key: cord-0936552-46mvk1zb authors: Richardson, T. G.; Fang, S.; Mitchell, R. E.; Holmes, M. V.; Davey Smith, G. title: Evaluating the effects of cardiometabolic exposures on circulating proteins which may contribute to SARS-CoV-2 severity date: 2020-09-11 journal: nan DOI: 10.1101/2020.09.10.20191932 sha: 5f2853ec59114c3a7cbe267aa91edfa9c0afc806 doc_id: 936552 cord_uid: 46mvk1zb Background: Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. Methods: We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence SARS-CoV-2 severity. Findings: In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyses. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P=2.19x10-16) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P=9.04x10-12). Further analyses using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protecting the body from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P=2.32x10-08, proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence SARS-CoV-2 severity was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P=0.002), a signal transductor for interleukin-6 type cytokines which are involved in the bodys inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. Interpretation: Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 are warranted to help elucidate therapeutic strategies for covid-19 disease severity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.10.20191932 doi: medRxiv preprint I n t r o d u c t i o n O n t h e 1 1 t h o f M a r c h 2 0 2 0 t h e W o r l d H e a l t h O r g a n i s a t i o n ( W H O ) d e c l a r e d t h e c o r o n a v i r u s d i s e a s e 2 0 1 9 ( c o v i d -1 9 ) a g l o b a l p a n d e m i c 1 . A l t h o u g h s t r i c t l o c k d o w n m e a s u r e s h a v e b e e n e n f o r c e d i n m a n y c o u n t r i e s t o c o n t r o l t h e s p r e a d o f i n f e c t i o n , t h e n u m b e r o f d e a t h s w o r l d w i d e w h i c h h a v e b e e n a t t r i b u t e d t o s e v e r e a c u t e r e s p i r a t o r y s y n d r o m e c o r o n a v i r u s . T o a d d r e s s t h i s c r i t i c a l a n d u r g e n t c h a l l e n g e , r e s e a r c h e r s i n t h e f i e l d , l e d b y c o l l e a g u e s f r o m t h e M R C E p i d e m i o l o g y U n i t , h a v e r a p i d l y g e n e r a t e d a c u r a t e d d a t a s e t c o n c e r n i n g t h e g e n e t i c a r c h i t e c t u r e o f 9 7 u n i q u e p r o t e i n s w h i c h m a y b e i n v o l v e d i n i n f l u e n c i n g S A R S -C o V -2 s e v e r i t y 6 . T h e s e i n c l u d e i n f l a m m a t o r y c y t o k i n e s w h i c h a r e i n v o l v e d i n t h e b o d y ' s i m m u n e r e s p o n s e t o i n f e c t i o n , p r o t e i n s i n v o l v e d i n f i b r i n o l y s i s a n d b l o o d c o a g u l a t i o n , a n t i b o d i e s w h i c h p l a y a c r i t i c a l r o l e i n t h e b o d y ' s i m m u n e r e s p o n s e t o i n f e c t i o n ( s u c h a s i m m u n o g l o b u l i n G ) a n d g e n e p r o d u c t s w h i c h h a v e b e e n r e p o r t e d t o i n t e r a c t w i t h S A R S -C o V -2 p r o t e i n s i n h u m a n c e l l s 7 . A c o m p l e t e l i s t o f t h e s e p r o t e i n s c a n b e f o u n d i n S u p p l e m e n t a r y T a b l e 1 . T h i s c u r a t e d r e s o u r c e p r o v i d e s a n o p p o r t u n i t y t o u n d e r t a k e M e n d e l i a n r a n d o . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . I n t h e s a m e s e t o f p a r t i c i p a n t s , i m p u t e d g e n o t y p e d a t a o n 1 7 , 6 5 2 , 7 9 7 g e n e t i c v a r i a n t s w e r e a v a i l a b l e a f t e r i m p u t a t i o n u s i n g t h e U K 1 0 K + 1 0 0 0 G p h a s e 3 r e f e r e n c e p a n e l . S u m m a r y s t a t i s t i c s w e r e a v a i l a b l e i n a t o t a l o f 9 7 u n i q u e p r o t e i n s f r o m t h e w e b s e r v e r a s t h e y h a d a t l e a s t 1 . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. W e f i r s t l y a p p l i e d M R t o e s t i m a t e t h e e f f e c t o f e a c h o f t h e 1 1 e x p o s u r e s i n t u r n o n e a c h p r o t e i n i n a t w o -s a m p l e s e t t i n g 2 7 . I n i t i a l l y w e u s e d t h e i n v e r s e v a r i a n c e w e i g h t e d ( I V W . d a t a f r o m t h e c o v i d -1 9 H G I a n d J o h n s o n e t a l a n a l y s e s 2 5 , 2 6 . F i n a l l y , w e a p p l i e d t h e c i s c o r r e l a t e d I V W a p p r o a c h s y s t e m a t i c a l l y t o a l l p r o t e i n s w i t h a t l e a s t 2 c i s -p Q T L ( a s t h i s i s t h e m i n i m u m n u m b e r r e q u i r e d f o r t h e I V W m e t h o d ) f o r e a c h c o v i d -1 9 G W A S d a t a s e t . T h i . W e a l s o n o t e t h e c o n f l i c t i n g d i r e c t i o n s o f e f f e c t w h i c h r i s k f a c t o r s h a v e o n t h e p r o t e i n s a s s e s s e d e v e n w i t h i n t h e s a m e c a t e g o r y . F o r e x a m p l e , w i t h i n t h e f i b r i n o l y s i s c a t e g o r y B M I p r o v i d e d e v i d e n c e o f a n e f f e c t o n h i g h e r l e v e l s o f f i b r i n o g e n ( B e t . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 11, 2020. B M I i s r e c o g n i z e d t o c a u s a l l y i n f l u e n c e t r i g l y c e r i d e s a n d w e t h e r e f o r e u n d e r t o o k m u l t i v a r i a b l e M R t o e v a l u a t e t h e d i r e c t e f f e c t s o f B M I a n d t r i g l y c e r i d e s o n t h e 7 p r o t e i n s w h i c h t h e y h a d i n c o m m o n b a s e d o n u n i v a r i a b l e e s t i m a t e s i n t h e p r e v i o u s a n a l y s i s . T ) . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. s 0 e n ' . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.10.20191932 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . D i s c u s s i o n W e h a v e u n d e r t a k e n a c o m p r e h e n s i v e M e n d e l i a n r a n d o m i z a t i o n s t u d y t o s y s t e m a t i c a l l y e v a l u a t e t h e e f f e c t o f 1 1 e s t a b l i s h e d r i s k f a c t o r s f o r d i s e a s e o n c i r c u l a t i n g l e v e l s o f p r o t e i n s r e l a t e d t o S A R S -C o V -2 . O u r m a i n f i n d i n g s a r e t h a t a m o n g t h e m o d i f i a b l e r i s k f a c t o r s a s s e s s e d , B M I a n d t r i g l y c e r i d e s s h o w e d t h e w i d e s t r e p e r t o i r e o f c a u s a l e f f e c t s o is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . a n d c a n t h e r e f o r e o n l y a c t a p r o x y f o r I g G r e s p o n s e t o i n f e c t i o n . A d d i t i o n a l l y , g e n e r i c I g G l e v e l s w e r e m e a s u r e d r a t h e r t h a n t h e s p e c i f i c a d a p t i v e i m m u n e r e s p o n s e t o S A R S -C o V T h i s s t u d y h a s s e v e r a l l i m i t a t i o n s w h i c h s h o u l d b e t a k e n i n t o a c c o u n t w h e n i n t e r p r e t i n g i t s f i n d i n g s . T h e c u r r e n t s a m p l e s i z e s o f t h e S A R S -C o V -2 G W A S a r e ( a s o n e w o u l d e x p e c t ) r e l a t i v e l y m o d e s t c o m p a r e d t o l a r g e -s c a l e G W A S d a t a w h i c h M R s t u d i e s a r e c o n t e m p o r a n e o u s l y a p p l i e d . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. . A c k n o w l e d g e m e n t s W e a r e e x t r e m e l y g r a t e f u l t o M a i k P i e t z n e r , C l a u d i a L a n g e n b e r g a n d a l l t h e i r c o l l e a g u e . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 11, 2020. An interactive web-based dashboard to track COVID-19 in real time Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention Obesity Is a Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Genetic architecture of host proteins interacting with SARS-CoV-2 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Mendelian randomization: genetic anchors for causal inference in epidemiological studies Distinguishing genetic correlation from causation across 52 diseases and complex traits Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study Second-generation PLINK: rising to the challenge of larger and richer datasets A global reference for human genetic variation Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor COVID-19 cytokine storm: the interplay between inflammation and coagulation Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19 Hypercoagulation and Antithrombotic Treatment in Coronavirus 2019: A New Challenge Genetic drug target validation using Mendelian randomisation Genomewide Association Study of Severe Covid-19 with Respiratory Failure Collider bias undermines our understanding of COVID-19 disease risk and severity The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic Commentary: Two-sample Mendelian randomization: opportunities and challenges Mendelian randomization analysis with multiple genetic variants using summarized data Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator Orienting the causal relationship between imprecisely measured traits using GWAS summary data An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects Consortium EP-I. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways Genetic studies of body mass index yield new insights for obesity biology Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods The MR-Base platform supports systematic causal inference across the human phenome MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data Elegant Graphics for Data Analysis LDassoc: an online tool for interactively exploring genomewide association study results and prioritizing variants for functional investigation C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization Principles of interleukin (IL)-6-type cytokine signalling and its regulation Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk Immunoglobulin G and its function in the human respiratory tract Antibody responses to SARS-CoV-2 in patients with COVID-19 SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes Effective treatment of severe COVID-19 patients with tocilizumab Genetic inhibition of interleukin-6 receptor signaling and Covid-19 Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development