What you carry at this position in your DNA and what research says about it.
Celiac Disease Risk: 8/10 evidence, 91 publications.
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Sample genotype (not yours): T/T
Higher Risk of Celiac and Autoimmune Conditions
Two copies of the T allele lead to an overactive immune system. This significantly increases the risk of celiac disease, type 1 diabetes, and high blood pressure, while offering better defense against severe infections.
What this genotype means: ~1.4x higher risk of celiac disease; Increased risk of type 1 diabetes and rheumatoid arthritis; Slightly higher blood pressure.
Sample genotype (not yours): C/C
Typical Risk of Celiac and Autoimmune Conditions
Two copies of the C allele represent the typical genetic baseline. This genotype is associated with standard risks for celiac disease, type 1 diabetes, and normal blood pressure.
What this genotype means: Typical risk of celiac disease; Typical risk of type 1 diabetes; Standard blood pressure regulation.
Sample genotype (not yours): T/C
Slightly Higher Risk of Celiac and Autoimmune Conditions
One copy of the T allele moderately increases immune system reactivity. This leads to a slightly elevated risk of celiac disease, type 1 diabetes, and high blood pressure.
What this genotype means: Slightly increased risk of celiac disease; Modestly higher risk of type 1 diabetes; Slightly elevated blood pressure.
Gene function and biological role
Gene Function: The SH2B3 gene encodes an adaptor protein, also known as LNK, that plays a critical role in regulating the human immune system and blood cell production [1]. It acts as a natural brake on cytokine signaling pathways, preventing immune cells from overreacting to external triggers [1]. By controlling the activity of key signaling molecules, this protein helps maintain a healthy balance between defense and inflammation [2]. When the gene functions normally, it keeps inflammatory proteins in check and regulates the proliferation of white blood cells and platelets [1]. Disruptions or variations in this gene can lead to an overactive immune response, contributing to both autoimmune disorders and cardiovascular issues [2].
Variant Impact: This missense variant, also known as R262W, alters a single amino acid in the SH2B3 protein, replacing arginine with tryptophan at position 262. This structural change results in a reduced-function version of the protein that is less effective at dampening immune signals [2]. Consequently, immune cells become hyper-reactive, leading to elevated inflammatory responses and increased blood cell counts [2]. While this heightened immune state increases susceptibility to autoimmune conditions like celiac disease, it historically provided a survival advantage by protecting against severe bacterial infections [3].
Key Insight: This variant represents an evolutionary trade-off where a genetic change that increases the risk of modern autoimmune diseases like celiac disease actually helped historical populations survive deadly bacterial infections.
Location: SH2B3. Chromosome 12 · 12q24.12 · 111.4 Mb
Origin Story: During human history in Europe, the T allele experienced strong positive selection because its hyper-reactive immune response helped carriers clear bacterial infections and survive sepsis, despite increasing the risk of autoimmune diseases later in life.
Estimated prevalence by population
Global 14.2%; European 23.7%; African 0.7%; East Asian < 0.1%; South Asian 0.9%; Americas 8.6%; Ashkenazi 44.9%; Finnish 15.9%; Middle Eastern 14.0%; Amish 20.9%.
Estimated TT genotype frequency.
Global 36.4%; European 50.0%; African 15.1%; East Asian 0.4%; South Asian 17.1%; Americas 41.5%; Ashkenazi 44.2%; Finnish 47.9%; Middle Eastern 46.8%; Amish 49.6%.
Estimated TC genotype frequency.
Global 49.4%; European 26.3%; African 84.2%; East Asian 99.6%; South Asian 82.0%; Americas 49.9%; Ashkenazi 10.9%; Finnish 36.2%; Middle Eastern 39.2%; Amish 29.5%.
Estimated CC genotype frequency.
Showing effects for T/T genotype
Immunity & Inflammation
Autoimmune Diseases
Celiac Disease. Evidence: 8/10. Source: PMID 26535636. ~1.4x Higher Risk.
Rheumatoid Arthritis. Evidence: 10/10. Source: PMID 20453842. Higher Risk.
Cardiovascular & Metabolic
Diabetes & Glycemic Traits
Type 1 Diabetes. Evidence: 10/10. Source: PMID 19430480. ~1.24x Higher Risk.
Hypertension
Blood Pressure. Evidence: 10/10. Source: PMID 19430479. Higher.
Heart Disease
Coronary Artery Disease. Evidence: 10/10. Source: PMID 21378990. Higher Risk.
Endocrine & Reproductive
Hormone Levels & Endocrine Regulation
Hypothyroidism. Evidence: 10/10. Source: PMID 22493691. ~1.2x Higher Risk.
Showing effects for C/C genotype
Celiac Disease. Evidence: 8/10. Source: PMID 26535636. Typical Risk.
Rheumatoid Arthritis. Evidence: 10/10. Source: PMID 20453842. Typical Risk.
Type 1 Diabetes. Evidence: 10/10. Source: PMID 19430480. Typical Risk.
Blood Pressure. Evidence: 10/10. Source: PMID 19430479. Typical.
Coronary Artery Disease. Evidence: 10/10. Source: PMID 21378990. Typical Risk.
Hypothyroidism. Evidence: 10/10. Source: PMID 22493691. Typical Risk.
Showing effects for T/C genotype
Celiac Disease. Evidence: 8/10. Source: PMID 26535636. Slightly Higher Risk.
Rheumatoid Arthritis. Evidence: 10/10. Source: PMID 20453842. Slightly Higher Risk.
Type 1 Diabetes. Evidence: 10/10. Source: PMID 19430480. Slightly Higher Risk.
Blood Pressure. Evidence: 10/10. Source: PMID 19430479. Slightly Higher.
Coronary Artery Disease. Evidence: 10/10. Source: PMID 21378990. Slightly Higher Risk.
Hypothyroidism. Evidence: 10/10. Source: PMID 22493691. Slightly Higher Risk.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Carrying two copies of the T allele results in a hyper-reactive immune system due to reduced regulation of inflammatory pathways [1]. This overactivity is strongly linked to a 1.4-fold increased risk of celiac disease, an autoimmune reaction to gluten [1]. Additionally, this genotype is associated with a higher risk of developing type 1 diabetes and rheumatoid arthritis [2]. Cardiovascular health is also affected, with studies showing elevated systolic and diastolic blood pressure [3]. However, this heightened immune state is not entirely negative; it historically provided robust protection against severe bacterial infections and sepsis [4]. Furthermore, individuals with this genotype may show a more favorable response to certain blood pressure medications like candesartan [5].
~1.4x higher risk of celiac disease; Increased risk of type 1 diabetes and rheumatoid arthritis; Slightly higher blood pressure; Better response to candesartan medication.
Sample genotype: CC (Homozygous)
Carrying two copies of the C allele represents the typical baseline for immune system regulation [1]. The SH2B3 protein functions normally, maintaining a proper balance in cytokine signaling and preventing unnecessary inflammation [1]. Consequently, there is no elevated genetic risk for celiac disease or other autoimmune disorders like type 1 diabetes and rheumatoid arthritis [2]. Blood pressure levels and blood cell counts generally remain within the typical, healthy range [3]. While this genotype avoids the autoimmune risks associated with the T allele, it does not benefit from the historical evolutionary protection against severe bacterial infections [4]. Response to certain blood pressure medications like candesartan is also typical [5].
Typical risk of celiac disease; Typical risk of type 1 diabetes; Standard blood pressure regulation; Typical response to blood pressure medications.
Sample genotype: TC (Heterozygous)
Carrying one copy of the T allele and one copy of the C allele results in moderate immune system reactivity [1]. This intermediate state is associated with a slightly increased risk of celiac disease compared to the typical population [1]. There is also a modest increase in the likelihood of developing other autoimmune conditions, such as type 1 diabetes and rheumatoid arthritis [2]. Blood pressure measurements tend to be slightly higher than those with the typical genotype [3]. On the positive side, this moderate immune activation may offer some level of enhanced protection against bacterial pathogens [4]. Additionally, clinical data suggests a potentially better response to candesartan for blood pressure management [5].
Slightly increased risk of celiac disease; Modestly higher risk of type 1 diabetes; Slightly elevated blood pressure; Potential for better response to candesartan.
Variants with shared genetic architecture
rs7310615 · SH2B3 Gene · Chr 12 · Cardiovascular and Blood Health
rs10774624 · SH2B3 Gene · Chr 12 · Autoimmune and Heart Risk
rs7454108 · HLA-DQA2 Gene · Chr 6 · Autoimmune Disease Risk
The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.
Association between IL2/IL21 and SH2B3 polymorphisms and risk of celiac disease: a meta-analysis.
Genome-wide association study of blood pressure and hypertension.
Content updated August 2026.
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