key: cord-0727081-h7f15s7a authors: Scalsky, R. J.; Desai, K.; Chen, Y.-J.; O'Connell, J. R.; Perry, J. A.; Hong, C. C. title: Baseline Cardiometabolic Profiles and SARS-CoV-2 Risk in the UK Biobank date: 2020-07-29 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2020.07.25.20161091 sha: edf923af9d11e8f72fdfb8beaa1770ba0b6a26ae doc_id: 727081 cord_uid: h7f15s7a Abstract Background SARS-CoV-2 is a rapidly spreading coronavirus with a high incidence of severe upper respiratory infection that first presented in Wuhan, China in December 2019. Many factors have been identified as risk factors for SARS-CoV-2, with much attention being paid to body mass index (BMI), but little investigation has been done to investigate dysregulation of lipid profiles and diabetes, which are often comorbid in high BMI patients. Objective This study seeks to describe the impact of BMI, HDL, LDL, ApoA, ApoB, triglycerides, hemoglobin A1c (HbA1c), diabetes, alcohol and red wine intake on SARS-CoV-2 risk in UK Biobank (UKB) study participants. Methods We examined the effect of BMI, lipid profiles, diabetes and alcohol intake on the risk of testing positive for SARS-Cov-2 among 9,005 UKB participants tested for SARS-CoV-2 from March 16 through June 29, 2020. Logistic regression was performed on the target variables controlling for age, sex and ancestry. Results BMI, Type II diabetes and HbA1c were associated with increased SARS-CoV-2 risk (p < 0.05) while HDL and ApoA were associated with decreased risk (p < 0.001). Additionally, red wine intake was associated with reduced SARS-CoV-2 risk (p < 0.05). LDL, ApoB and triglyceride levels were not found to be significantly associated with increased risk. Conclusion Elevated HDL and ApoA levels and alcohol intake, specifically red wine intake, were associated with reduced risk of testing positive for SARS-CoV-2, while type II diabetes and HbA1c were associated with increased risk. The effects of alcohol, type II diabetes and HbA1c levels may be indirect, mediated in part through regulation of HDL levels. In summary, our study corroborates the emerging picture that high HDL levels may confer protection against SARS-CoV-2. Since early December 2019, when the first cases of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID- 19) were identified in Wuhan, China, nearly 13 million individuals have tested positive for the virus (1). Researchers have rapidly attempted to define the clinical characteristics associated with increased risk of becoming infected with SARS-CoV-2 to improve our understanding and clinical management of this pandemic. Early data from across the globe have identified pre-existing cardiovascular disease and obesity as risk factors associated with acquiring SARS-CoV-2 (2) (3) (4) (5) (6) . There remains limited research on how an individual's baseline cardiometabolic profile, specifically lipid levels, affects one's risk for contracting the virus. This has received particular attention as the known viral entry mechanism for SARS-CoV-1, a closely related virus responsible for the 2003 SARS outbreak in China, is cholesterol-dependent (7) . In this paper, we analyze the association of a positive SARS-CoV-2 test with an individual's lipid profile in the UK Biobank resource and find that baseline HDL levels strongly correlate with testing positive SARS-CoV-2. The UK Biobank Resource began releasing SARS-CoV-2 test results in April 2020 to approved researchers. Full details on these test results are available online (8) Using test results released on July 14, 2020, we performed quality control by removing closely related subjects, and subjects with mismatch between self-reported sex and genetically determined sex. Related subjects were removed in an iterative fashion by randomly removing one subject at a time from pairs of subjects listed as related in the dataset provided by the UK Biobank. This removal process was repeated until no related subjects remained. Subjects testing positive for SARS-CoV-2 were classified as cases. If multiple tests were performed, we classified a subject as a case if any test gave a positive result, based on the rationale that false positives are less likely than false negatives. Those with only negative test results were classified as controls. This approach yielded 1,508 cases, and 7,497 controls for a total of 9,005 subjects. There was a significant difference in sex (p=1.3 x 10 -3 ) and ancestry (p=1.1 x 10 -15 ) between cases and controls. Age difference between cases and controls was also significant (p=3.4 x 10 -8 ). See Table 1 for details. The association analysis was performed with Plink2 (9) using logistic regression. The binary outcome of "SARS-CoV-2 test status" (cases tested positive, controls tested negative) was run against continuous, categorical, and binary ICD10 code phenotypes supplied by the UK Biobank. Continuous and categorical phenotypes were collected when subjects were enrolled into the UK Biobank (2006) (2007) (2008) (2009) (2010) . ICD10 diagnostic codes are current for all subjects through October 2019. We also grouped the ICD10 code data into Phecodes (10) in order to increase statistical power. The analysis included covariates of sex, age, and principal components (PCs) 1 through 4 to adjust for ancestry differences indicated in Table 1 using data provided by the UK Biobank. Our preliminary analysis showed that only the first 4 PCs were significant at p < 0.05. The analysis yielded odds ratios (OR) and 95% confidence intervals (CI) for each phenotype tested against the "SARS-CoV-2 test status". An OR greater than 1.0 indicates increased risk of a SARS-CoV-2 positive test compared to the controls. An OR less than 1.0 indicates a decreased risk. For continuous phenotypes, the OR indicates the increased risk (for OR > 1.0) or decreased risk (for OR < 1.0) per standard deviation increase in the continuous phenotype. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint Prior to the association analysis we compared the cases and controls for differences in sex, ancestry and age. Significant differences were found between the sex (p-value = 1.3x10 -3 ; Table 1 ), ancestry (p-value = 1.1x10 -15 ; Table 1 ) and age (p-value = 3.4x10 -8 ; Table 1 ) of cases and controls. *N/Male/Female/Non-white/White indicate number of subjects. Age is the mean age as of 2020, SD is standard deviation. P-values are from chi-squared test for sex and ancestry, and t-test for age, comparing cases and controls. White ancestry includes subjects self-reporting as White, British, Irish, or "Any other white background". Nonwhite ancestry includes all other self-report categories. Body mass index (BMI) has been shown to increase SARS-CoV-2 risk across many populations. Indeed, we found that BMI was associated with an increased risk of SARS-CoV-2 positive testing (OR = 1.12, 95% CI = 1.06 -1.18, p-value = 6.14x10 -5 ; Table 2 ). These findings were consistent when BMI was measured by electrical impedance (OR = 1.12, 95% CI = 1.06 -1.18, p-value = 8.54x10 -5 ; Table 2 ). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . After controlling for age, sex and 4pc, we found that plasma HDL levels were associated with a reduced risk of testing positive for SARS-CoV-2 (OR = 0.845, 95% CI = 0.788 -0.907, p-value = 2.45x10 -6 ; Table 3 ). Moreover, we found that plasma levels of Apolipoprotein A (ApoA), the major protein component of HDL particles in plasma, were also associated with a reduced risk of SARS-CoV-2 (OR = 0.849, 95% CI = 0.793 -0.910, p-value = 2.90x10 -6 ; Table 3 ). Consistent with high collinearity between HDL and ApoA, the effect of either is negligible when the opposite is controlled for (Table 3) . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint The diagnosis of hyperlipidemia (ICD10 codes E78.4 and E78.5) was modestly associated with an elevated risk of testing positive for SARS-CoV-2 (OR=1.362, 95% CI=1.021 -1.817, p-value 0.036; Table 4 ). However, when ApoA or HDL were controlled, for this effect dissipated (Table 4 ). In contrast to prior studies, we did not find any association between LDL levels and risk of testing positive for SARS-CoV-2 (OR = 0.995, 95% CI = 0.939 -1.055, pvalue = 0.872; Table 4 ). Consistent with this, apolipoprotein B, the major constituent of plasma LDL, was not associated with any significant effect on risk of testing positive for SARS-CoV-2 (OR = 1.003, 95% CI = 0.947 -1.063, p-value = 0.910; Table 4 ). Additionally, no significant effect of triglyceride levels on risk of testing positive for SARS-CoV-2 were found (OR = 1.026, 95% CI = 0.969 -1.087, p-value = 0.375; Table 4 ). Frequency of alcohol intake was associated with reduced risk of testing positive for SARS-CoV-2 ( Figure 1 ). There appears to be a "dosage effect" as the significant OR reduction is note only above 3-4 alcohol consumption per week (OR = 0.716, 95% CI = 0.578 -0.997), p-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint value = 2.28x10 -3 , Table 5 ), with maximal impact seen with daily alcohol consumption (OR = 0.660, 95% CI = 0.530 -0.821, p-value = 1.98 x 10 -4 ; Table 5 ). Interestingly, this effect is diminished slightly after controlling for HDL (3-4x/week: OR = 0.752, 95% CI = 0.593 -0.953, p = 0.0183; daily: OR = 0.733, 95% CI = 0.574 -0.936, p-value = 0.0129; Table 5 ). Of types of alcohol beverages recorded (Spirits, Fortified Wine, Red Wine, White Wine and Beer), only increased red wine intake was associated with reduced risk of testing positive for SARS-CoV-2 (OR = 0.883, 95% CI = 0.811 -0.960, p-value = 3.75x10 -3 ; Table 6 ). Again, this effect is diminished slightly after controlling for HDL (OR = 0.904, 95% CI = 0.825 -0.991, p-value = 0.0314; Table 6 ), suggesting that HDL, at least in part, mediates the effect of alcohol intake on SARS-CoV-2 risk. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . Figure 1 -Dose dependent effect of alcohol consumption on SARS-CoV-2 positive testing risk. Alcohol intake assessed by questionnaire with multiple choice answers. Question was "About how often do you drink alcohol?" All answers compared to those who chose "never". *Odds-ratio = 0.716, 95% CI = 0.58 -0.89, p-value = 2.28x10 -3 # Odds-ratio = 0.660, 95% CI = 0.53 -0.82, p-value = 1.98x10 -4 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . The diagnosis of Type II diabetes (Phecode phe250.2) was associated with an elevated risk of testing positive for SARS-CoV-2 (OR =1.213, 95% CI =1.028 -1.432, p-value = 0.0225; Table 7 ). Consistent with this, we found that HbA1c level was associated with a significant increase in risk of testing positive for SARS-CoV-2 (OR = 1.061, 95% CI = 1.005 -1.121, p-value = 0.0332; Table 7 ). However, when ApoA or HDL were controlled for, the effects of both the type II diabetes diagnosis and HgA1c level dissipated (Table 7) . Curiously, Type I diabetes (Phecode phe250.1) was not associated with an elevated risk of testing positive for SARS-CoV-2 (Table 7 ). This analysis of the effect of baseline BMI, lipoproteins, their respective apolipoproteins and diabetes on testing positive for SARS-CoV-2 in a cohort from the UK Biobank dataset. Though lipids have been under much investigation for their potential implications in SARS-CoV-2 disease development, much less attention has been paid to their potential contributions to patient's risk of infection with SARS-CoV-2. Our study suggests that decreased levels of HDL, independent of BMI, may play a role in predisposing patients to SARS-CoV-2. In contrast, our analysis suggests that LDL and triglycerides, which have been shown to play a role in worsening SARS-CoV-2 severity (11), are not implicated in predisposing patients to infection by SARS- BMI has been of much focus in the scientific communities' search for the factors that are responsible for worsening SARS-CoV-2 disease progression. BMI is known to contribute significantly to a wide range of disease risk and disease development from cardiovascular disease, to musculoskeletal problems and even cancer (12) . Naturally, this was a good place to begin our understanding of SARS-CoV-2 risk factors and studies have shown that increasing BMI was associated with severe SARS-CoV-2 infection and was overrepresented in nonsurvivors of SARS-CoV-2 (13). Our study demonstrates that increases in BMI are not only associated with worsened SARS-CoV-2 outcomes but is also implicated in increasing the risk of contracting SARS-CoV-2. This suggest that underlying metabolic disease may be involved in much more of the SARS-CoV-2 disease process than was once expected. Our analysis found association of Type II (but not Type I) Diabetes and HbA1c levels with SARS-CoV-2 diagnosis. Importantly, when ApoA or HDL were controlled for, the effects of both the Type II diabetes diagnosis and HbA1c level dissipated. As metabolic syndrome and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint Type II diabetes are associated with reduced HDL levels, we hypothesize that the elevated risk associated with Type II diabetes is mediated in part through modulation of HDL levels. Interestingly, red wine intake was associated with reduced risk of testing positive for SARS-CoV-2. This is counter to intuition and prior research that suggest there is a dose dependent relationship between alcohol intake and viral infections (14) . Nevertheless, red wine, in particular, has been shown to have positive effects on endothelial function, glucose metabolism and HDL upregulation when consumed in moderate quantities (15) . Red wine intake and HDL may modulate inflammatory, endothelial and lipid characteristics in such a way confer some protection to SARS-CoV-2 infection. Preliminary work has demonstrated decreased HDL is associated with worsening SARS-CoV-2 severity (16) . How HDL levels might influence susceptibility to SARS-CoV-2 is unknown, but given HDL's established antioxidant, antithrombotic and anti-inflammatory characteristics it remains possible that they play a protective role in preventing the establishment of SARS-CoV-2 (17) . Alternatively, HDL is now known to transport a wide range of cargo other than cholesterol, such as microRNAs (miRNAs) (18) . These non-canonical roles of HDL are consistent with the direct, nonselective antiviral effects of HDL (19) . Though the findings of this study persist when appropriate controls are applied, we acknowledge the inherent limitations of association studies. Additionally, association studies are subject to sampling bias. For instance, we don't know the context in which the SARS-CoV-2 testing was carried out, the HDL status at the time of testing, and the disease severity of each All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint case. Despite these limitations, we believe that our exploration of SARS-CoV-2 corroborates some of the earlier studies and provides valuable mechanistic insight and guidance for future studies. For instance, our study corroborates several earlier studies showing higher prevalence of SARS-CoV-2 infection in non-white populations and in obese individuals. At the same time, we cannot draw causal inferences, for example that older age may confer protection (Table 1) . Nevertheless, we wonder whether low HDL, mediated in part by underlying metabolic disorders, may indeed play a in SARS-CoV-2 pathophysiology, driving or exaggerating antithrombotic and anti-inflammatory effects of SARS-CoV-2. Moreover, given the recent discovery of HDL's myriad non-traditional cargoes, such as miRNAs and nonselective antiviral effects, high HDL level may provide protection from SARS-CoV-2 via direct antiviral effects. Prior studies have demonstrated associations of lipoprotein levels to SARS-CoV-2 infection, but our analysis suggests that the association with HDL in particular may be worth further study, for example, to examine the possibility that HDL may in fact confer protection against SARS-CoV-2 infection, to determine whether baseline HDL levels can identify high risk patients, or even to exploe whether pharmacological modulation of HDL levels may confer protection against SARS-CoV-2 infection. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation Obesity in patients younger than 60 years is a risk factor for Covid-19 hospital admission 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 Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area Clinical Characteristics of Covid-19 in New York City Lipid rafts are involved in SARS-CoV entry into Vero E6 cells Current and future availability of COVID-19 related health outcome data No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Second-generation PLINK: rising to the challenge of larger and richer datasets Mapping ICD-10 and ICD-10-CM Codes to Phecodes: Workflow Development and Initial Evaluation Hypolipidemia is associated with the severity of COVID-19 The Medical Risks of Obesity Risk of COVID 19 for patients with obesity Are Patients With Alcohol Use Disorders at Increased Risk for Covid-19 Infection? Contribution of Red Wine Consumption to Human Health Protection Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Role of HDL-Associated Proteins and Lipids in the Regulation of Inflammation Lipoprotein carriers of microRNAs Lipoproteins account for part of the broad non-specific antiviral activity of human serum This research was conducted using the UK Biobank Resource under Application Number 49852. This work was supported by 5T32GM092237-10 to RS, NIGMS R01GM118557, NHLBI R01HL135129 to CCH, and NHLBI 1U01HL137181 to JP. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication. The authors declare no competing interests.All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 29, 2020. . https://doi.org/10.1101/2020.07.25.20161091 doi: medRxiv preprint