The novel variants (which were not reported in 1000 Genomes Project Phase 3) with high impacts identified in the 171 individuals.

The novel variants (which were not reported in 1000 Genomes Project Phase 3) with high impacts identified in the 171 individuals.</p

This file contains S1-S4 Tables.

(DOCX)</p

Average read depth.

The overview of the average read depths of the 51 pharmacogenes (blue and red) and three control genes, EGFR (pink), VDR (green), and RYR1 (yellow). Four red boxes represent genes with low depth coverage, which are GSTM1, GSTT1, UGT2B15, and UGT2B17.</p

This file contains S1-S5 Figs.

(DOCX)</p

Variant or altered phenotype: Genes and number of individuals.

(A) Percentage of individuals with variant or altered phenotype. Poor metabolizer (PM; red) or poor function (PF; red) for SLCO1B1, SLCO1B3, and SLCO2B1; slow metabolizer (SM; pink); decreased function (DF; purple); intermediate metabolizer (IM; yellow); increased function (IF; dark green); rapid metabolizer (RM; green) or unfavorable response (UR; green) for IFNL3; ultra-rapid metabolizer (UM; dark blue). (B) The number of individuals with a particular number of genes where individuals had variant or altered phenotype. (C) The number of individuals with at least a particular number of genes where individuals had variant or altered phenotype.</p

Allele frequency comparisons of the 35 high impact variants among Thais (THA), African (AFR), admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS) were obtained from the 1000 genome project database.

(A) Variants whose allele frequencies are not available on the 1000 Genome Project database but found in Thai are denoted with Novel1-Novel21. (B) Δ, ▲, ○, ●, ■, * denote allele frequency of AFR, AMR, EAS, EUR, SAS, and THA, respectively. Allele frequencies that were significantly different (p < 0.05) between THA and other populations were shown in red, and the non-statistically significant variants were shown in blue.</p

DataSheet1_Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach.pdf

Background: Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail.Methods: Healthy young participants (n = 20), healthy elderly participants (n = 16) and elderly patients with CKD (n = 17) received, in study period 1, a single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After a 14-day wash-out period, healthy young participants continued to study period 2 with the microdose cocktail plus rifampicin. PK parameters including area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (Cmax), and half-life were estimated before making pairwise comparisons of geometric mean ratios (GMR) between groups.Results: AUC and Cmax GMR (95% confidence interval; CI) of midazolam, a CYP3A probe substrate, were increased 2.30 (1.70–3.09) and 2.90 (2.16–3.88) fold in healthy elderly and elderly patients with CKD, respectively, together with a prolonged half-life. AUC and Cmax GMR (95%CI) of atorvastatin, another CYP3A substrate, was increased 2.14 (1.52–3.02) fold in healthy elderly and 4.15 (2.98–5.79) fold in elderly patients with CKD, indicating decreased CYP3A activity related to ageing. Associated AUC changes in the probe drug whose activity could be modified by intestinal P-glycoprotein (P-gp) activity, dabigatran etexilate, were observed in patients with CKD. However, whether the activity of pitavastatin and rosuvastatin is modified by organic anion transporting polypeptide 1B (OATP1B) and of breast cancer resistance protein (BCRP), respectively, in elderly participants with or without CKD was inconclusive.Conclusions: CYP3A activity is reduced in ageing. Intestinal P-gp function might be affected by CKD, but further confirmation appears warranted.Clinical Trial Registration:http://www.thaiclinicaltrials.org/ (TCTR 20180312002 registered on March 07, 2018)</p

<i>TLR7</i> beta coefficients (on logistic scale) with 95% interval for the severe COVID-19 phenotype, MAF<1%.

X-axes are cut at -10 and 10. (DOCX)</p

Members of DeCOI, GEN-COVID (Italy), GEN-COVID (Spain), Mount Sinai Biobank, COVID-19 Host Genetics Initiative.

(XLSX)</p

<i>TLR7</i> beta coefficients (on logistic scale) with 95% interval for the severe COVID-19 phenotype, MAF<0.1%.

X-axes are cut at -10 and 10. (DOCX)</p