanese population we found a protective effect for ESR1 SNP12 on cryptorchidism in the Italian population. No association between SNP12 and severe spermatogenic disturbances was observed. The observed associations (although with opposite effect) with cryptorchidism encourage future studies on independent cases and controls from different ethnic and geographic origins. On the other hand, in contrast with other ESR1 polymorphisms, SNP12 polymorphism is not associated with severe male factor infertility in two independent European population.