Identification and Replication of Six Loci Associated With Gallstone Disease.

Gallstone disease is a common complex disease that confers a substantial economic burden on society. The genetic underpinnings of gallstone disease remain incompletely understood. We aimed to identify genetic associations with gallstone disease using publicly available data from the UK Biobank and two large Danish cohorts. We extracted genetic associations with gallstone disease from the Global Biobank Engine (GBE), an online browser of genome-wide associations in UK Biobank participants (14,940 cases and 322,268 controls). Significant associations (P < 5 × 10-8 ) were retested in two Copenhagen cohorts (comprising 1,522 cases and 18,266 controls). In the Copenhagen cohorts, we also tested whether a genetic risk score was associated with gallstone disease and whether individual gallstone loci were associated with plasma levels of lipids, lipoproteins, and liver enzymes. We identified 19 loci to be associated with gallstone disease in the GBE. Of these, 12 were replicated in the Copenhagen cohorts, including six previously unknown loci (in hepatocyte nuclear factor 4 alpha [HNF4A], fucosyltransferase 2, serpin family A member 1 [SERPINA1], jumonji domain containing 1C, AC074212.3, and solute carrier family 10A member 2 [SLC10A2]) and six known loci (in adenosine triphosphate binding cassette subfamily G member 8 [ABCG8], sulfotransferase family 2A member 1, cytochrome P450 7A1, transmembrane 4 L six family member 4, ABCB4, and tetratricopeptide repeat domain 39B). Five of the gallstone associations are protein-altering variants, and three (HNF4A p.Thr139Ile, SERPINA1 p.Glu366Lys, and SLC10A2 p.Pro290Ser) conferred per-allele odds ratios for gallstone disease of 1.30-1.36. Individuals with a genetic risk score >2.5 (prevalence 1%) had a 5-fold increased risk of gallstones compared to those with a score <1.0 (11%). Of the 19 lithogenic loci, 11 and ten exhibited distinct patterns of association with plasma levels of lipids and liver enzymes, respectively. Conclusion: We identified six susceptibility loci for gallstone disease.

Association of Blood Eosinophil and Blood Neutrophil Counts with Asthma Exacerbations in the Copenhagen General Population Study.

BACKGROUND: Blood eosinophil count is a marker of eosinophilic airway inflammation and disease severity in asthma. However, blood neutrophil count might also be associated with disease severity. We tested the hypothesis that high blood eosinophil and neutrophil counts are both associated with the risk of asthma exacerbations among individuals with asthma from the general population. METHODS: From the Copenhagen General Population Study with 81351 participants, we included 4838 with self-reported asthma. We recorded baseline blood eosinophil and neutrophil counts, and asthma exacerbations during follow-up in 2003-2011, defined as moderate (short-course treatment of prednisolone) or severe (hospitalization). RESULTS: The multivariable-adjusted incidence rate ratios (IRRs) were 1.28 (95% CI, 1.06-1.55) for moderate exacerbations and 1.55 (1.20-2.00) for severe exacerbations for individuals with blood eosinophil counts >0.29 × 109/L (highest tertile) vs individuals with blood eosinophil counts <0.18 × 109/L (lowest tertile). For blood neutrophils, the multivariable-adjusted IRRs were 2.14 (1.74-2.63) for moderate exacerbations and 1.18 (0.89-1.55) for severe exacerbations for individuals with blood neutrophil counts >4.85 × 109/L (highest tertile) vs individuals with blood neutrophil counts <3.77 × 109/L (lowest tertile). Blood eosinophil and neutrophil counts interacted on moderate exacerbations (P = 3 × 10-4), but not on severe exacerbations. CONCLUSIONS: High blood eosinophil counts are associated with an increased risk of both moderate and severe asthma exacerbations, while high blood neutrophil counts are associated with an increased risk of moderate, but not severe exacerbations.

Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of ß = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.