What you carry at this position in your DNA and what research says about it.
Autoimmune Disease Risk: 9/10 evidence, 51 publications.
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Sample genotype (not yours): C/C
Higher Autoimmune Risk and Lower Infection Risk
An optimal Kozak sequence leads to higher CD40 protein levels, which enhances immune responses. While this helps defend against certain infections, it also increases the risk of developing autoimmune conditions like rheumatoid arthritis.
What this genotype means: Higher CD40 protein levels; Increased risk of rheumatoid arthritis; Lower risk of chronic hepatitis B.
Sample genotype (not yours): T/C
Typical Autoimmune and Infection Risk
Carrying one copy of each allele results in intermediate CD40 protein levels. This provides a balanced immune response, maintaining typical baseline risks for both autoimmune diseases and chronic infections.
What this genotype means: Intermediate CD40 protein levels; Typical baseline risk for autoimmune diseases; Typical baseline risk for infections.
Sample genotype (not yours): T/T
Higher Osteoporosis and Infection Risk
Reduced translation efficiency leads to lower CD40 protein levels, which decreases the risk of autoimmune diseases. However, this lower immune activity increases susceptibility to chronic infections, osteoporosis, and lymphoma.
What this genotype means: Lower CD40 protein levels; Increased risk of osteoporosis; Lower risk of rheumatoid arthritis.
Gene function and biological role
Gene Function: The CD40 gene encodes a critical cell-surface receptor belonging to the tumor necrosis factor receptor superfamily [1]. It is primarily expressed on antigen-presenting cells, such as B lymphocytes and dendritic cells, where it plays a pivotal role in mediating immune and inflammatory responses [1]. Interaction between CD40 and its ligand is essential for T-cell-dependent immunoglobulin class switching, B-cell proliferation, and memory B-cell development [1]. Beyond immune cells, CD40 is also expressed on non-immune cells, including endothelial cells and thyroid epithelial cells [2]. Proper regulation of this pathway is vital, as excessive signaling can trigger autoimmune diseases, while insufficient signaling can impair the body's ability to fight off infections [1] [2].
Variant Impact: The rs1883832 variant is a single-nucleotide polymorphism located at the -1 position relative to the start codon within the Kozak consensus sequence of the CD40 gene [3]. This specific position is highly critical for the initiation of protein translation from mRNA transcripts [3]. The major C allele provides an optimal Kozak sequence that enhances translation efficiency, leading to higher levels of CD40 protein [3] [2]. Conversely, the minor T allele reduces translation efficiency, resulting in approximately 15% to 30% less CD40 protein production [3]. This genetically determined difference in CD40 expression levels creates a biological trade-off, shifting the balance between autoimmune susceptibility and infectious disease defense [3] [2].
Key Insight: A single letter change in the Kozak sequence acts as a translational dial, adjusting CD40 protein levels by up to 30% and shifting the body's immune balance between fighting infections and avoiding autoimmunity.
Location: CD40. Chromosome 20 · 20q13.12 · 46.1 Mb
Estimated prevalence by population
Global 5.3%; European 6.6%; African 0.4%; East Asian 18.6%; South Asian 7.0%; Americas 5.1%; Ashkenazi 7.4%; Finnish 7.6%; Middle Eastern 7.6%; Amish 5.8%.
Estimated TT genotype frequency.
Global 31.0%; European 38.2%; African 11.4%; East Asian 49.1%; South Asian 38.9%; Americas 34.9%; Ashkenazi 39.6%; Finnish 40.0%; Middle Eastern 39.9%; Amish 36.6%.
Estimated TC genotype frequency.
Global 63.7%; European 55.1%; African 88.3%; East Asian 32.3%; South Asian 54.1%; Americas 60.0%; Ashkenazi 52.9%; Finnish 52.4%; Middle Eastern 52.5%; Amish 57.6%.
Estimated CC genotype frequency.
Showing effects for C/C genotype
Immunity & Inflammation
Autoimmune Diseases
Rheumatoid Arthritis. Evidence: 9/10. Source: PMID 24532676. ~1.11x Increased Risk.
Graves' Disease. Evidence: 4/10. Source: PMID 12593727. Increased Risk.
Infection Susceptibility & Resistance
Chronic Hepatitis B. Evidence: 6/10. Source: PMID 25802187. Lower Risk.
Chronic Inflammatory Diseases
Kawasaki Disease. Evidence: 6/10. Source: PMID 33106546. ~1.28x Increased Risk.
Organ Systems
Bone, Joint & Connective Tissue Health
Osteoporosis. Evidence: 4/10. Source: PMID 26545336. Lower Risk.
Cancer & Oncology
Blood Cancers
Lymphoma. Evidence: 3/10. Source: PMID 20473910. Lower Risk.
Showing effects for T/C genotype
Rheumatoid Arthritis. Evidence: 9/10. Source: PMID 24532676. Typical Risk.
Graves' Disease. Evidence: 4/10. Source: PMID 12593727. Typical Risk.
Chronic Hepatitis B. Evidence: 6/10. Source: PMID 25802187. Typical Risk.
Kawasaki Disease. Evidence: 6/10. Source: PMID 33106546. Typical Risk.
Osteoporosis. Evidence: 4/10. Source: PMID 26545336. Typical Risk.
Lymphoma. Evidence: 3/10. Source: PMID 20473910. Typical Risk.
Showing effects for T/T genotype
Rheumatoid Arthritis. Evidence: 9/10. Source: PMID 24532676. Lower Risk.
Graves' Disease. Evidence: 4/10. Source: PMID 12593727. Lower Risk.
Chronic Hepatitis B. Evidence: 6/10. Source: PMID 25802187. ~1.19x Increased Risk.
Kawasaki Disease. Evidence: 6/10. Source: PMID 33106546. Lower Risk.
Osteoporosis. Evidence: 4/10. Source: PMID 26545336. Increased Risk.
Lymphoma. Evidence: 3/10. Source: PMID 20473910. ~1.6x Increased Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Higher translation efficiency of the CD40 gene results in elevated levels of the CD40 receptor on immune cells [1]. This robust expression amplifies the interaction between antigen-presenting cells and T lymphocytes, boosting overall immune responsiveness [1]. Consequently, there is a significantly increased susceptibility to autoimmune disorders, particularly rheumatoid arthritis and Graves disease [2] [3]. Large-scale genetic studies show a clear association between this genotype and elevated rheumatoid factor levels [3]. However, the heightened immune surveillance offers a protective advantage against chronic infections, such as hepatitis B [4]. It is also associated with a lower risk of developing osteoporosis and certain types of lymphoma [5]. This genotype represents an evolutionary trade-off favoring active pathogen defense at the cost of self-tolerance.
Higher CD40 protein levels; Increased risk of rheumatoid arthritis; Lower risk of chronic hepatitis B.
Sample genotype: TC (Heterozygous)
An intermediate level of CD40 translation efficiency is maintained by carrying both the high-expressing C allele and the low-expressing T allele [1]. This heterozygous state avoids the extreme ends of the immune spectrum, resulting in typical baseline risks for most associated conditions [1]. Susceptibility to rheumatoid arthritis and Graves disease remains at average population levels [2] [3]. Similarly, the risk of developing chronic hepatitis B or experiencing low bone mineral density is not significantly elevated [4] [5]. This balanced genetic profile represents the most common state in many populations, providing a stable middle ground between autoimmune susceptibility and pathogen defense. No specific clinical interventions or heightened monitoring are typically suggested based on this genotype alone.
Intermediate CD40 protein levels; Typical baseline risk for autoimmune diseases; Typical baseline risk for infections.
Sample genotype: TT (Homozygous)
A less efficient Kozak sequence results in a 15% to 30% reduction in CD40 protein translation [1]. This lower receptor density dampens the activation of immune pathways, which significantly lowers the risk of autoimmune conditions like rheumatoid arthritis and Graves disease [2] [3]. However, the reduced immune surveillance makes it harder for the body to clear certain pathogens, leading to an increased risk of chronic hepatitis B infection [4]. Additionally, lower CD40 signaling is linked to reduced bone mineral density, elevating the risk of osteopenia and osteoporosis in postmenopausal women [5]. There is also an associated increase in susceptibility to non-Hodgkin lymphoma [6]. This genotype highlights how a dampened immune system reduces autoimmune self-attack but increases vulnerability to external pathogens and bone loss.
Lower CD40 protein levels; Increased risk of osteoporosis; Lower risk of rheumatoid arthritis.
Variants with shared genetic architecture
rs1569723 · CD40 Gene · Chr 20 · Inflammatory Disease Risk
rs4810485 · CD40 Gene · Chr 20 · Rheumatoid Arthritis Risk
rs6074022 · CD40 Gene · Chr 20 · Autoimmune Disease Risk
Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.
A novel polymorphism of the human CD40 receptor with enhanced function.
Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B.
A functional TNFRSF5 polymorphism and risk of non-Hodgkin lymphoma, a pooled analysis.
Content updated August 2026.
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