# Clinical Pharmacogenomic Variants Among the Saudi Population and Their Impact on Drug Response: A Review of Saudi-Based Evidence

## TL;DR

This review examines how genetic variants affect drug response in the Saudi population, showing that gene-guided dosing could improve treatment outcomes.

## Contribution

The study provides high-certainty evidence for genotype-guided dosing in Saudi populations and identifies key pharmacogenomic associations.

## Key findings

- VKORC1 and CYP2C9 variants are strongly linked to lower warfarin maintenance doses in Saudis.
- CYP2C19 loss-of-function alleles are associated with clopidogrel non-response.
- CYP3A5 genotype significantly influences tacrolimus trough levels.

## Abstract

Pharmacogenomic implementation depends on the validity of gene-drug relationships within specific ethnic groups. However, the Saudi Arabian population, which had distinctive characteristics and high rates of marriage between relatives, remains underrepresented in global dosing algorithms. This systematic review and meta-analysis synthesized quantitative evidence from 16 studies encompassing 4,111 Saudi Arabian participants to examine the clinical impact of pharmacogenomic variants on drug efficacy, toxicity, and dosing requirements. The quality of the studies was assessed using the ROBINS-I tool, and the certainty of the evidence was graded according to the GRADE framework. The primary meta-analysis revealed a high-certainty association between VKORC1 and CYP2C9 variants and warfarin sensitivity, with variant carriers requiring a substantially lower maintenance dose (pooled mean difference: -20.68 mg/week; 95% confidence interval [CI]: -35.66 to -5.70). Trial sequential analysis confirmed that the required information size for this association was surpassed, establishing definitive evidence for genotype-guided anticoagulation. Regarding findings from individual studies and single gene-drug pairs, CYP2C19 loss-of-function alleles were strongly associated with clopidogrel non-response in the primary study on this topic (odds ratio: 3.43), and the CYP3A5 genotype was identified as a critical determinant of tacrolimus trough levels with a large effect size (Hedges’ g = 1.59). Significant statistical heterogeneity was observed, particularly within warfarin studies (I2 > 90%), which subgroup analysis suggested that geographical differences between the Eastern and Central provinces contributed to this variation. These findings indicate that the standard dosing regimens are suboptimal for a significant proportion of the Saudi population. These findings support the immediate integration of VKORC1 and CYP2C9 genotyping into local anticoagulation guidelines. They also highlight the need for large-scale pragmatic trials to confirm the effectiveness of genotype-guided strategies in antiplatelet and immunosuppressive therapies.