Genetic analysis of over half a million people characterises C-reactive protein loci.
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ABSTRACT:
SUBMITTER: Said S
PROVIDER: S-EPMC9033829 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
| S-EPMC6284793 | biostudies-literature
Project description:Background: The association between smoking and blood pressure (BP) has been explored extensively, yet the results remain inconclusive. Using real-world evidence of a large Chinese population, we examine the effect of smoking on BP levels. Methods: We utilize half a million adults from the China Kadoorie Biobank (CKB) study with baseline sampling collected between 2004 and 2008. Multivariable linear regression analyses are used to estimate linear regression coefficients of smoking for systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results: 459,815 participants (180,236 males and 279,579 females) are included in the analysis. Regular smoking is significantly associated with lower SBP (-0.57 mm Hg, p < 0.001) and DBP (-0.35 mm Hg, p < 0.001) when compared with non-smoking in men. Additionally, SBP and DBP decrease significantly among all groups of different smoking status in women (p < 0.001). Additionally, pack-years show negative associations with SBP and DBP in both men and women. Further analysis shows the interaction of smoking and alcohol consumption is associated with an increase of SBP and DBP (men: 2.38 mm Hg and 0.89 mm Hg; women: 5.21 mm Hg and 2.62 mm Hg) among co-regular smokers and regular drinkers when compared with regular smokers who are not exposed to alcohol consumption. Conclusions: A negative association between smoking and BP is observed. However, the interaction between smoking and alcohol consumption is associated with BP increase. The findings suggest the importance of considering smoking and alcohol consumption in BP control in addition to antihypertensive treatment in clinical and public health practice.
| S-EPMC7215755 | biostudies-literature
Project description:Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
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Project description:Evidence for Quaternary climate change in East Africa has been derived from outcrops on land and lake cores and from marine dust, leaf wax, and pollen records. These data have previously been used to evaluate the impact of climate change on hominin evolution, but correlations have proved to be difficult, given poor data continuity and the great distances between marine cores and terrestrial basins where fossil evidence is located. Here, we present continental coring evidence for progressive aridification since about 575 thousand years before present (ka), based on Lake Magadi (Kenya) sediments. This long-term drying trend was interrupted by many wet-dry cycles, with the greatest variability developing during times of high eccentricity-modulated precession. Intense aridification apparent in the Magadi record took place between 525 and 400 ka, with relatively persistent arid conditions after 350 ka and through to the present. Arid conditions in the Magadi Basin coincide with the Mid-Brunhes Event and overlap with mammalian extinctions in the South Kenya Rift between 500 and 400 ka. The 525 to 400 ka arid phase developed in the South Kenya Rift between the period when the last Acheulean tools are reported (at about 500 ka) and before the appearance of Middle Stone Age artifacts (by about 320 ka). Our data suggest that increasing Middle- to Late-Pleistocene aridification and environmental variability may have been drivers in the physical and cultural evolution of Homo sapiens in East Africa.
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Project description:Background and Aim:Post-ERCP pancreatitis (PEP) is the most common complication following endoscopic retrograde cholangiopancreatography (ERCP). It is still controversial whether the presence of a trainee would increase the risk of PEP. Additionally, the effects of demographic factors and comorbidities on the risk and severity of PEP are not fully understood. Our aim was to evaluate these factors using national database. Methods:Nationwide Inpatient Sample 2000-2014 was used to identify adult patients admitted with biliary obstruction without acute pancreatitis and had an inpatient ERCP. PEP was defined as having a subsequent diagnosis of acute pancreatitis. The presence of major organs failure marked moderate-severe PEP. Demographic information, hospital characteristics, and ERCP intervention types were collected. Results:We included 654?394 patients. Overall PEP rate was 5.4%. The PEP rate was lower in teaching (4.8%) compared with nonteaching (6.2%, P <?0.001) hospitals. The highest PEP rate was observed among patients undergoing Sphincter of Oddi Manometry (15.1%, odds ratio [OR] = 2.5, P <?0.001) as compared to diagnostic cholangiography (4.4%). Asians and Hispanics had higher rate of PEP (10% and 7.9%, respectively) compared with Caucasians and African Americans (4.9% and 5%, respectively, P <?0.001). Multivariate analysis showed that after controlling for the ERCP intervention types, Asians and Hispanics continued to have higher odds of PEP (OR = 1.3, P <?0.001). Seventeen percent of patients were classified as moderate-severe PEP. Older patients (OR = 3.2, P <?0.001), males (OR = 1.4, P <?0.001), and high comorbidities (1.3, P <?0.001) were major predictors of moderate-severe PEP. Conclusion:No evidence of higher PEP rates in teaching hospitals. Asians and Hispanics had higher PEP rates. Although ERCP intervention type is the major PEP predictor, its severity is dependent on patient characteristics.
| S-EPMC7411627 | biostudies-literature
Project description:Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.
| S-EPMC10217792 | biostudies-literature
Project description:Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.
| S-EPMC4358943 | biostudies-literature
Project description:ContextPlasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.ObjectiveTo investigate association of genetic loci with CRP levels and risk of coronary heart disease.Design, setting, and participantsWe first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.Main outcome measureRisk of coronary heart disease.ResultsPolymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.ConclusionThe lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.
| S-EPMC2803020 | biostudies-literature
Project description:BackgroundThere is a plethora of real-world data on the safety and effectiveness of direct-acting oral anticoagulants (DOACs); however, study heterogeneity has contributed to inconsistent findings. We compared the effectiveness and safety of apixaban with those of other direct-acting oral anticoagulants (DOACs) and vitamin K antagonists (VKA e.g., warfarin).MethodsA systematic review and meta-analysis was conducted retrieving data from PubMed, SCOPUS and Web of Science from January 2009 to December 2021. Studies that evaluated apixaban (intervention) prescribed for adults (aged 18 years or older) with AF for stroke prevention compared to other DOACs or VKAs were identified. Primary outcomes included stroke/systemic embolism (SE), all-cause mortality, and major bleeding. Secondary outcomes were intracranial haemorrhage (ICH) and ischaemic stroke. Randomised controlled trials and non-randomised trials were considered for inclusion.ResultsIn total, 67 studies were included, and 38 studies were meta-analysed. Participants taking apixaban had significantly lower stroke/SE compared to patients taking VKAs (relative risk (RR) 0.77, 95% confidence interval (CI) 0.64-0.93, I2 = 94%) and dabigatran (RR 0.84, 95% CI 0.74-0.95, I2 = 66%), but not to patients administered rivaroxaban. There was no statistical difference in mortality between apixaban and VKAs or apixaban and dabigatran. Compared to patients administered rivaroxaban, participants taking apixaban had lower mortality rates (RR 0.83, 95% CI 0.71-0.96, I2 = 96%). Apixaban was associated with a significantly lower risk of major bleeding compared to VKAs (RR 0.58, 95% CI 0.52-0.65, I2 = 90%), dabigatran (RR 0.79, 95% CI 0.70-0.88, I2 = 78%) and rivaroxaban (RR 0.61, 95% CI 0.53-0.70, I2 = 87%).ConclusionsApixaban was associated with a better overall safety and effectiveness profile compared to VKAs and other DOACs.
| S-EPMC9267894 | biostudies-literature
Project description:Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
| S-EPMC6713272 | biostudies-literature