Publications by authors named "Iona Y Millwood"

72 Publications

Alcohol drinking and risks of liver cancer and non-neoplastic chronic liver diseases in China: a 10-year prospective study of 0.5 million adults.

BMC Med 2021 Sep 17;19(1):216. Epub 2021 Sep 17.

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Alcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations.

Methods: The prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30-79 years recruited from ten areas during 2004-2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years' follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease.

Results: Overall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23-1.69) for liver cancer (n = 547), 1.83 (1.60-2.09) for liver cirrhosis (n = 388), 2.01 (1.77-2.28) for ALD (n = 200), 1.71 (1.35-2.16) for NAFLD (n = 198), and 1.52 (1.40-1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing (i.e., with low alcohol tolerance). After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD (2.15, 1.40-3.31) compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer (1.32, 1.01-1.72), liver cirrhosis (1.37, 1.02-1.85), and ALD (1.60, 1.09-2.33) compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers.

Conclusions: In Chinese men, alcohol intake was associated with significantly increased risks of several major chronic liver diseases, and certain drinking patterns (e.g. drinking daily, drinking without meals) may further exacerbate the disease risks.
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http://dx.doi.org/10.1186/s12916-021-02079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447782PMC
September 2021

Association of heart rate and diabetes among 0.5 million adults in the China Kadoorie biobank: Results from observational and Mendelian randomization analyses.

Nutr Metab Cardiovasc Dis 2021 07 27;31(8):2328-2337. Epub 2021 Apr 27.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China. Electronic address:

Background And Aims: Observational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults.

Methods And Results: The China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20]).

Conclusions: This study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation.
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http://dx.doi.org/10.1016/j.numecd.2021.04.015DOI Listing
July 2021

Metabolic risk factors, genetic predisposition, and risk of severe liver disease in Chinese: a prospective study of 0.5 million people.

Am J Clin Nutr 2021 08;114(2):496-504

Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China.

Background: Metabolic risk factors have been shown to be associated with severe liver disease (SLD) in Chinese populations. However, there is limited evidence on the combined impact of these factors, or the genetic variants associated with SLD.

Objectives: We examined the associations of combined metabolic risk factors with risks of SLD, both overall and by genetic predisposition to SLD.

Methods: The study population involved 486,828 participants of the prospective China Kadoorie Biobank aged 30-79 years from 10 diverse areas in China without a history of cancer or liver disease at baseline. Cox regression was used to estimate adjusted HRs for SLD associated with combined metabolic risk factors (central adiposity, physical inactivity, and diabetes) by stratum of genetic risk [assessed separately by a PNPLA3 variant (rs738409) and a BMI genetic risk score].

Results: During ∼10 years of follow-up, 3279 incident cases of SLD were recorded. The overall mean BMI was 23.8 kg/m2 (SD, 3.4 kg/m2), and 5.9% participants had diabetes. Compared with those with 3 metabolic factors, participants with 2, 1, and 0 metabolic factors had 31% (HR, 0.69; 95% CI: 0.65-0.73), 43% (HR, 0.57; 95% CI: 0.53-0.60), and 52% (HR, 0.48; 95% CI: 0.42-0.56) lower risks of SLD, respectively. For both BMI and nonalcoholic fatty liver disease variants, participants with fewer metabolic factors had a lower risk of SLD, lower levels of gamma-glutamyl transferase, and lower fatty liver index scores, in participants with low and high genetic risks (P value for interaction > 0.05).

Conclusions: In relatively lean Chinese adults, individuals with fewer metabolic risk factors had a lower relative risk of SLD and a more favorable profile of liver biomarkers across all strata of genetic risk.
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http://dx.doi.org/10.1093/ajcn/nqab099DOI Listing
August 2021

Causal effects of gallstone disease on risk of gastrointestinal cancer in Chinese.

Br J Cancer 2021 May 26;124(11):1864-1872. Epub 2021 Mar 26.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China.

Background: Gallstone disease (GSD) is associated with a higher risk of gastrointestinal (GI) cancer. However, it is unclear whether the associations are causal.

Methods: The prospective China Kadoorie Biobank (CKB) recorded 17,598 cases of GI cancer among 510,137 participants without cancer at baseline during 10 years of follow-up. Cox regression was used to estimate hazard ratios (HRs) for specific cancer by GSD status and duration. Mendelian randomisation was conducted to assess the genetic associations of GSD with specific cancer.

Results: Overall 6% of participants had symptomatic GSD at baseline. Compared with those without GSD, individuals with symptomatic GSD had adjusted HRs of 1.13 (1.01-1.29) for colorectal, 2.01 (1.78-2.26) for liver, 3.70 (2.88-4.87) for gallbladder, 2.31 (1.78-3.07) for biliary tract, and 1.38 (1.18-1.74) for pancreatic cancer. Compared with participants without GSD, the risks of colorectal, liver, gallbladder, biliary tract, and pancreatic cancer were highest during 0 to <5 years following disease diagnosis. There was evidence of genetic associations of GSD with these cancers, with odds ratios per 1-SD genetic score of 1.08 (1.05-1.11) for colorectal, 1.22 (1.19-1.25) for liver, 1.56 (1.49-1.64) for gallbladder, 1.39 (1.31-1.46) for biliary tract, and 1.16 (1.10-1.22) for pancreatic cancer. When meta-analysing the genetic estimates in CKB and UK Biobank, there was evidence of causal associations of GSD with colon cancer, gallbladder and biliary tract cancer (GBTC), and total GI cancer (RR per 1-SD: 1.05 [0.99-1.11], 2.00 [1.91-2.09], and 1.09 [1.05-1.13]).

Conclusions: GSD was associated with higher risks of several GI cancers, warranting future studies on the underlying mechanisms.
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http://dx.doi.org/10.1038/s41416-021-01325-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144569PMC
May 2021

A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic etiology with obesity.

Eur Respir J 2021 Mar 25. Epub 2021 Mar 25.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, the knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWAS in other populations are lacking.We included 100 285 subjects from China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS were performed on FEV1, FVC, FEV1/FVC in CKB. We then performed genome-wide cross-trait analysis between the lung function and obesity traits (body mass index [BMI], BMI-adjusted waist-to-hip ratio, and BMI-adjusted waist circumference) to investigate the shared genetic effects in CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in CKB and its interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with CKB using 457 756 subjects from UK Biobank (UKB) for replication and investigation of ancestry specific effect.We identified 9 genome-wide significant novel loci for FEV1, 6 for FVC and 3 for FEV1/FVC in CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important pathways, including cell proliferation, embryo and tissue development. Mendelian randomisation analysis suggested significant negative causal effect of BMI on FEV1 and on FVC in both CKB and UKB. Lung function PRSs significantly modified the effect of change-in-BMI on change-in-lung function during an average follow-up of 8 years.This large-scale GWAS of lung function identified novel loci and shared genetic etiology between lung function and obesity. Change-in-BMI might affect change-in-lung function differently according to a subject's polygenic background. These findings may open new avenue for the development of molecular-targeted therapies for obesity and lung function improvement.
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http://dx.doi.org/10.1183/13993003.00199-2021DOI Listing
March 2021

Alcohol drinking and risks of total and site-specific cancers in China: A 10-year prospective study of 0.5 million adults.

Int J Cancer 2021 08 9;149(3):522-534. Epub 2021 Mar 9.

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Alcohol drinking is associated with increased risks of several site-specific cancers, but its role in many other cancers remains inconclusive. Evidence is more limited from China, where cancer rates, drinking patterns and alcohol tolerability differ importantly from Western populations. The prospective China Kadoorie Biobank recruited >512 000 adults aged 30 to 79 years from 10 diverse areas during 2004 to 2008, recording alcohol consumption patterns by a standardised questionnaire. Self-reported alcohol consumption was estimated as grams of pure alcohol per week based on beverage type, amount consumed per occasion and drinking frequency. After 10 years of follow-up, 26 961 individuals developed cancer. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) relating alcohol consumption to incidence of site-specific cancers. Overall, 33% (n = 69 734) of men drank alcohol regularly (ie, ≥weekly) at baseline. Among male current regular drinkers, alcohol intake showed positive dose-response associations with risks of cancers in the oesophagus (655 events; HR = 1.98 [95%CI 1.79-2.18], per 280 g/wk), mouth and throat (236; 1.74 [1.48-2.05]), liver (573; 1.52 [1.31-1.76]), colon-rectum (575; 1.19 [1.00-1.43]), gallbladder (107; 1.60 [1.16-2.22]) and lung (1017; 1.25 [1.10-1.42]), similarly among never- and ever-regular smokers. After adjustment for total alcohol intake, there were greater risks of oesophageal cancer in daily drinkers than nondaily drinkers and of liver cancer when drinking without meals. The risks of oesophageal cancer and lung cancer were greater in men reporting flushing after drinking than not. In this male population, alcohol drinking accounted for 7% of cancer cases. Among women, only 2% drank regularly, with no clear associations between alcohol consumption and cancer risk. Among Chinese men, alcohol drinking is associated with increased risks of cancer at multiple sites, with certain drinking patterns (eg, daily, drinking without meals) and low alcohol tolerance further exacerbating the risks.
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http://dx.doi.org/10.1002/ijc.33538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359462PMC
August 2021

Metabolic Signatures of Genetically Elevated Vitamin D Among Chinese: Observational and Mendelian Randomization Study.

J Clin Endocrinol Metab 2021 Jul;106(8):e3249-e3260

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, China.

Context: Observational studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with favorable serum lipids and related metabolites. However, whether such observations reflect causality remains unclear.

Objective: We aimed to investigate the causal effect of elevated 25(OH)D with a detailed systemic metabolite profile in Chinese adults.

Methods: A total of 225 lipid and other metabolites were quantified in 4662 individuals in the China Kadoorie Biobank. Instrumental variable analyses were performed to test the causal associations of plasma 25(OH)D with lipids and metabolites.

Results: Higher plasma 25(OH)D was related to favorable lipid profiles in observational analyses. The genetic risk score was robustly correlated with observed 25(OH)D (beta[SE] = 3.54 [0.32]; P < 1 × 10-5, F-statistic = 122.3) and explained 8.4% of the variation in 25(OH)D in the Chinese population. For all individual metabolites, the causal estimates were not significant at the threshold P < 5 × 10-4 (multiple testing corrected). However, a Mendelian randomization (MR) estimate showed that per 1-SD increase in genetically determined 25(OH)D was suggestive of association with decreased levels of cholesterol, lipoprotein particles, and phospholipids within very small very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) (P ≤ 0.05, nominal significance). For amino acids, fatty acids, ketone bodies, glycoprotein acetyls, fatty acids, and other traits, we did not observe any significant causal association.

Conclusions: The MR analysis of metabolic data based a population-based cohort suggested a potential causal association of plasma 25(OH)D with cholesterol, lipoprotein particle, phospholipid concentrations, and total lipids within very small VLDL and IDL. Our findings highlight a long-term effect of 25(OH)D levels in maintaining healthy lipid metabolism.
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http://dx.doi.org/10.1210/clinem/dgab097DOI Listing
July 2021

Spicy food consumption and risk of gastrointestinal-tract cancers: findings from the China Kadoorie Biobank.

Int J Epidemiol 2021 03;50(1):199-211

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Previous case-control studies have reported positive associations of spicy food consumption with risks of certain gastrointestinal-tract (GI) cancers. However, there is no prospective evidence on such associations, particularly from China, where there are high incidence rates of GI cancers and spicy food is widely consumed.

Methods: The prospective China Kadoorie Biobank study recruited >512 000 adults aged 30-79 years from 10 areas in China during 2004-2008; 2350 oesophageal, 3350 stomach and 3061 colorectal incident cancer cases were recorded by 1 January 2017, after a median of 10.1 years of follow-up. Cox regression yielded adjusted hazard ratios (HRs) for each cancer associated with spicy food intake.

Results: Overall, 30% of participants reported daily spicy food consumption at baseline. Spicy food consumption was inversely associated with oesophageal cancer risk, with adjusted HRs of 1.00, 0.88, 0.76, 0.84 and 0.81 for those who never/rarely consumed (reference) and consumed monthly, 1-2 days/week, 3-5 days/week and 6-7 days/week, respectively (ptrend < 0.002). The association remained similar after excluding the first 3 years of follow-up but appeared stronger in participants who did not smoke or drink alcohol regularly (ptrend < 0.0001). The corresponding HRs for stomach cancer were 1.00, 0.97, 0.95, 0.92 and 0.89 (ptrend = 0.04), with the association disappearing after excluding the first 3 years of follow-up. For colorectal cancer, the HRs were 1.00, 1.00, 0.95, 0.87 and 0.90, respectively (ptrend = 0.04) and the inverse association appeared to be restricted to rectal rather than colon cancer (pheterogeneity = 0.004). The types and strength of spice used showed little additional effects on these associations.

Conclusion: In Chinese adults, higher spicy food consumption was associated with lower risks of certain GI cancers, particularly among individuals who never smoked or drank alcohol regularly.
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http://dx.doi.org/10.1093/ije/dyaa275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938514PMC
March 2021

Associations of Adiposity, Circulating Protein Biomarkers, and Risk of Major Vascular Diseases.

JAMA Cardiol 2021 Mar;6(3):276-286

Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom.

Importance: Obesity is associated with a higher risk of cardiovascular disease (CVD), but little is known about the role that circulating protein biomarkers play in this association.

Objective: To examine the observational and genetic associations of adiposity with circulating protein biomarkers and the observational associations of proteins with incident CVD.

Design, Setting, And Participants: This subcohort study included 628 participants from the prospective China Kadoorie Biobank who did not have a history of cancer at baseline. The Olink platform measured 92 protein markers in baseline plasma samples. Data were collected from June 2004 to January 2016 and analyzed from January 2019 to June 2020.

Exposures: Measured body mass index (BMI) obtained during the baseline survey and genetically instrumented BMI derived using 571 externally weighted single-nucleotide variants.

Main Outcomes And Measures: Cross-sectional associations of adiposity with biomarkers were examined using linear regression. Associations of biomarkers with CVD risk were assessed using Cox regression among those without prior cancer or CVD at baseline. Mendelian randomization was conducted to derive genetically estimated associations of BMI with biomarkers.

Findings: In observational analyses of 628 individuals (mean [SD] age, 52.2 [10.5] years; 385 women [61.3%]), BMI (mean [SD], 23.9 [3.6]) was positively associated with 27 proteins (per 1-SD higher BMI; eg, interleukin-6: 0.21 [95% CI, 0.12-0.29] SD; interleukin-18: 0.13 [95% CI, 0.05-0.21] SD; monocyte chemoattractant protein-1: 0.12 [95% CI, 0.04-0.20] SD; hepatocyte growth factor: 0.31 [95% CI, 0.24-0.39] SD), and inversely with 3 proteins (Fas ligand: -0.11 [95% CI, -0.19 to -0.03] SD; TNF-related weak inducer of apoptosis, -0.14 [95% CI, -0.23 to -0.06] SD; and carbonic anhydrase 9: (-0.14 [95% CI, -0.22 to -0.05] SD), with similar associations identified for other adiposity traits (eg, waist circumference [r = 0.96]). In mendelian randomization, the associations of genetically elevated BMI with specific proteins were directionally consistent with the observational associations. In meta-analyses of genetically elevated BMI with 8 proteins, combining present estimates with previous studies, the most robust associations were shown for interleukin-6 (per 1-SD higher BMI; 0.21 [95% CI, 0.13-0.29] SD), interleukin-18 (0.16 [95% CI, 0.06-0.26] SD), monocyte chemoattractant protein-1 (0.21 [95% CI, 0.11-0.30] SD), monocyte chemotactic protein-3 (0.12 [95% CI, 0.03-0.21] SD), TNF-related apoptosis-inducing ligand (0.23 [95% CI, 0.13-0.32] SD), and hepatocyte growth factor (0.14 [95% CI, 0.06-0.22] SD). Of the 30 BMI-associated biomarkers, 10 (including interleukin-6, interleukin-18, and hepatocyte growth factor) were nominally associated with incident CVD.

Conclusions And Relevance: Mendelian randomization shows adiposity to be associated with a range of protein biomarkers, with some biomarkers also showing association with CVD risk. Future studies are warranted to validate these findings and assess whether proteins may be mediators between adiposity and CVD.
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http://dx.doi.org/10.1001/jamacardio.2020.6041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711564PMC
March 2021

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

Observational and Genetic Associations of Body Mass Index and Hepatobiliary Diseases in a Relatively Lean Chinese Population.

JAMA Netw Open 2020 10 1;3(10):e2018721. Epub 2020 Oct 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute University of Oxford, Oxford, United Kingdom.

Importance: There is some support for the existence of genetic associations between adiposity and certain hepatobiliary diseases in Western populations. However, there is little evidence of such genetic associations in China, where the causes of these diseases may differ from those in Western populations and the mean body mass index (BMI) is much lower.

Objectives: To compare the observational associations of BMI with hepatobiliary diseases and liver biomarkers with the genetic associations between BMI and these factors and to assess whether the genetic associations of BMI with liver diseases differed by hepatitis B virus infection status.

Design, Setting, And Participants: This cohort study used data from the prospective China Kadoorie Biobank, including 473 938 adults aged 30 to 79 years without hepatobiliary diseases at baseline from 10 diverse areas in China from June 25, 2004, to July 15, 2008. A random sample of 75 736 participants with genotyping data was included in the Mendelian randomization analysis. Follow-up was completed January 1, 2017 (median [interquartile range] length of follow-up, 10.2 [9.2-11.1] years). Data were analyzed from January to October 2019.

Exposures: Measured BMI obtained during the baseline survey and genetically instrumented BMI derived using 92 single-nucleotide variations.

Main Outcomes And Measures: Incident cases of hepatobiliary diseases, liver enzymes, fatty liver index, and fibrosis score.

Results: Among 473 938 individuals (276 041 [58.2%] women), the mean (SD) age was 52 (10.9) years and mean (SD) BMI was 23.8 (3.4). Baseline BMI was associated with higher risks of chronic liver disease (adjusted risk ratio per 1-SD increase, 1.14; 95% CI, 1.11 to 1.17) and gallbladder disease (adjusted risk ratio per 1-SD increase, 1.29; 95% CI, 1.27 to 1.31), with heterogeneity by disease subtype (P < .001). Genetically instrumented BMI was associated with higher risks of chronic liver disease (risk ratio per 1-SD increase, 1.55; 95% CI, 1.08 to 2.24) and gallbladder disease (risk ratio per 1-SD increase, 1.40; 95% CI, 1.11 to 1.76), with no heterogeneity between subtypes. A meta-analysis of the genetic associations in China Kadoorie Biobank and those calculated in UK Biobank gave a risk ratio of 1.55 (95% CI, 1.30 to 1.84) for chronic liver disease and 1.42 (95% CI, 1.22 to 1.64) for gallbladder disease. In the China Kadoorie Biobank study, there were positive genetic associations of BMI with liver enzymes, steatosis, and fibrosis scores, consistent with observational associations. The genetic associations of BMI with liver diseases and biomarkers did not differ by hepatitis B virus infection status.

Conclusions And Relevance: In this cohort study of a relatively lean Chinese population, there were positive genetic associations of BMI with hepatobiliary diseases. These results suggest that maintaining a healthy weight through diet and physical activity may help prevent hepatobiliary diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532388PMC
October 2020

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

Lancet Oncol 2020 10;21(10):1378-1386

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk.

Methods: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10 p=5 × 10 p=5 × 10 p=5 × 10, and p=5 × 10) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor.

Findings: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10) showed the strongest association with gastric cancer risk (p=7·56 × 10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (p<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (p<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56).

Interpretation: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer.

Funding: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30460-5DOI Listing
October 2020

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Sci Transl Med 2020 06;12(549)

Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
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http://dx.doi.org/10.1126/scitranslmed.aay6570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116615PMC
June 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
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http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

Publisher Correction: Systemic inflammation is associated with incident stroke and heart disease in East Asians.

Sci Rep 2020 May 12;10(1):8084. Epub 2020 May 12.

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-64764-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217894PMC
May 2020

Systemic inflammation is associated with incident stroke and heart disease in East Asians.

Sci Rep 2020 03 27;10(1):5605. Epub 2020 Mar 27.

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Systemic inflammation, reflected by increased plasma concentrations of C-reactive protein (CRP) and fibrinogen, is associated with increased risk of coronary heart disease, but its relevance for stroke types remains unclear. Moreover, evidence is limited in non-European populations. We investigated associations of CRP and fibrinogen with risks of incident major coronary events (MCE), ischemic stroke (IS) and intracerebral hemorrhage (ICH) in a cohort of Chinese adults. A nested case-control study within the prospective China Kadoorie Biobank included 1,508 incident MCE cases, 5,418 IS cases, 4,476 ICH cases, and 5,285 common controls, aged 30-79 years. High-sensitivity CRP and low-density lipoprotein cholesterol (LDL-C) were measured in baseline plasma samples from all participants, and fibrinogen in a subset (n = 9,380). Logistic regression yielded adjusted odds ratios (ORs) per SD higher usual levels of log-transformed CRP and fibrinogen. The overall mean (SD) baseline LDL-C was 91.6 mg/dL (24.0) and geometric mean (95% CI) CRP and fibrinogen were 0.90 mg/L (0.87-0.93) and 3.01 g/L (2.98-3.03), respectively. There were approximately log-linear positive associations of CRP with each outcome, which persisted after adjustment for LDL-C and other risk factors, with adjusted ORs (95% CI) per SD higher CRP of 1.67 (1.44-1.94) for MCE and 1.22 (1.10-1.36) for both IS and ICH. No associations of fibrinogen with MCE, IS, or ICH were identified. Adding CRP to prediction models based on established risk factors improved model fit for each of MCE, IS, and ICH, with small improvements in C-statistic and correct reclassification of controls to lower risk groups. Among Chinese adults, who have low mean LDL-C, CRP, but not fibrinogen, was independently associated with increased risks of MCE and stroke.
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http://dx.doi.org/10.1038/s41598-020-62391-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101367PMC
March 2020

Socioeconomic Status in Relation to Risks of Major Gastrointestinal Cancers in Chinese Adults: A Prospective Study of 0.5 Million People.

Cancer Epidemiol Biomarkers Prev 2020 04 27;29(4):823-831. Epub 2020 Jan 27.

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Background: Low socioeconomic status (SES) is associated with higher risk of certain gastrointestinal (e.g., colorectal, pancreatic, and liver) cancers in Western populations. Evidence is very limited in China, where correlates and determinants of SES differ from those in the West.

Methods: The prospective China Kadoorie Biobank recruited 512,715 adults (59% women, mean age 51 years) from 10 (5 urban, 5 rural) regions. During 10 years of follow-up, 27,940 incident cancers (including 3,061 colorectal, 805 pancreatic, and 2,904 liver) were recorded among 510,131 participants without prior cancer at baseline. Cox regression was used to estimate adjusted HRs for specific cancers associated with area-level (e.g., per capita gross domestic product, disposable income) and individual-level (e.g., education, household income) SES.

Results: Area-level SES and household income showed positive associations with incident colorectal and pancreatic cancers and inverse associations with liver cancer ( < 0.05). Education showed no association with colorectal cancer but inverse associations with pancreatic and liver cancers, with adjusted HRs comparing university to no formal schooling being 1.05 [95% confidence interval (CI), 0.85-1.29], 0.49 (95% CI, 0.28-0.85), and 0.61 (95% CI, 0.47-0.81), respectively. Potential risk factors (e.g., smoking, alcohol) partly explained the inverse associations of education with pancreatic and liver cancers (17.6% and 60.4%), respectively.

Conclusions: Among Chinese adults, the associations of SES with gastrointestinal cancers differed by cancer type and SES indicator. Potential risk factors partially explained the inverse associations of education with pancreatic and liver cancers.

Impact: The different associations between SES with gastrointestinal cancers may inform cancer prevention strategies.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242093PMC
April 2020

Genetic risk, adherence to a healthy lifestyle, and type 2 diabetes risk among 550,000 Chinese adults: results from 2 independent Asian cohorts.

Am J Clin Nutr 2020 03;111(3):698-707

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Background: Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown.

Objectives: The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes.

Methods: We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes.

Results: In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle.

Conclusions: In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population.
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http://dx.doi.org/10.1093/ajcn/nqz310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049535PMC
March 2020

Red meat, poultry and fish consumption and risk of diabetes: a 9 year prospective cohort study of the China Kadoorie Biobank.

Diabetologia 2020 04 22;63(4):767-779. Epub 2020 Jan 22.

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.

Aims/hypothesis: Previous evidence linking red meat consumption with diabetes risk mainly came from western countries, with little evidence from China, where patterns of meat consumption are different. Moreover, global evidence remains inconclusive about the associations of poultry and fish consumption with diabetes. Therefore we investigated the associations of red meat, poultry and fish intake with incidence of diabetes in a Chinese population.

Methods: The prospective China Kadoorie Biobank recruited ~512,000 adults (59% women, mean age 51 years) from ten rural and urban areas across China in 2004-2008. At the baseline survey, a validated interviewer-administered laptop-based questionnaire was used to collect information on the consumption frequency of major food groups including red meat, poultry, fish, fresh fruit and several others. During ~9 years of follow-up, 14,931 incidences of new-onset diabetes were recorded among 461,036 participants who had no prior diabetes, cardiovascular diseases or cancer at baseline. Cox regression analyses were performed to calculate adjusted HRs for incident diabetes associated with red meat, poultry and fish intake.

Results: At baseline, 47.0%, 1.3% and 8.9% of participants reported a regular consumption (i.e. ≥4 days/week) of red meat, poultry and fish, respectively. After adjusting for adiposity and other potential confounders, each 50 g/day increase in red meat and fish intake was associated with 11% (HR 1.11 [95% CI 1.04, 1.20]) and 6% (HR 1.06 [95% CI 1.00, 1.13]) higher risk of incident diabetes, respectively. For both, the associations were more pronounced among men and women from urban areas, with an HR (95% CI) of 1.42 (1.15, 1.74) and 1.18 (1.03, 1.36), respectively, per 50 g/day red meat intake and 1.15 (1.02, 1.30) and 1.11 (1.01, 1.23), respectively, per 50 g/day fish intake. There was no significant association between diabetes and poultry intake, either overall (HR 0.96 [95% CI 0.83, 1.12] per 50 g/day intake) or in specific population subgroups.

Conclusions/interpretation: In Chinese adults, both red meat and fish, but not poultry, intake were positively associated with diabetes risk, particularly among urban participants. Our findings add new evidence linking red meat and fish intake with cardiometabolic diseases.

Data Availability: Details of how to access the China Kadoorie Biobank data and rules of China Kadoorie Biobank data release are available from www.ckbiobank.org/site/Data+Access.
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http://dx.doi.org/10.1007/s00125-020-05091-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054352PMC
April 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Problem drinking, wellbeing and mortality risk in Chinese men: findings from the China Kadoorie Biobank.

Addiction 2020 05 6;115(5):850-862. Epub 2020 Jan 6.

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Aims: To assess the associations of problem drinking with wellbeing and mortality in Chinese men.

Design: Population-based prospective cohort study.

Setting: Ten diverse areas across China.

Participants: A total of 210 259 men aged 30-79 years enrolled into China Kadoorie Biobank between 2004 and 2008.

Measurements: Self-reported alcohol intake and indicators of problem drinking (i.e. drinking in the morning, unable to stop drinking, unable to work due to drinking, negative emotions after drinking, having shakes after stopping drinking) were assessed by questionnaire at baseline, along with stressful life events (e.g. divorce, income loss, violence) and wellbeing-related measures (e.g. life satisfaction, sleep problems, depression, anxiety). Problem drinking was defined as reporting at least one of the drinking problem indicators. Follow-up for mortality and hospitalized events was through linkage to death registries and national health insurance systems. Multivariate logistic regression models assessed cross-sectional relationships between problem drinking and stressful life events/wellbeing. Cox proportional hazards regression models estimated prospective associations of problem drinking with mortality/hospitalized events.

Findings: A third of men were current regular drinkers (i.e. drank alcohol at least weekly), 24% of whom reported problem drinking: 8% of all men. Experience of stressful life events in the past 2 years, especially income loss [odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.45-2.39], was associated with increased problem drinking. Compared with low-risk drinkers (i.e. intake < 200 g/week, no reported problem drinking or habitual heavy drinking episodes), men with problem drinking had poorer self-reported health, poorer life satisfaction and sleep problems, and were more likely to have symptoms of depression and anxiety. Men with two or more problem drinking indicators had an approximately twofold higher risk for all-cause mortality as well as mortality and morbidity from external causes (i.e. injuries), respectively, and 15% higher risk for any hospitalization, compared with low-risk drinkers (all P < 0.01).

Conclusion: Eight per cent of men in China are problem drinkers, and this is associated with significantly increased risk of physical and mental health problems and premature death.
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http://dx.doi.org/10.1111/add.14873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156287PMC
May 2020

Alcohol consumption and vascular disease: other points to consider - Authors' reply.

Lancet 2019 11;394(10209):1618

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)31907-5DOI Listing
November 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

The transferability of lipid loci across African, Asian and European cohorts.

Nat Commun 2019 09 24;10(1):4330. Epub 2019 Sep 24.

Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.
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http://dx.doi.org/10.1038/s41467-019-12026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760173PMC
September 2019

Vitamin D and cause-specific vascular disease and mortality: a Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults.

BMC Med 2019 08 30;17(1):160. Epub 2019 Aug 30.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.

Background: Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans.

Methods: We used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults.

Results: In Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction.

Conclusions: We found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding.
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http://dx.doi.org/10.1186/s12916-019-1401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716818PMC
August 2019

Physical Activity, Sedentary Leisure Time, Circulating Metabolic Markers, and Risk of Major Vascular Diseases.

Circ Genom Precis Med 2019 09 28;12(9):386-396. Epub 2019 Aug 28.

Clinical Trial Service Unit and Epidemiological Studies Unit (Y.P., C.K., H.D., I.Y.M., Y.C., L.Y., R.W., F.B., R.P., R. Clarke, R. Collins, D.A.B., L.L., M.V.H., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

Background: Physical inactivity and sedentary behavior are associated with higher risk of cardiovascular disease (CVD). Little is known about the relevance of circulating metabolites for these associations.

Methods: A nested case-control study within the prospective China Kadoorie Biobank included 3195 incident CVD cases (2057 occlusive CVD and 1138 intracerebral hemorrhage) and 1465 controls aged 30 to 79 years without prior CVD or statin use at baseline. Nuclear magnetic resonance spectroscopy was used to measure 225 metabolic markers and derived traits in baseline plasma samples. Linear regression was used to relate self-reported physical activity and sedentary leisure time to biomarkers, adjusting for potential confounders. These were contrasted with associations of biomarkers with occlusive CVD risk.

Results: Physical activity and sedentary leisure time were associated with >100 metabolic markers, with patterns of associations generally mirroring each other. Physical activity was inversely associated with very low and low-density and positively with large and very large HDL (high-density lipoprotein) particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and the inflammatory marker glycoprotein acetyls. In general, associations of physical activity and sedentary leisure time with specific metabolic markers were directionally consistent with the associations of these metabolic markers with occlusive CVD risk. Overall, metabolic markers potentially explained ≈70% of the protective associations of physical activity and ≈50% of the positive associations of sedentary leisure time with occlusive CVD.

Conclusions: Among Chinese adults, physical activity and sedentary behavior have opposing associations with a diverse range of circulating metabolites, which may partially explain their associations with CVD risk.
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http://dx.doi.org/10.1161/CIRCGEN.118.002527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752700PMC
September 2019

Genetic Predisposition to Type 2 Diabetes and Risk of Subclinical Atherosclerosis and Cardiovascular Diseases Among 160,000 Chinese Adults.

Diabetes 2019 11 9;68(11):2155-2164. Epub 2019 Aug 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

In observational studies, type 2 diabetes is associated with two- to fourfold higher risk of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank (CKB), we examined associations of genetically predicted type 2 diabetes with CVD among ∼160,000 participants to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (odds ratio 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; = 6,819) and elevated risk of ischemic stroke (IS) (1.08 [1.02, 1.14]; = 17,097), nonlacunar IS (1.09 [1.03, 1.16]; = 13,924), and major coronary event (1.12 [1.02, 1.23]; = 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], = 3,173) or intracerebral hemorrhage (ICH) (1.01 [0.94, 1.10], = 6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB ( for heterogeneity >0.3) and with the associations of type 2 diabetes with IS, ICH, and coronary heart disease in two-sample Mendelian randomization analyses based on summary statistics from European population genome-wide association studies ( for heterogeneity >0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.
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http://dx.doi.org/10.2337/db19-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804628PMC
November 2019

Identification of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations.

Lancet Respir Med 2019 10 17;7(10):881-891. Epub 2019 Jul 17.

Department of Environmental Health, Harvard School of Public Health, Department of Medicine, Harvard Medical School, Boston, MA, USA.

Background: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations.

Methods: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up.

Findings: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p=2·02 × 10). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years.

Interpretation: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.

Funding: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
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http://dx.doi.org/10.1016/S2213-2600(19)30144-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015703PMC
October 2019
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