What you carry at this position in your DNA and what research says about it.
Drug Metabolism and Gut Health: 5/10 evidence, 15 publications.
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Sample genotype (not yours): G/G
Typical Gut Risk and Enhanced Drug Tolerance
This genotype is associated with standard baseline risks for inflammatory gut conditions and a lower likelihood of side effects from specific medications.
What this genotype means: Lower risk of liver damage from methotrexate; Reduced likelihood of side effects from temsirolimus; Typical baseline risk of sunitinib-induced high blood pressure.
Sample genotype (not yours): A/A
Increased Risk of Treatment-Induced Hypertension
This genotype is linked to a higher risk of high blood pressure during specific therapies and lacks the protective drug-tolerance benefits of the G allele.
What this genotype means: Elevated risk of high blood pressure during sunitinib treatment; Typical baseline risk of methotrexate-induced liver damage; Altered susceptibility to chronic gut inflammation.
Sample genotype (not yours): G/A
Variable Drug Response and Altered Inflammatory Risk
This heterozygous genotype presents a mix of protective drug-tolerance traits alongside an increased risk of specific medication-induced side effects.
What this genotype means: Increased risk of high blood pressure during sunitinib therapy; Slower metabolism of afatinib; Altered susceptibility to ulcerative colitis.
Gene function and biological role
Gene Function: The NR1I2 gene encodes the pregnane X receptor, a vital nuclear receptor that senses foreign substances and coordinates the body's detoxification response. It acts as a master regulator for key drug-metabolizing enzymes, including cytochrome P450 3A4, which processes nearly half of all clinical medications [1]. Beyond drug clearance, this receptor plays a critical role in maintaining the intestinal barrier and suppressing inflammatory pathways in the gut [2]. Proper receptor function helps protect tissues from toxic bile acids and environmental chemicals.
Variant Impact: The rs6785049 variant is an intron variation located within the NR1I2 gene that influences the expression and activity of the pregnane X receptor. Alterations at this genetic site modify how effectively the receptor triggers the breakdown of medications and toxins [1]. This genetic change has been linked to altered susceptibility to inflammatory bowel conditions and variations in liver health [3]. It also significantly impacts the pharmacokinetics of several specialized therapies, including chemotherapy and immunosuppressants.
Key Insight: This variant acts as a genetic dial for drug processing, where the same genetic letter that protects the liver from chemotherapy side effects can simultaneously alter susceptibility to chronic gut inflammation.
Location: NR1I2. Chromosome 3 · 3q13.33 · 119.8 Mb
Estimated prevalence by population
Global 33.6%; European 15.3%; African 77.5%; East Asian 34.4%; South Asian 24.5%; Americas 17.8%; Ashkenazi 15.3%; Finnish 15.0%; Middle Eastern 22.4%; Amish 11.6%.
Estimated GG genotype frequency.
Global 40.5%; European 47.6%; African 21.0%; East Asian 48.5%; South Asian 50.0%; Americas 48.8%; Ashkenazi 47.6%; Finnish 47.5%; Middle Eastern 49.9%; Amish 44.9%.
Estimated GA genotype frequency.
Global 25.8%; European 37.0%; African 1.4%; East Asian 17.1%; South Asian 25.5%; Americas 33.4%; Ashkenazi 37.1%; Finnish 37.6%; Middle Eastern 27.8%; Amish 43.6%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Immunity & Inflammation
Chronic Inflammatory Diseases
Ulcerative Colitis. Evidence: 3/10. Source: PMID 21245992. Typical Risk.
Pharmacogenomics
Chemotherapy Response
Sunitinib Blood Pressure. Evidence: 5/10. Source: PMID 25344452. Typical Risk.
Temsirolimus Side Effects. Evidence: 5/10. Source: PMID 28676933. Lower Side Effect Risk.
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 5/10. Source: PMID 27566582. Lower Toxicity Risk.
Adverse Drug Reactions
Drug-Induced Liver Injury. Evidence: 3/10. Source: PMID 19940802. Typical Risk.
Showing effects for A/A genotype
Ulcerative Colitis. Evidence: 3/10. Source: PMID 21245992. Altered Risk.
Sunitinib Blood Pressure. Evidence: 5/10. Source: PMID 25344452. Increased Risk.
Temsirolimus Side Effects. Evidence: 5/10. Source: PMID 28676933. Typical Side Effect Risk.
Methotrexate Toxicity. Evidence: 5/10. Source: PMID 27566582. Typical Toxicity Risk.
Drug-Induced Liver Injury. Evidence: 3/10. Source: PMID 19940802. Altered Risk.
Showing effects for G/A genotype
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Inheriting two copies of the G allele provides standard baseline regulation of the pregnane X receptor. Clinical studies show this genotype is linked to a lower risk of liver damage during high-dose methotrexate therapy due to slower drug clearance [1]. Similarly, individuals with this profile exhibit a decreased likelihood of experiencing adverse side effects when treated with temsirolimus [2]. Slower metabolism is also observed for other medications like sirolimus and voriconazole [2] [3]. While this genotype generally maintains typical baseline risks for inflammatory bowel disease, some regional studies suggest variations in susceptibility depending on environmental factors [4]. Overall, this genetic makeup supports robust cellular defense mechanisms in the liver and intestines.
Lower risk of liver damage from methotrexate; Reduced likelihood of side effects from temsirolimus; Typical baseline risk of sunitinib-induced high blood pressure.
Sample genotype: AA (Homozygous)
Having two copies of the A allele alters the regulatory dynamics of the pregnane X receptor, impacting both drug processing and inflammatory responses. Clinical data associates this genotype with a significantly increased risk of developing high blood pressure when treated with the cancer drug sunitinib [1]. Unlike carriers of the G allele, individuals with this profile do not experience the genetic protection against methotrexate-induced liver damage or temsirolimus side effects, returning to typical baseline toxicity risks [2] [3]. Slower metabolism of afatinib is still expected due to the presence of the A alleles [4]. Furthermore, this genetic profile is linked to altered susceptibility to chronic inflammatory bowel conditions, including ulcerative colitis, depending on environmental triggers and population background [5].
Elevated risk of high blood pressure during sunitinib treatment; Typical baseline risk of methotrexate-induced liver damage; Altered susceptibility to chronic gut inflammation.
Sample genotype: GA (Heterozygous)
Carrying one G allele and one A allele results in a balanced but highly variable pharmacological profile. This genetic combination offers protection against liver toxicity during methotrexate treatment and reduces side effects from temsirolimus [1] [2]. However, the presence of the A allele introduces distinct sensitivities, such as an elevated risk of developing high blood pressure when undergoing sunitinib therapy [3]. Slower metabolism is also noted for the oncology drug afatinib [4]. In terms of digestive health, this genotype is associated with altered susceptibility to ulcerative colitis and inflammatory bowel disease, with risks heavily influenced by geographic ancestry and smoking status [5]. This mixture of benefits and risks highlights the complex, dual nature of the heterozygous state.
Increased risk of high blood pressure during sunitinib therapy; Slower metabolism of afatinib; Altered susceptibility to ulcerative colitis.
Variants with shared genetic architecture
rs3732356 · NR1I2 Gene · Chr 3 · Cholesterol and Lipids
rs3732359 · NR1I2 Gene · Chr 3 · Cholesterol and Drug Clearance
rs3814055 · NR1I2 Gene · Chr 3 · Liver and Gut Health
Polymorphisms in NF-κB, PXR, LXR, PPARγ and risk of inflammatory bowel disease.
Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.
Content updated August 2026.
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