What you carry at this position in your DNA and what research says about it.
Esophageal Cancer Risk: 6/10 evidence, 21 publications.
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Sample genotype (not yours): G/G
Higher Metabolic Risk but Lower Esophageal Cancer Risk
Carrying two copies of the common G allele is linked to a typical risk of esophageal cancer. However, this genotype is associated with a slightly higher likelihood of developing hypertension and type 2 diabetes.
What this genotype means: Typical risk of esophageal cancer; Slightly increased risk of hypertension; Slightly increased risk of type 2 diabetes.
Sample genotype (not yours): A/A
Significantly Increased Risk of Esophageal Cancer
Carrying two copies of the A allele is linked to a 2.2-fold increased risk of esophageal squamous cell carcinoma. This risk is significantly amplified by alcohol consumption and tobacco use.
What this genotype means: ~2.2x increased risk of esophageal squamous cell carcinoma; Significantly lower risk of hypertension and type 2 diabetes; Strongly reduced tendency to consume alcohol.
Sample genotype (not yours): G/A
Increased Risk of Esophageal Cancer
Carrying one copy of the A allele is associated with a 1.5-fold increased risk of esophageal squamous cell carcinoma. This risk is significantly amplified by alcohol consumption and tobacco use.
What this genotype means: ~1.5x increased risk of esophageal squamous cell carcinoma; Lower risk of hypertension and type 2 diabetes; Reduced tendency to consume alcohol.
Gene function and biological role
Gene Function: The HECTD4 gene encodes the HECT domain E3 ubiquitin protein ligase 4, an enzyme involved in targeting specific proteins for degradation within cells. This gene plays a significant role in metabolic pathways, particularly in how the body processes nutrients and responds to environmental factors like alcohol. Research indicates that variations in HECTD4 influence metabolic syndrome, body mass index, and waist circumference [1]. It is also highly expressed in liver tissues, where it interacts with alcohol-metabolizing enzymes [2]. Additionally, HECTD4 has been linked to the regulation of blood pressure and renal function traits [3].
Variant Impact: The rs2074356 variant is an intronic change located within the HECTD4 gene on chromosome 12. This genetic variation is known to influence a wide array of physiological traits, ranging from beverage preferences to cancer susceptibility. The minor A allele is particularly common in East Asian populations, where it significantly alters metabolic and behavioral patterns. It is strongly associated with a reduced drive for alcohol consumption but an increased intake of coffee and tea [4] [5]. However, this same allele is also linked to an elevated risk of esophageal squamous cell carcinoma, especially when combined with alcohol use [6].
Key Insight: The same genetic variant that reduces the urge to drink alcohol also significantly increases the risk of esophageal cancer if alcohol is consumed.
Location: HECTD4. Chromosome 12 · 12q24.13 · 112.2 Mb
Estimated prevalence by population
Global 98.9%; European 100.0%; African 100.0%; East Asian 71.2%; South Asian 99.8%; Americas 99.9%; Ashkenazi 100.0%; Middle Eastern 100.0%; Amish 100.0%.
Estimated GG genotype frequency.
Global 1.0%; European 0.0%; African 0.0%; East Asian 26.3%; South Asian 0.2%; Americas 0.1%; Ashkenazi 0.0%; Middle Eastern 0.0%; Amish 0.0%.
Estimated GA genotype frequency.
Global 0.1%; European 0.0%; African 0.0%; East Asian 2.4%; South Asian < 0.1%; Americas < 0.1%; Ashkenazi 0.0%; Middle Eastern 0.0%; Amish 0.0%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Cancer & Oncology
Gastrointestinal Cancers
Esophageal Cancer. Evidence: 6/10. Source: PMID 21642993. Typical Risk.
Cardiovascular & Metabolic
Hypertension
Hypertension. Evidence: 6/10. Source: PMID 32709000. ~1.28x Increased Risk.
Diabetes & Glycemic Traits
Type 2 Diabetes. Evidence: 6/10. Source: PMID 23575436. Increased Risk.
Neurology & Mental Health
Behavioral & Personality Traits
Coffee Consumption. Evidence: 6/10. Source: PMID 29367735. Typical.
Addiction & Reward
Alcohol Consumption. Evidence: 8/10. Source: PMID 21270382. Typical.
Organ Systems
Kidney Function & Disease
Blood Urea Nitrogen. Evidence: 6/10. Source: PMID 22797727. Typical.
Showing effects for A/A genotype
Esophageal Cancer. Evidence: 6/10. Source: PMID 21642993. ~2.2x Increased Risk.
Hypertension. Evidence: 6/10. Source: PMID 32709000. Lower Risk.
Type 2 Diabetes. Evidence: 6/10. Source: PMID 23575436. Lower Risk.
Coffee Consumption. Evidence: 6/10. Source: PMID 29367735. Higher.
Alcohol Consumption. Evidence: 8/10. Source: PMID 21270382. Lower.
Blood Urea Nitrogen. Evidence: 6/10. Source: PMID 22797727. Higher.
Showing effects for G/A genotype
Esophageal Cancer. Evidence: 6/10. Source: PMID 21642993. ~1.5x Increased Risk.
Hypertension. Evidence: 6/10. Source: PMID 32709000. Typical Risk.
Type 2 Diabetes. Evidence: 6/10. Source: PMID 23575436. Typical Risk.
Coffee Consumption. Evidence: 6/10. Source: PMID 29367735. Slightly Higher.
Alcohol Consumption. Evidence: 8/10. Source: PMID 21270382. Slightly Lower.
Blood Urea Nitrogen. Evidence: 6/10. Source: PMID 22797727. Slightly Higher.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Metabolic health and lifestyle preferences are significantly shaped by this common genetic profile. Carrying the G/G genotype is associated with a typical, baseline risk of developing esophageal squamous cell carcinoma, avoiding the elevated risk seen in carriers of the A variant [1]. However, large-scale genetic studies in Asian populations show that this genotype is linked to an increased risk of hypertension [2]. It is also associated with a higher susceptibility to type 2 diabetes and elevated fasting blood glucose levels [3]. Furthermore, individuals with this profile tend to have higher body mass index and waist-hip ratios [4]. Interestingly, this genotype is also linked to higher habitual alcohol consumption, which can further compound these metabolic risks [5].
Typical risk of esophageal cancer; Slightly increased risk of hypertension; Slightly increased risk of type 2 diabetes.
Sample genotype: AA (Homozygous)
A strong genetic link to esophageal squamous cell carcinoma characterizes this homozygous minor genotype. Studies show that carrying two copies of the A allele elevates the risk of esophageal cancer by approximately 2.2-fold [1]. This risk is heavily modulated by lifestyle, with alcohol consumption and smoking dramatically increasing the likelihood of disease development [2]. Conversely, this genetic profile offers some metabolic advantages, including a lower risk of hypertension and type 2 diabetes [3] [4]. Individuals with this genotype also tend to have lower body weight, lower waist-hip ratios, and a naturally reduced intake of alcohol [5] [6]. They also exhibit a higher genetic predisposition for habitual coffee and tea consumption [7].
~2.2x increased risk of esophageal squamous cell carcinoma; Significantly lower risk of hypertension and type 2 diabetes; Strongly reduced tendency to consume alcohol.
Sample genotype: GA (Heterozygous)
Susceptibility to esophageal squamous cell carcinoma is notably increased for individuals carrying one copy of the A allele. Research in East Asian populations indicates that this genotype carries approximately a 1.5-fold higher risk of developing this specific cancer [1]. This risk is particularly pronounced among individuals who regularly consume alcohol or use tobacco, as the genetic variant interacts with these lifestyle factors [2]. On the positive side, this genotype is associated with a lower risk of developing hypertension and type 2 diabetes compared to the common G/G profile [3] [4]. It is also linked to a natural tendency to consume less alcohol, which can help mitigate some of the associated cancer risks [5]. Additionally, carriers often show a preference for higher coffee and tea consumption [6].
~1.5x increased risk of esophageal squamous cell carcinoma; Lower risk of hypertension and type 2 diabetes; Reduced tendency to consume alcohol.
Variants with shared genetic architecture
rs11066280 · HECTD4 Gene · Chr 12 · Hypertension Risk
rs11066188 · HECTD4 Gene · Chr 12 · Heart and Weight Health
rs12229654 · MYL2 Gene · Chr 12 · Hypertension Risk
Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men.
Content updated September 2026.
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