Pharmacogenomics

GLP-1 receptor signal peptide variant that enhances semaglutide and tirzepatide weight loss efficacy but increases nausea and vomiting risk

Rare protective missense variant in the GLP-1 receptor associated with lower fasting glucose, reduced T2D risk, and coronary heart disease protection

Intronic CYP2B6 haplotype-tagging variant associated with altered plasma concentrations of efavirenz, S-methadone, and other CYP2B6-metabolized drugs

GLP-1 receptor variant in intracellular loop 2 that alters receptor surface expression and signaling, influencing antipsychotic response, cortisol regulation, and bone metabolism

Synonymous variant in P-glycoprotein affecting drug efflux pump expression and hundreds of substrate drugs

No-function CYP2C9 variant with major warfarin implications

Synonymous CYP2D6 variant that promotes exon 3 skipping, reducing functional enzyme expression by ~50% and affecting metabolism of ~25% of prescription drugs

CYP2C8 3-prime UTR variant associated with cardiovascular risk via altered epoxyeicosatrienoic acid metabolism and hydroxychloroquine-related renal adverse effects

Decreased function CYP2D6 variant common in Asian populations

CYP2D6 promoter variant (-1584C>G) that reduces enzyme expression; the C allele is associated with lower CYP2D6 activity and impaired response to donepezil and other CYP2D6-metabolized drugs

Intronic tagging SNP for CYP2C8 haplotype C, a low-activity haplotype associated with reduced paclitaxel metabolism and increased repaglinide exposure

No-function variant causing deficient thiopurine methylation; most common TPMT deficiency allele in East Asian and African populations

Nucleotide diphosphatase that inactivates toxic thiopurine metabolites; reduced function causes severe myelosuppression at standard drug doses

Missense variant in IFNL4 exon 2 that reduces IFN-λ4 protein activity; the Ser70 form (A allele) produces weaker antiviral signalling and is associated with better hepatitis C clearance among ΔG carriers

Increased function CYP2C19 variant - rapid/ultrarapid metabolizer

Missense variant reducing CYP3A4 enzyme activity by 50–74% depending on substrate, found primarily in East Asian populations at ~2% allele frequency

Missense variant causing substrate-dependent reduced CYP3A4 activity, most prevalent in Japanese and East Asian populations

Intronic variant in IFNL4 — the strongest host genetic predictor of hepatitis C spontaneous clearance and treatment response, controlling interferon lambda antiviral immunity

Downstream variant near IFNL3 — third IL28B locus predictor of hepatitis C spontaneous clearance and treatment response; preferred tag for HCV pharmacogenomics in Asian populations where it was the original GWAS discovery signal

Intronic CYP2C8 haplotype-tagging variant linked to altered drug metabolism capacity and bisphosphonate-related osteonecrosis of the jaw risk

Intronic CYP2C8 variant tagging a haplotype associated with altered taxane drug clearance and survival outcomes in chemotherapy-treated patients

Common CYP2D6 variant defining the *2 allele; previously considered normal-function but recent evidence shows reduced expression through altered splicing

Synonymous CYP2D6 variant that causes allele dropout in standard CYP2D6*3 genotyping assays, potentially masking co-inherited non-functional alleles

Decreased function variant affecting warfarin, phenytoin, and NSAIDs

Mu-opioid receptor variant affecting opioid response, pain sensitivity, and potentially naltrexone efficacy

Decreased-function variant causing reduced thiopurine methylation; pairs with TPMT*3C on the same chromosome to form the TPMT*3A haplotype, the most common cause of TPMT deficiency in Europeans

The original TPMT deficiency allele — a no-function star allele causing ~100-fold loss of thiopurine methylation activity through accelerated proteolysis; independent of the TPMT*3 cluster and found almost exclusively in people of European ancestry

Loss-of-function CYP2A6 variant that abolishes nicotine metabolism, slowing clearance of nicotine, cotinine, coumarin, letrozole, tegafur, and efavirenz

Intronic CYP2C8 variant associated with paclitaxel-induced toxicity and bisphosphonate-related osteonecrosis risk in multiple myeloma

Intronic CYP2C8 variant linked to epoxygenase pathway activity, hypertension susceptibility, COPD risk, and bladder cancer protection

Deep intronic CYP2C9 variant associated with altered drug response to sulfonylurea antidiabetics and other CYP2C9 substrates

Intronic CYP2C9 haplotype tag associated with altered warfarin sensitivity and NSAID metabolism in Asian populations

Intronic CYP2C8 variant linked to altered enzyme expression and associated with bisphosphonate-related jaw complications and clopidogrel response

Promoter variant increasing CYP2E1 inducibility, elevating oxidative stress from ethanol and procarcinogen metabolism

Intronic CYP1A2 variant near the 5' end; G allele is associated with altered metabolic ratios for CYP1A2 substrates including escitalopram

CYP2E1 promoter variant affecting enzyme expression and susceptibility to acetaminophen hepatotoxicity, alcohol-induced liver injury, and drug-induced hepatotoxicity

Intronic CYP2E1 variant tagging the *1B haplotype; C allele marks reduced CYP2E1 expression and is associated with adverse drug reactions during tuberculosis treatment

Reduces vitamin K metabolism, requiring higher warfarin doses to achieve anticoagulation

Reduces ABCG2 transporter function affecting rosuvastatin levels and uric acid excretion, increasing risk for statin side effects and gout

Intronic variant in CYP3A4 intron 10 that upregulates a suppressive lncRNA, reducing CYP3A4 and CYP3A5 expression by ~30%; affects dosing of tacrolimus, sirolimus, statins, and psychiatric drugs

Intronic CYP3A4 variant associated with altered drug clearance, affecting metabolism of methadone, cyclosporine, and other CYP3A4 substrates

Intronic variant in CYP2J2 that tags reduced epoxyeicosatrienoic acid (EET) production, lowering the vasodilatory and cardioprotective signaling molecules derived from arachidonic acid

Intronic variant in MATE1, the renal and hepatic metformin efflux transporter; the A allele reduces tubular secretion, prolongs metformin retention, and enhances glucose-lowering response in type 2 diabetes

3' UTR variant that increases CYP2E1 expression, raising hepatotoxicity risk from acetaminophen, isoniazid, ethanol, and occupational solvents

Synonymous exon-8 variant that reduces CYP2E1 mRNA and protein expression, altering metabolism of acetaminophen, isoniazid, ethanol, and volatile anesthetics

Promoter variant affecting CYP3A4 expression, most common in African populations

Decreased-function CYP2D6 allele common in African populations, reducing metabolism of antidepressants, antipsychotics, opioids, and tamoxifen

Intronic splice variant causing decreased CYP2D6 enzyme activity through aberrant splicing

Rare CYP2D6 stop-gain variant (Glu418Ter) that eliminates enzyme activity, causing poor metabolism of opioids, antidepressants, antipsychotics, and tamoxifen

Rare missense variant causing a Leu293Arg substitution in CYP3A4, associated with reduced enzyme activity and altered metabolism of tacrolimus, warfarin, and other CYP3A4 substrates; most frequent in East Asian populations

Promoter variant that reduces CYP2A6 expression by ~50%, slowing nicotine metabolism and altering response to several cancer and antiretroviral drugs

CYP2A6*7 missense variant that nearly abolishes nicotine C-oxidase activity; prevalent in East Asian populations and affects nicotine metabolism, smoking behavior, and several drug clearance pathways

Deep intronic CYP2D6 variant in intron 2 that serves as a haplotype tag in specific CYP2D6 sub-alleles; independent functional effect on enzyme activity is not established

Reduces OCT2 organic cation transporter function in the kidney, lowering metformin renal clearance and conferring partial protection against cisplatin ototoxicity and nephrotoxicity

Intronic splice variant causing ~50% reduced CYP3A4 mRNA expression, affecting metabolism of ~50% of all prescription drugs

Causal frameshift polymorphism controlling IFNL4 protein production; the ΔG allele creates functional interferon lambda 4 which paradoxically impairs hepatitis C clearance

Near-complete loss-of-function CYP2B6 variant causing severely impaired metabolism of efavirenz, bupropion, methadone, and other CYP2B6 substrates

Decreased-function variant affecting metabolism of efavirenz, methadone, bupropion, and cyclophosphamide

Common CYP2C19 missense variant defining the *1B allele; the G (Val331) allele is the population-major normal-function form, while the rare A (Ile331) allele marks loss-of-function haplotype backgrounds

Missense variant in the GLP-1 receptor that alters drug response to GLP-1 agonists (Ozempic, Wegovy, Saxenda) and DPP-4 inhibitors, with genome-wide significant protection against type 2 diabetes in East Asians

Intronic variant in KDM4A histone demethylase associated with problematic opioid prescription use in a 132,113-participant GWAS

Upstream CYP2C19 variant associated with altered R-warfarin clearance and increased exposure to CYP2C19 substrates

CYP2D6 *4 splice-defect null allele — the most common loss-of-function CYP2D6 variant in Europeans (~20% allele frequency) and the most-prescribed-against PGx variant worldwide. Determines codeine and tramadol failure (no morphine/O-desmethyltramadol conversion), reduced tamoxifen→endoxifen activation, and elevated exposure to many SSRIs and tricyclic antidepressants metabolized by CYP2D6.

Most critical pharmacogenomic variant causing complete loss of DPD enzyme function; increases fatal 5-FU/capecitabine toxicity risk 25-fold without dose reduction

Phase II glucuronidation enzyme that metabolizes bilirubin and many drugs including irinotecan; reduced activity causes Gilbert syndrome and severe chemotherapy toxicity

Statin transport - affects muscle side effect risk with statins

No-function CYP2C19 variant affecting PPIs, clopidogrel, and some antidepressants

Frameshift insertion in CYP3A4 exon 9 that produces a truncated, non-functional enzyme — carriers have essentially no CYP3A4 activity from this allele, making them poor metabolizers for tacrolimus, cyclosporine, midazolam, and ~50% of prescribed drugs

CYP2E1 intronic haplotype tag — affects enzyme activity and susceptibility to drug-induced liver injury and chemical toxicity

3' untranslated region variant in IFNL3 (IL28B) that controls mRNA stability via AU-rich elements and miRNA binding — independently predicts hepatitis C spontaneous clearance and treatment response

No-function CYP2C19 stop-gain variant — second most common loss-of-function allele, highest in East Asian ancestry

Rare CYP2A6 missense variant (p.Thr294Ile) that likely reduces nicotine-metabolising enzyme activity, affecting smoking behaviour, cessation pharmacotherapy response, and metabolism of letrozole and tegafur

Frameshift deletion causing no enzyme function, defining poor metabolizer status for many drugs including codeine, tramadol, and antidepressants

Missense variant reducing CYP3A4-mediated nifedipine clearance, causing elevated exposure to statins and other CYP3A4 substrates in heterozygous carriers

No-function DPYD star allele (I560S) causing severe DPD deficiency; one of four CPIC high-priority variants requiring 50% fluoropyrimidine dose reduction

CYP2E1*3 missense variant with no demonstrated change in enzyme activity for acetaminophen, ethanol, or industrial solvent substrates

Synonymous exon-11 tag SNP for the DPYD HapB3 haplotype; benign on its own but in near-complete linkage with the causal deep intronic splice variant rs75017182 that causes ~50% DPD activity loss

Intronic variant in EIPR1 (endosomal trafficking protein) associated with pain sensitivity via neuropeptide vesicle regulation

Intronic CYP2D6 variant tagging East Asian *10-lineage suballeles; the C allele co-segregates with reduced-function haplotypes affecting metabolism of ~25% of prescribed medications

Factor V Leiden - blood clotting disorder affecting thrombosis risk

Intronic variant in the OCT1 organic cation transporter reducing hepatic metformin uptake and altering response to multiple cation-transported drugs

Intergenic variant near LRRIQ3 associated with problematic opioid prescription use in a large GWAS; the T allele tags elevated risk of using opioids not as prescribed

Missense variant (Val179Ile) defining the CYP2E1*4 allele; associated with altered CYP2E1 enzyme activity affecting metabolism of acetaminophen, ethanol, isoniazid, halogenated anesthetics, benzene, and tobacco nitrosamines

Alcohol metabolism - flush reaction and cancer risk

Decreased-function variant reducing DPD enzyme activity ~30%, requiring 50% fluoropyrimidine dose reduction

Rare missense variant in CYP3A4 that reduces protein expression and enzymatic activity across multiple drug substrates

Rare CYP2C9 N-terminal missense variant of uncertain functional significance in a CYP2C9 substrate metabolizer gene

GLP-1 receptor variant that alters response to GLP-1 agonist medications used for weight loss and type 2 diabetes

Intronic CYP2D6 haplotype tag variant (rs28371702 canonical form) associated with altered drug metabolism ratios for CYP2D6 substrates including aripiprazole and praziquantel

Rare CYP1A2 missense variant at the critical Pro42 position; nearly abolishes enzyme activity, impairing metabolism of caffeine, clozapine, theophylline, and tizanidine

Nearly-inactive CYP1A2 missense variant — carriers have severely impaired metabolism of caffeine, theophylline, tizanidine, and other CYP1A2 substrates

Rare CYP1A2 missense variant (Ile386Val) associated with potentially reduced enzyme activity and altered metabolism of caffeine, clozapine, theophylline, and other CYP1A2 substrates

CYP1A2*8 — near-complete loss-of-function missense variant causing severely reduced CYP1A2 enzyme activity; predominantly found in East Asian (Japanese) populations

Frameshift insertion creating a null CYP2D6 allele; carriers cannot metabolize ~25% of common drugs including opioids, antidepressants, and antipsychotics

Deep intronic splice-site variant that is the functional driver of the DPYD HapB3 haplotype; creates a cryptic splice site causing ~50% DPD activity loss and requiring 50% fluoropyrimidine dose reduction

CYP1A2 *1F intronic inducibility variant — defines fast vs slow caffeine metabolizer status and affects clearance of clozapine, theophylline, and tizanidine. The slow-metabolizer C allele blunts the smoking-induced enzyme upregulation that normally accelerates these drugs in heavy smokers.

Splice site variant creating a non-functional CYP3A5 enzyme, dramatically affecting metabolism of tacrolimus and other immunosuppressants

Intergenic variant upstream of IFNL3 — second major IL28B locus predictor of hepatitis C spontaneous clearance and treatment response, with independent predictive value over rs12979860 in Asian populations

Downstream regulatory variant near CYP2E1 associated with nasopharyngeal carcinoma risk in smokers through altered carcinogen metabolism

Warfarin sensitivity - determines initial dosing