Differences in RAAS/vitamin D linked to genetics and socioeconomic factors could explain the higher mortality rate in African Americans with COVID-19

Abstract

COVID-19 is said to be a pandemic that does not distinguish between skin color or ethnic origin. However, data in many parts of the world, especially in the United States, begin to show that there is a sector of society suffering a more significant impact from this pandemic. The Black population is more vulnerable than the White population to infection and death by COVID-19, with hypertension and diabetes mellitus as probable predisposing factors. Over time, multiple disparities have been observed between the health of Black and White populations, associated mainly with socioeconomic inequalities. However, some mechanisms and pathophysiological susceptibilities begin to be elucidated that are related directly to the higher prevalence of multiple diseases in the Black population, including infection and death by COVID-19. Plasma vitamin D levels and evolutionary adaptations of the renin-angiotensin-aldosterone system (RAAS) in Black people differ considerably from those of other races. The role of these factors in the development and progression of hypertension and multiple lung diseases, among them SARS-CoV-2 infection, is well established. In this sense, the present review attempts to elucidate the link between vitamin D and RAAS ethnic disparities and susceptibility to infection and death by COVID-19 in Black people, and suggests possible mechanisms for this susceptibility.

Keywords

African Americans COVID-19 renin-angiotensin-aldosterone system vitamin D

Introduction

Currently, morbidity and mortality rates due to COVID-19 are highest in Black populations in many places around the world. The American Community Survey and Johns Hopkins University have indicated that the infection rate is over 3-fold, and the mortality rate 6-fold, higher in countries with a large Black population than in those with White majorities.¹

In general, there are marked health disparities between White and African Americans, where the mortality rate of multiple etiologies (cardiovascular and renal disease, diabetes, cancer, and others) for African Americans is significantly higher than for White Americans. Some explanations for such disparities generally include social environment, lifestyle behaviors, socioeconomic status, and access to preventive health care services. Nevertheless, many studies indicate that these factors are not enough to explain such differences. In this sense, it is well established that high vitamin D serum levels have essential benefits on health through multiple mechanisms. African Americans have considerably lower vitamin D serum levels than White Americans. These differences in vitamin D serum concentrations between groups may account for many of the aforementioned health disparities,^2–8 including the susceptibility of Black people to suffering hypertension, diabetes mellitus, and COVID-19. The latter was recently highlighted by the Wall Street Journal in its article entitled “Vitamin D and Coronavirus Disparities” (https://www.wsj.com/articles/vitamin-d-and-coronavirus-disparities-11587078141). Low vitamin D values are also associated with a higher incidence of respiratory infection.⁹ Moreover, in controlled clinical trials, vitamin D administration has shown a protective effect against respiratory infections in healthy patients as well as in patients with chronic obstructive pulmonary disease and other related pathologies, including COVID-19.^10–25

Additionally, it has been observed that hypertension is an essential risk factor for SARS-CoV-2 infection,²⁶ and that the renin-angiotensin-aldosterone system (RAAS) is implicated in this process.^27,28 In this regard, it is known that hypertension has a significantly higher prevalence in Black people, possibly because this race presents certain peculiarities compared with the White race.²⁹ Since the leading causes of death in Black people during slavery were salt-depletive diseases such as vomiting, fevers, and diarrhea, it is argued that African slaves with an improved genetic capacity to conserve salt had a unique survival advantage over the rest. This also allowed them to bequeath their genotype to the next generations of Western Black people. Therefore, it is assumed that, for this reason, African Americans have a higher frequency of subjects with an improved genetic ability to retain salt than African Black people.³⁰ The sodium retention observed in Black populations causes the inhibition of systemic RAAS (sRAAS) by negative feedback. Thus, decreased renin plasma levels compensate for the tendency to retain salt.³¹

An analogy of the natural sRAAS inhibition observed in Black people is that induced using RAAS inhibitors. In this regard, in the context of the COVID-19 pandemic, the hypothesis has been proposed that RAAS blocker drugs could be a risk factor for patients with SARS-CoV-2 infection since their mechanism of action raises the synthesis of angiotensin-converting enzyme 2 (ACE2) by negative feedback.³² Indeed, experimental work has demonstrated that the use of these antihypertensive drugs increases ACE2 levels.³³ ACE2 is the receptor to which SARS-CoV-2 binds to enter the cell to cause infection.^34,35

It has also been suggested that SARS-CoV-2, upon entering the cell through its binding to ACE2 receptors, causes a decrease in intracellular levels of ACE2. ACE2, unlike classical ACE, is responsible for the degradation of angiotensin II. In this way, SARS-CoV-2 would induce the reduction of this protective mechanism of ACE2 on pulmonary parenchyma, worsening the harmful action of angiotensin II on the lungs of patients infected by this virus.³⁶ As shown in Figure 1, disadvantageous environmental factors, such as social adversity, favor an imbalance between ACE/ACE2.^37–43 This is critical in the African American population due to the lower activity of the ACE2 enzyme, as determined by genetics or epigenetics. This disequilibrium predisposes Black subjects to high blood pressure and cardiovascular risk as well as to lung damage by COVID-19. Additionally, the consequent low levels of angiotensin 1–7 and Mas receptor activation may reduce tissue protection and increase inflammatory response upon a stimulus such as a coronavirus aggression.^36,37 Genetic and epigenetic changes were also detected that seem to correspond to the increased risk among African Americans of developing both diabetes and a greater number of related cardiac, vascular, and renal complications.^44,45 In this context, a controlled interventional study was designed, with high doses of vitamin D in African Americans in an attempt to counteract the described adverse situations. A selected laboratory and genomic response will confirm whether the effect is beneficial.⁴⁶

Figure 1.

Imbalanced protective and harmful factors related to SARS-CoV-2 infection in African Americans. Multiple genetic and epigenetic factors added to the lack of balance between ACE/ACE2 are critical in the African American population, predisposing it to diseases such as hypertension and diabetes mellitus that worsen the pathophysiology of COVID-19 and increase morbidity and mortality in Black people.

For these reasons, we suggest that, in addition to disadvantageous socioeconomic and environmental factors present in Black populations, the higher susceptibility of dark-skinned people to infection and mortality by COVID-19 could be influenced by vitamin D deficiency/insufficiency and the particularities of RAAS in this race.

Vitamin D deficiency/insufficiency in dark-skinned people

A study based on the analysis of data from the National Health and Nutrition Examination Survey cycles 2007/2008 through 2013/2014 was performed to describe the prevalence of vitamin D deficiency and insufficiency in adults aged ⩾60 years from the United States (US). In this study, followed by other related studies,^47–55 Black patients showed a higher prevalence of vitamin D deficiency and insufficiency than White patients.

Reduced 25-hydroxyvitamin D serum levels in Black people are related to the increase in skin pigment and consequent decrease in dermal and hepatic vitamin D3 synthesis.^56–58 People with darker skin need higher doses of ultraviolet B radiation from sunlight than White people to synthesise sufficient amounts of vitamin D.^59,60 In this regard, vitamin D serum levels of a customarily pigmented population were compared with those of an albino Black population in a province of South Africa. Albino children had considerably higher vitamin D levels than normally pigmented children, even though dietary intake and sunlight exposure was similar in both groups. Despite these differences, the parathyroid hormone, plasma and red blood cell magnesium, and plasma calcium levels remained practically unchanged in both groups. This reinforces the idea that the vitamin D deficiency observed in Black people is due mainly to their increased skin pigmentation.⁶¹ A study on infant rickets in North America reported that vitamin D deficiency might occur in children with dark skin, regardless of their social or ethnic origin. Therefore, the administration of vitamin D supplements to children with over pigmented skin whatever their race or economic and social background becomes essential.^62–64 A clinical trial demonstrated that supplementation with 4000 IU/day of vitamin D3 for 1 year in African American men caused the disappearance of any significant difference between their serum levels of 25(OH)D and that of White men.^65,66 Likewise, vitamin D supplementation is especially recommended in obese Black people, since this population group, in particular, has a significant risk of suffering from secondary hyperparathyroidism and vitamin D deficiency.^67,68 In this sense, vitamin D deficiency was compared in obese and non-obese African American children. The obese group had a more significant initial vitamin D deficiency and was even more resistant to treatment with vitamin D3 supplements than the non-obese group.⁶⁹ Another study compared vitamin D serum levels of a Norwegian population with an African population (both groups comprised healthy young people and pregnant women). The results showed that, despite the abundant ultraviolet radiation available in the African region studied, vitamin D deficiency was significantly higher in the African population group.⁷⁰ Serum levels of vitamin D in winter were measured in a low-income, multiracial elderly population composed of Black, White, and Asian people. The results showed that all groups had low levels of vitamin D, but the lowest percentage (almost half compared with the other ethnic groups) of vitamin D insufficiency was observed in Black subjects. In contrast, percentages in the White and Asian subsets were very similar between them.⁷¹ It has also been suggested that, although Black people synthesise lower concentrations of vitamin D3 than White people in response to normal sunlight exposure levels in winter and summer, both Black and White populations seem to have a similar ability to absorb and produce vitamin D after repeated exposure to B ultraviolet light at high doses.⁷² Although vitamin D synthesis decreases with age in both older Black and White people, the health ABC prospective cohort study showed that mortality was higher in Black than in older White patients, which could be related to the lower vitamin D serum levels found in Black people.⁷³

The distinctive vitamin D deficiency observed in Black populations does not seem to affect their bone health (except for the elderly) since their bones are resistant to resorption caused by parathyroid hormone. They also display a superior ability to achieve a more effective renal conservation of calcium than White people. Despite this, vitamin D deficiency may affect many other homeostatic mechanisms, predisposing the Black race to several pathologies.^74–77 It has been observed, for instance, that Black people with tuberculosis have lower serum levels of vitamin D than healthy Black subjects. These circumstances suggest that there may be an association between vitamin D deficiency and susceptibility to pulmonary pathologies.^78,79 A similar situation was observed in young African patients with vitamin D deficiency whose low vitamin D serum level was related to the severity and prevalence of asthma in these patients.^80,81

The incidence of end-stage renal disease is markedly higher in Black than in White populations, which would be related to the renoprotective effects of vitamin D and its deficiency in dark-skinned people.^82,83 It has been suggested that vitamin D also plays an essential role in the regulation of blood pressure, where deficient concentrations of vitamin D may cause an elevation of blood pressure values. This response would be a possible explanation for the greater susceptibility of Black people to developing hypertension compared with White people.⁸⁴ It has also been determined that there is a strong inverse association between C-reactive protein and vitamin D plasma levels. Patients with vitamin D deficiency have higher levels of C-reactive protein, which may influence the development of cancer and multiple cardiovascular diseases (another explanation for the high prevalence of these pathologies in the Black race).^85,86 Additionally, it has been observed that vitamin D deficiency would be related to the development of cardiovascular disease in African American people with type 2 diabetes mellitus. The explanation for this is that vitamin D deficiency would cause downregulation of hydrogen sulfide and cyclic adenosine monophosphate – two crucial signalling molecules related to the prevention of cardiovascular oxidative stress and inflammation. Interestingly enough, this downregulation has not been observed in White diabetic patients. In this sense, in vitro studies have shown that vitamin D supplementation increases hydrogen sulfide and cyclic adenosine monophosphate levels. It also contributes to reducing oxidative stress caused by elevated glucose levels, which would be responsible for greater cardiovascular inflammation in African American diabetic subjects. The results suggest that the higher incidence of cardiovascular disease in African American patients compared with White diabetic patients would be a consequence of, among other causes, vitamin D deficiency.⁸⁷ Another study has also demonstrated that vitamin D deficiency causes methylation changes in leukocyte DNA, which could induce immune system impairment in patients with vitamin D deficiency.⁸⁸ For instance, systemic lupus erythematosus is an autoimmune pathology with a high incidence among African American women. This would also be related to vitamin D deficiency since this vitamin may prevent cellular aging due to telomere shortening, which is a crucial factor in the development and progression of this chronic disease.⁸⁹

Furthermore, another study suggests that skin pigmentation and dietary habits are not the only determining factors in vitamin D deficiency. There is also a genetic association between vitamin D status and the degree of African ancestry of the studied population, since serum concentrations of vitamin D were correlated inversely with high, medium, low, or null African ancestry. Moreover, the effects of diet and sunlight on the rise in vitamin D serum levels were significantly lower in the high African ancestry group than in low/medium ancestry groups.⁹⁰ However, vitamin D supplementation may reduce this relationship.⁹¹ The possible ethnic association was supported by the results of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents and the National Health and Nutrition Examination Survey (NHANES), which compared children from different ethnic groups to assess the influence of ethnicity on the concentration of multiple biomarkers. The results showed that vitamin D was one of the biomarkers whose serum levels are influenced by ethnicity.^92,93 Vitamin D binding protein (the leading vitamin D carrier protein in plasma) levels are also lower in Black than in White Americans, which suggests that plasma levels of this protein do not affect the bioavailability of vitamin D in Black people. Despite this, the existence of racial differences in common genetic polymorphisms of Vitamin D binding protein may be responsible for lower vitamin D serum levels in Black subjects, since changes in their affinity for vitamin D directly influence its bioavailability.⁹⁴

Collectively, it is clear that there is a close relationship between vitamin D deficiency (due to either genetic, ethnic, or phenotypic causes) and the prevalence of morbidity and mortality in many pathologies, such as COVID-19 in Black people.

Peculiarities of RAAS in Black populations

African Americans have significantly higher rates of hypertension and related diseases, with Black hypertensive patients being less responsive to treatment with RAAS inhibitors than White hypertensive patients.^95,96 Changes in plasma renin activity, angiotensin II, and aldosterone levels were studied in White and Black hypertensive patients undergoing a high-salt diet followed by a low-salt diet. It was observed that the increase in all plasma components of RAAS after the reduction in salt intake was significantly higher in White than in Black patients, suggesting a less responsive sRAAS in Black patients.⁹⁷ The lower sRAAS responsiveness in Black people usually causes hypertension treatment in these patients to require the administration of diuretic drugs or calcium channel blockers in a higher percentage of cases than in White hypertensive patients. This is because antihypertensive monotherapy with RAAS blockers does not achieve efficient results.⁹⁸

Black people are usually characterized by having a significantly reduced plasma renin activity compared with White subjects, which cannot be explained by differences in dietary sodium intake between Black and White populations.⁹⁹ Hence, it has been proposed that this lower activity could be related to the maintenance of sodium balance, given the higher tendency of Black people to retain this ion as a genetic adaptation for improving sodium conservation in people that initially inhabited semitropical regions where sodium intake was usually low and hard to acquire.⁹⁹ A study of the differences in renal plasma flow in healthy Black populations under a high-salt diet has shown an overactivation of renal RAAS but not of sRAAS in Black people. Slight vasoconstriction was observed in response to angiotensin II infusion before the administration of an ACE inhibitor (captopril). Significant renal vasodilation caused by this inhibitor was also observed, in addition to an improvement of vasoconstriction response to angiotensin II infusion after captopril administration. Continuous renal plasma flow under modulation from a low-salt to a high-salt diet was also noted. These observations suggest higher renal concentrations of angiotensin II in these Black patients. The overactivated intrarenal RAAS would also be responsible for the negative feedback to reduce renin plasma levels in Black people.¹⁰⁰ The capacity of the Black race to retain sodium and water through the genetic polymorphisms of the renal tubular epithelial sodium channel would have allowed the survival of African slaves. It is known that a typical biochemical profile in hypertensive Black people is low or high plasma aldosterone levels, low or null plasma angiotensin I and II levels, and low or null renin activity/concentration. Therefore, there are two hypertension phenotypes in Black people: low or null renin and increased aldosterone concentrations (primary aldosteronism) or low levels of both renin and aldosterone (Liddle syndrome).^30,101,102 Following this, by using RAAS equilibrium analysis (a novel, highly precise method of RAAS assessment), lowered systemic levels of angiotensin I and II were observed in Black hypertensive patients compared with White hypertensive patients.¹⁰³

It is worth noting that the elevated sodium reabsorption observed in African American patients with obesity and hypertension was accompanied by functional medullary hypoxia associated with increased solute reabsorption. This suggests an increase in oxidative stress in African Americans that can worsen hypertension, diabetes mellitus, and many other pathologies (including COVID-19) in comparison with White hypertensive patients.¹⁰⁴

This evidence would support the idea that, in Black populations, RAAS is inhibited naturally at a systemic level. Therefore, an analogy between this particular behavior and the effect of RAAS inhibitors on ACE2 receptors could be established in COVID-19. However, some studies propose the idea that hypertension in Black people could develop from an imbalance between the RAAS (ACE/Ang II/AT1 receptor) pressor arm and the depressor axis [ACE2/Ang-(1-7)/Mas receptor], where ACE2 as protective RAAS axis would be reduced in hypertensive Black patients.¹⁰⁵ Moreover, another study reported that ACE2 expression was increased only in Asians but not in other ethnic populations.¹⁰⁶ Concerning genetic polymorphisms, African American people have an insertion/deletion polymorphism in the angiotensin I converting enzyme gene, which stimulates higher production of tissue angiotensin II and would predispose them to the development of hypertension and related diseases more frequently than White people.¹⁰⁷

Moreover, the frequency of the T235 allele of the angiotensinogen gene and the angiotensinogen level was found to be more significant in Black than in White individuals. This racial RAAS disparity would also contribute to the differences in blood pressure levels between White and Black subjects.^108,109 It has also been suggested that the (–535)T allele of angiotensin II type 1 receptor and (–344)T allele of aldosterone synthase can increase the risk of developing hypertension in African Americans but not in Latinos.¹¹⁰

Therefore, how RAAS influences mechanisms of susceptibility of Black populations to infection and death by COVID-19 remains unclear. For this reason, more studies should be performed to confirm the proposed hypotheses.

Conclusions and perspectives

Figure 2 summarizes our conceptual explanation of why African American people have the abovementioned susceptibility in the current pandemic. Either due to African genetic ancestry or phenotypic features of the Black race – such as increased skin pigmentation – and the vitamin D deficiency/insufficiency prevalent in Black people, there is greater susceptibility in this ethnic group to infection and death due to SARS-CoV-2 infection. As a consequence, it is of vital importance to encourage vitamin D intake in the Black population, not only through the diet but also through nutritional supplements. Moreover, it would be necessary to carefully analyze and adjust current vitamin D recommendations since they have been determined assuming there are no disparities between vitamin D requirements in White people and other racial/ethnic groups. In this sense, Rusińska et al. have made specific recommendations for people with a dark complexion.¹¹¹

Figure 2.

Differential susceptibility to SARS-CoV-2 infection of Black and White populations. Unfavorable socioeconomic factors, low vitamin D levels, and a less-responsive sRAAS impact the susceptibility to infection and death by COVID-19 in Black people. Compared to White people, African Americans have a higher prevalence of hypertension and diabetes mellitus, which are important risk factors for SARS-CoV-2 infection. Dark-skinned, African ancestry level and an increased ability to retain sodium are some of the main genetic and evolutionary factors of this differential ethnic susceptibility. Solid lines indicate stimulation/induction, while dashed lines indicate inhibition/blocking.

Regarding its peculiarities in the Black race, RAAS could participate in the higher prevalence of infection and death by SARS-CoV-2 in this population. The specific mechanisms involved, however, remain unclear. The expression level of human ACE2 in different tissues, especially in the lungs, may be crucial for the susceptibility to, development, symptoms, and progression of COVID-19. The lower responsiveness of the RAAS in Black people could be related to this, although data are conflicting and this hypothesis is yet to be confirmed.

Footnotes

Author contributions

All authors participated in the conception and design of this review with a substantial contribution to data analysis and interpretation, as well as drafting and critical revision of the article for content and form.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by grants from the Research and Technology Council of Cuyo University (SECyT), Mendoza, Argentina, and from ANPCyT FONCyT, both of which were awarded to Walter Manucha. Grant no. PICT 2016-4541

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iD

Walter Manucha

References

Yancy

CW.

COVID-19 and African Americans. JAMA 2020; 323: 1891–1892.

Grant

Peiris

AN.

Possible role of serum 25-hydroxyvitamin D in Black-White health disparities in the United States. J Am Med Dir Assoc 2010; 11: 617–628.

Williams

Mohammed

Leavell

, et al. Race, socioeconomic status, and health: complexities, ongoing challenges, and research opportunities. Ann N Y Acad Sci 2010; 1186: 69–101.

Harris

SS.

Does vitamin D deficiency contribute to increased rates of cardiovascular disease and type 2 diabetes in African Americans?

Am J Clin Nutr 2011; 93: 1175S–1178S.

Gupta

Brashear

Johnson

WD.

Low vitamin D levels, prediabetes and prehypertension in healthy African American adults. Nutr Metab Cardiovasc Dis 2012; 22: 877–882.

Signorello

Han

Cai

, et al. A prospective study of serum 25-hydroxyvitamin D levels and mortality among African Americans and non-African Americans. Am J Epidemiol 2013; 177: 171–179.

Durazo-Arvizu

Aloia

Dugas

, et al. 25-hydroxyvitamin D levels in African American and Nigerian women. Am J Hum Biol 2013; 25: 560–562.

Chauveau

Aparicio

Ethnicity and vitamin D. Nephrol Ther 2013; 9: 398–402.

Carpagnano

Di Lecce

Quaranta

, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. Epub ahead of print 9 August 2020. DOI: 10.1007/s40618-020-01370-x.

10.

Grant

Giovannucci

The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermatoendocrinol 2009; 1: 215–219.

11.

Urashima

Segawa

Okazaki

, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010; 91: 1255–1260.

12.

Gruber-Bzura

BM.

Vitamin D and influenza-prevention or therapy?

Int J Mol Sci 2018; 19: 2419–2436.

13.

Greiller

Martineau

Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 2015; 7: 4240–4270.

14.

Jolliffe

Greenberg

Hooper

, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019; 74: 337–345.

15.

Rejnmark

Bislev

Cashman

, et al. Non-skeletal health effects of vitamin D supplementation: a systematic review on findings from meta-analyses summarizing trial data. PLoS One 2017; 12: e0180512.

16.

Yamshchikov

Desai

Blumberg

, et al. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009; 15: 438–449.

17.

Charan

Goyal

Saxena

, et al. Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis. J Pharmacol Pharmacother 2012; 3: 300–303.

18.

Bergman

Lindh

Bjorkhem-Bergman

, et al. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2013; 8: e65835.

19.

Mao

Huang

Vitamin D supplementation and risk of respiratory tract infections: a meta-analysis of randomized controlled trials. Scand J Infect Dis 2013; 45: 696–702.

20.

Das

Singh

Panigrahi

, et al. Vitamin D supplementation for the treatment of acute childhood pneumonia: a systematic review. ISRN Pediatr 2013; 2013: 459160.

21.

Jolliffe

Griffiths

Martineau

AR.

Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol 2013; 136: 321–329.

22.

Xiao

Xing

Yang

, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. Br J Nutr 2015; 114: 1026–1034.

23.

Yakoob

Salam

Khan

, et al. Vitamin D supplementation for preventing infections in children under five years of age. Cochrane Database Syst Rev 2016; 11: CD008824.

24.

Vuichard Gysin

Dao

Gysin

, et al. Effect of vitamin D3 supplementation on respiratory tract infections in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2016; 11: e0162996.

25.

Grant

Lahore

McDonnell

, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020; 12: 988.

26.

Zuin

Rigatelli

Zuliani

, et al. Arterial hypertension and risk of death in patients with COVID-19 infection: systematic review and meta-analysis. J Infect 2020; 81: e84–e86.

27.

Busse

Chow

McCurdy

, et al. COVID-19 and the RAAS-a potential role for angiotensin II? Crit Care 2020; 24: 136.

28.

South

Diz

Chappell

MC.

COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol 2020; 318: H1084–H1090.

29.

Lackland

DT.

Racial differences in hypertension: implications for high blood pressure management. Am J Med Sci 2014; 348: 135–138.

30.

Wilson

Grim

CE.

Biohistory of slavery and blood pressure differences in Blacks today. A hypothesis. Hypertension 1991; 17(Suppl. 1): I122–I128.

31.

Zilbermint

Hannah-Shmouni

Stratakis

CA.

Genetics of hypertension in African Americans and others of African descent. Int J Mol Sci 2019; 20: 1081.

32.

Sommerstein

Grani

Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020; 368: m810.

33.

Zhang

Zhuo

JL.

The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 2017; 125: 21–38.

34.

Moore

Vasilieva

, et al. Angiotensin- converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426: 450–454.

35.

Hoffmann

Kleine-Weber

Schroeder

, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 1–10.

36.

Kuba

Imai

Rao

, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436: 112–116.

37.

Perlot

Penninger

JM.

ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect 2013; 15: 866–873.

38.

Bousquet

Anto

Iaccarino

, et al. Is diet partly responsible for differences in COVID-19 death rates between and within countries? Clin Transl Allergy 2020; 10: 16.

39.

Fernández-Quintela

Milton-Laskibar

Trepiana

, et al. Key aspects in nutritional management of COVID-19 patients. J Clin Med 2020; 9: E2589.

40.

Ajilore

Thames

AD.

The fire this time: the stress of racism, inflammation and COVID-19. Brain Behav Immun 2020; 88: 66–67.

41.

Steenblock

Todorov

Kanczkowski

, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol Psychiatry 2020; 25: 1611–1617.

42.

Frontera

Cianfanelli

Vlachos

, et al. Severe air pollution links to higher mortality in COVID-19 patients: the “double-hit” hypothesis. J Infect 2020; 81: 255–259.

43.

Alifano

Forgez

, et al. Renin-angiotensin system at the heart of COVID-19 pandemic. Biochimie 2020; 174: 30–33.

44.

Chatterjee

Maruthur

Edelman

Novel risk factors for type 2 diabetes in African-Americans. Curr Diab Rep 2015; 15: 103.

45.

Akinyemiju

Patki

, et al. Epigenome-wide association study of metabolic syndrome in African-American Adults. Clin Epigenetics 2018; 10: 49.

46.

Norris

Edwina Barnett

Meng

Y-X

, et al. Rationale and design of a placebo controlled randomized trial to assess short term, high-dose oral cholecalciferol on select laboratory and genomic responses in African Americans with hypovitaminosis D. Contemp Clin Trials 2018; 72: 20–25.

47.

Orces

Lorenzo

Guarneros

JE.

The prevalence and determinants of vitamin D inadequacy among U.S. older adults: National Health and Nutrition Examination Survey 2007-2014. Cureus 2019; 11: e5300.

48.

Patience

Vitamin D deficiency in at-risk groups. Community Pract 2013; 86: 38–40.

49.

Darji

Tobin

Bryan

, et al. Vitamin D deficiency and atopic dermatitis: consider disease, race, and body mass. Skinmed 2017; 15: 415–420.

50.

Shea

Houston

Tooze

, et al. Health, aging and body composition study. Correlates and prevalence of insufficient 25-hydroxyvitamin D status in Black and White older adults: the health, aging and body composition study. J Am Geriatr Soc 2011; 59: 1165–1174.

51.

Burke

Harville

Wickliffe

, et al. Determinants of vitamin D status among Black and White low-income pregnant and non-pregnant reproductive-aged women from Southeast Louisiana. BMC Pregnancy Childbirth 2019; 19: 111.

52.

Nesby-O’Dell

Scanlon

Cogswell

, et al. Hypovitaminosis D prevalence and determinants among African American and White women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002; 76: 187–192.

53.

Reed

Laya

Melville

, et al. Prevalence of vitamin D insufficiency and clinical associations among veiled East African women in Washington State. J Womens Health (Larchmt) 2007; 16: 206–213.

54.

Talwar

Swedler

Yeh

, et al. Vitamin-D nutrition and bone mass in adolescent Black girls. J Natl Med Assoc 2007; 99: 650–657.

55.

Davis

Chang

Mancini

, et al. Vitamin D insufficiency is prevalent among pregnant African American adolescents. J Pediatr Adolesc Gynecol 2010; 23: 45–52.

56.

Bell

NH.

Bone and mineral metabolism in African Americans. Trends Endocrinol Metab 1997; 8: 240–245.

57.

Benitez-Aguirre

Wood

Biesheuvel

, et al. The natural history of vitamin D deficiency in African refugees living in Sydney. Med J Aust 2009; 190: 426–428.

58.

Gallagher

Peacock

Yalamanchili

, et al. Effects of vitamin D supplementation in older African American women. J Clin Endocrinol Metab 2013; 98: 1137–1146.

59.

Horton-French

Dunlop

Lucas

, et al. Prevalence and predictors of vitamin D deficiency among African immigrants living in Australia. Int J Environ Res Public Health 2019; 16: E2855.

60.

Harris

SS.

Vitamin D and African Americans. J Nutr 2006; 136: 1126–1129.

61.

Cornish

Maluleke

Mhlanga

An investigation into a possible relationship between vitamin D, parathyroid hormone, calcium and magnesium in a normally pigmented and an albino rural Black population in the Northern Province of South Africa. Biofactors 2000; 11: 35–38.

62.

Shah

Salhab

Patterson

, et al. Nutritional rickets still afflict children in north Texas. Tex Med 2000; 96: 64–68.

63.

McGillivray

Skull

Davie

, et al. High prevalence of asymptomatic vitamin D and iron deficiency in East African immigrant children and adolescents living in a temperate climate. Arch Dis Child 2007; 92: 1088–1093.

64.

Tseng

Giri

Bruner

, et al. Prevalence and correlates of vitamin D status in African American men. BMC Public Health 2009; 9: 191.

65.

Garrett-Mayer

Wagner

Hollis

, et al. Vitamin D3 supplementation (4000 IU/d for 1 y) eliminates differences in circulating 25-hydroxyvitamin D between African American and White men. Am J Clin Nutr 2012; 96: 332–336.

66.

Cashman

Ritz

Adebayo

, et al. Differences in the dietary requirement for vitamin D among Caucasian and East African women at Northern latitude. Eur J Nutr 2019; 58: 2281–2291.

67.

Yanoff

Parikh

Spitalnik

, et al. The prevalence of hypovitaminosis D and secondary hyperparathyroidism in obese Black Americans. Clin Endocrinol (Oxf) 2006; 64: 523–529.

68.

Saintonge

Bang

Gerber

LM.

Implications of a new definition of vitamin D deficiency in a multiracial us adolescent population: the National Health and Nutrition Examination Survey III. Pediatrics 2009; 123: 797–803.

69.

Rajakumar

Fernstrom

Holick

, et al. Vitamin D status and response to vitamin D₃ in obese vs. non-obese African American children. Obesity (Silver Spring) 2008; 16: 90–95.

70.

Feleke

Abdulkadir

Mshana

, et al. Low levels of serum calcidiol in an African population compared to a North European population. Eur J Endocrinol 1999; 141: 358–360.

71.

Harris

Soteriades

Coolidge

, et al. Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 2000; 85: 4125–4130.

72.

Dawson-Hughes

Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am J Clin Nutr 2004; 80(Suppl. 6): 1763S–1766S.

73.

Kritchevsky

Tooze

Neiberg

, et al.; Health ABC Study. 25-Hydroxyvitamin D, parathyroid hormone, and mortality in Black and White older adults: the health ABC study. J Clin Endocrinol Metab 2012; 97: 4156–4165.

74.

Aloia

JF.

African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox. Am J Clin Nutr 2008; 88: 545S–550S.

75.

Cosman

Nieves

Dempster

, et al. Vitamin D economy in Blacks. J Bone Miner Res 2007; 22(Suppl. 2): V34–V38.

76.

Akhter

Sinnott

Mahmood

, et al. Effects of vitamin D insufficiency on bone mineral density in African American men. Osteoporos Int 2009; 20: 745–750.

77.

Sakamoto

Thorpe

Knutsen

, et al. Ethnic variations in serum 25(OH)D levels and bone ultrasound attenuation measurements in Blacks and Whites. J Racial Ethn Health Disparities 2018; 5: 439–448.

78.

Gibney

MacGregor

Leder

, et al. Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin Infect Dis 2008; 46: 443–446.

79.

Abhimanyu

Meyer V

Jeffery

, et al. Vitamin D status in South Africa and tuberculosis. Lung 2015; 193: 975–984.

80.

Freishtat

Iqbal

Pillai

, et al. High prevalence of vitamin D deficiency among inner-city African American youth with asthma in Washington, DC. J Pediatr 2010; 156: 948–952.

81.

Pillai

Iqbal

Benton

, et al. Associations between genetic variants in vitamin D metabolism and asthma characteristics in young African Americans: a pilot study. J Investig Med 2011; 59: 938–946.

82.

Melamed

Astor

Michos

, et al. 25-hydroxyvitamin D levels, race, and the progression of kidney disease. J Am Soc Nephrol 2009; 20: 2631–2639.

83.

Manucha

Juncos

LI.

The protective role of vitamin D on the heart and the kidney. Ther Adv Cardiovasc Dis 2017; 11: 1753944716675820.

84.

Rostand

SG.

Vitamin D, blood pressure, and African Americans: toward a unifying hypothesis. Clin J Am Soc Nephrol 2010; 5: 1697–1703.

85.

Chandler

Scott

Drake

, et al. Impact of vitamin D supplementation on inflammatory markers in African Americans: results of a four-arm, randomized, placebo-controlled trial. Cancer Prev Res (Phila) 2014; 7: 218–225.

86.

Myburgh

Towers

Kruger

, et al. CRP genotypes predict increased risk to co-present with low vitamin D and elevated CRP in a group of healthy Black South African women. Int J Environ Res Public Health 2018; 15: E111.

87.

Jain

Manna

Micinski

, et al. In African American type 2 diabetic patients, is vitamin D deficiency associated with lower blood levels of hydrogen sulfide and cyclic adenosine monophosphate, and elevated oxidative stress? Antioxid Redox Signal 2013; 18: 1154–1158.

88.

Zhu

Wang

Shi

, et al. A genome-wide methylation study of severe vitamin D deficiency in African American adolescents. J Pediatr 2013; 162: 1004–1009.e1.

89.

Hoffecker

Raffield

Kamen

, et al. Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: a case-control study. PLoS One 2013; 8: e63725.

90.

Signorello

Williams

Zheng

, et al. Blood vitamin D levels in relation to genetic estimation of African ancestry. Cancer Epidemiol Biomarkers Prev 2010; 19: 2325–2331.

91.

Haddad

Ruiz-Narváez

Cozier

, et al. Association of degree of European genetic ancestry with serum vitamin D levels in African Americans. Am J Epidemiol 2018; 187: 1420–1423.

92.

Tahmasebi

Asgari

Hall

, et al. Influence of ethnicity on biochemical markers of health and disease in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med 2020; 58: 605–617.

93.

Schleicher

Sternberg

Looker

, et al. National estimates of serum total 25-hydroxyvitamin D and metabolite concentrations measured by liquid chromatography-tandem mass spectrometry in the US population during 2007-2010. J Nutr 2016; 146: 1051–1061.

94.

Powe

Evans

Wenger

, et al. Vitamin D-binding protein and vitamin D status of Black Americans and White Americans. N Engl J Med 2013; 369: 1991–2000.

95.

Williams

Nicholas

Vaziri

, et al. African Americans, hypertension and the renin angiotensin system. World J Cardiol 2014; 6: 878–889.

96.

Papademetriou

Narayan

Kokkinos

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in African-American patients with hypertension. J Clin Hypertens (Greenwich) 2004; 6: 310–314.

97.

Markandu

Sagnella

, et al. Importance of the renin system in determining blood pressure fall with salt restriction in Black and White hypertensives. Hypertension 1998; 32: 820–824.

98.

Bakris

Smith

Giles

, et al. Comparative antihypertensive efficacy of angiotensin receptor blocker-based treatment in African-American and White patients. J Clin Hypertens (Greenwich) 2005; 7: 587–595.

99.

Sagnella

GA.

Why is plasma renin activity lower in populations of African origin?

J Hum Hypertens 2001; 15: 17–25.

100.

Price

Fisher

ND.

The renin-angiotensin system in Blacks: active, passive, or what?

Curr Hypertens Rep 2003; 5: 225–230.

101.

Spence

JD.

Lessons from Africa: the importance of measuring plasma renin and aldosterone in resistant hypertension. Can J Cardiol 2012; 28: 254–257.

102.

Akintunde

Salawu

Oloyede

, et al. Renin activity and aldosterone assay among Nigerians with hypertension and normotension: an insight into normative values and clinical correlates. Curr Hypertens Rev 2018; 14: 29–34.

103.

van Rooyen

Poglitsch

Huisman

, et al. Quantification of systemic renin-angiotensin system peptides of hypertensive Black and White African men established from the RAS-Fingerprint®. J Renin Angiotensin Aldosterone Syst 2016; 17: 1470320316669880.

104.

Textor

Gloviczki

Flessner

, et al. Association of filtered sodium load with medullary volumes and medullary hypoxia in hypertensive African Americans as compared with Whites. Am J Kidney Dis 2012; 59: 229–237.

105.

Cohall

Ojeh

Ferrario

, et al. Is hypertension in African-descent populations contributed to by an imbalance in the activities of the ACE2/Ang-(1-7)/Mas and the ACE/Ang II/AT1 axes? J Renin Angiotensin Aldosterone Syst 2020; 21: 1470320320908186.

106.

Cao

Feng

, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 2020; 6: 11.

107.

Moskowitz

DW.

Hypertension, thermotolerance, and the “African gene”: an hypothesis. Clin Exp Hypertens 1996; 18: 1–19.

108.

Bloem

Manatunga

Tewksbury

, et al. The serum angiotensinogen concentration and variants of the angiotensinogen gene in White and Black children. J Clin Invest 1995; 95: 948–953.

109.

Rotimi

Puras

Cooper

, et al. Polymorphisms of renin-angiotensin genes among Nigerians, Jamaicans, and African Americans. Hypertension 1996; 27: 558–563.

110.

Henderson

Haiman

Mack

Multiple polymorphisms in the renin- angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort. Am J Med Sci 2004; 328: 266–273.

111.

Rusiń

Płudowski

Walczak

, et al. Vitamin D supplementation guidelines for general population and groups at risk of vitamin D deficiency in Poland-recommendations of the polish society of pediatric endocrinology and diabetes and the expert panel with participation of national specialist consultants and representatives of scientific societies-2018 update. Front Endocrinol (Lausanne) 2018; 9: 246.