Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

Chronic kidney disease (CKD) is a serious and increasingly common condition ( 1 ). Patients with CKD have a greatly increased risk of CVD, which represents the most common cause of mortality and morbidity in these patients, to the extent that CKD is considered an independent risk factor for CVD ( 2, 3 ). In CKD, many conventional risk factors for CVD are prevalent, including hypertension, dyslipidemia, and insulin resistance. Underlying conditions that are typical of CVD also occur, such as heightened infl ammatory status, oxidative stress, endothelial dysfunction, and arterial stiffness ( 3, 4 ). Consequently, understanding the factors in CKD that could contribute to increased CVD risk is very important.In CVD there is a clearly established link between dyslipidemia (specifi cally hypercholesterolemia and hypertriglyceridemia) and atherosclerosis, an underlying pathology of most CVD ( 5, 6 ). In view of the clear cardiorenal relationship, there has been considerable interest in the possible contribution of hyperlipidemia to CKD-associated CVD ( 7,8 )

The aim of this study was to investigate the safety and pharmacokinetic profiles of a newly developed, standardized extract of Centella asiatica (ECa 233) capsule in healthy Thai volunteers. This study was designed as an open-labeled, 2-sequence dosage, single- and repeated-dose study investigated under fasting conditions. Plasma concentrations of the parent compounds and their relative acid metabolites were measured and pharmacokinetic parameters were calculated using noncompartmental analysis. Tolerability was assessed based on physical examinations, monitoring of vital signs, clinical laboratory tests, and any observed adverse events. A key finding of this study was that the pharmacokinetics of ECa 233 in healthy volunteers did not correspond with its pharmacokinetics in animal studies. As indicated in human pharmacokinetic parameters, maximum plasma concentration and area under the curve of the parent compounds (madecassoside and asiaticoside) were very low, while their respective metabolites (madecassic acid and asiatic acid) demonstrated higher values. Based on the pharmacokinetic results observed in the dose comparison, accumulation of active metabolites after repeated dose is highly suggestive. In addition, the asiatic acid profile showed 2-fold increase in Cmax and AUC(0–t) after increasing dose from 250 to 500 mg of ECa 233. Lastly, the safety and tolerability evaluation illustrated that single and multiple doses in both 250 and 500 mg oral administration of ECa 233 were well tolerated, and none of the volunteers discontinued their participation due to adverse effects during the study.