Regression mapping of association between the human leukocyte antigen region and Graves' disease

The human leukocyte antigen class II genes DRB1, DQB1, and DQA1 are associated with Graves disease (GD), but, because of strong linkage disequilibrium within this region, the primary etiological variant(s) remains unknown. In the present study, 871 patients with GD and 621 control subjects were genotyped at the DRB1, DQB1, and DQA1 loci. All three loci were associated with GD (P = 1.45 x 10-12, P = 3.20 x 10-5, and P = 9.26 x 10-12, respectively). Stepwise logistic-regression analysis showed that the association could be explained by either DRB1 or DQA1 but not by DQB1. To extend previous results, the amino acid sequence of the exon 2-encoded peptide-binding domain of DRB1 was predicted for each subject, and, by use of logistic regression, each position was analyzed for association with GD. Of 102 amino acids, 70 were uninformative; of the remaining 32 amino acids, 13 were associated with GD (P values ranged from 2.20x10-4 to 1.2x10-12). The strongest association was at position B74. This analysis is consistent with the possibility that position B74 of exon 2 of the DRB1 molecule may have a specific and central role in autoantigen presentation by DRB1 to T lymphocytes. However, we cannot yet exclude a primary role for DQA1 or for other polymorphisms that affect DRB1 function or expression

Global SGD and CO2 data

<p>This dataset is a global compilation of 40 coastal ecosystems across 14 countries. It consists of continuous time series for carbon dioxide and radon. Other parameters included are latitude, longitude, depth, temperature, salinity, dissolved oxygen, and water-air flux for carbon dioxide. Timestamps of each measurement correspond to the local time zone. Carbon dioxide and radon were measured using Licor and RAD7, respectively. Depth, temperature, salinity, and dissolved oxygen were measured using probes. This dataset was used to interpret the impact of SGD on CO2 dynamics in globally distributed coastal ecosystems. </p> <p>Data sources are mentioned in the sheet References. </p> <p>Column names in the "Master File" sheet: </p> <ul> <li>Location: Name of the location of measurement</li> <li>Location ID: ID of the location </li> <li>Country: Country of location </li> <li>Ecosystem Type: categorical ecosystem type </li> <li>Latitude: Latitudinal coordinate of the location (DD)</li> <li>Longitude: Longitudinal coordinate of the location (DD)</li> <li>Date (DD/MM/YYYY): Date when the measurement was taken (DD/MM/YYYY)</li> <li>Time (hh:mm): Local time of when the measurement was taken</li> <li>Time since start (Days): Duration of the continuous measurement since the first measurement was started (days)</li> <li>Wind Speed (m/s): Wind speed at the location at the time of measurement</li> <li>Depth (m): Depth at which the measurement was taken (m)</li> <li>Temperature (°C): Temperature at the point of radon/carbon dioxide measurement</li> <li>Salinity: Salinity of water at the point of radon/carbon dioxide measurement</li> <li>DO (%): Dissolved oxygen in the water at the point where radon measurement was taken (%)</li> <li>Radon (dpm/L): Radon measurement in water (dpm/L). Measured using Durridge RAD7 </li> <li>CO2 (µatm) at sst: measurement of Carbon Dioxide dissolved in water at sea surface temperature (µatm). Measured using LiCor.  </li> <li>Water-air CO2 flux (mmol m-2 day-1): Calculated water-air flux of carbon dioxide. </li> </ul&gt

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR