rs7091565 — ANXA11 ANXA11 rs7091565

3' UTR variant in ANXA11 (annexin A11) in strong LD with the functional R230C missense variant (rs1049550); the C allele tags the sarcoidosis-risk haplotype and is associated with increased susceptibility to pulmonary granulomatous inflammation

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ANXA11 — The Sarcoidosis Susceptibility Gene on Chromosome 10

Sarcoidosis is a mysterious inflammatory disease in which the immune system forms granulomas11 granulomas
Compact clusters of activated macrophages and lymphocytes that represent a failed attempt to wall off a perceived pathogen; in sarcoidosis no infectious agent is consistently found in the lungs and other organs. It strikes disproportionately in people of African descent and in Scandinavians, peaks between ages 25–45, and ranges from self-resolving (Löfgren's syndrome) to chronic and progressive lung disease. The gene ANXA11 — encoding annexin A11, a calcium-dependent membrane-binding protein — lies on chromosome 10q22.3, and rs7091565 sits in its 3' untranslated region, tagging a haplotype that alters sarcoidosis susceptibility by roughly 30–50%.

The Mechanism

Annexin A11 is a 56-kDa protein in the annexin superfamily, characterized by conserved C-terminal repeats that bind calcium and phospholipid membranes22 repeats that bind calcium and phospholipid membranes
These repeats are shared across all 12 human annexins; the unique N-terminal domain of ANXA11 is the region most divergent between family members and the functional hotspot for genetic variants. It is expressed broadly across tissues, with particularly high levels in the esophagus, heart, and lung. Its roles include regulating apoptosis (programmed cell death), cytokinesis, phagocytosis, and calcium-dependent signaling in immune cells — all processes central to the macrophage hyperactivation that characterizes sarcoidosis.

The functional missense variant rs1049550 (ANXA11 R230C) lies 13 kb downstream of rs7091565 within the same gene. This substitution — arginine to cysteine at position 230 of the protein — falls in the N-terminal regulatory domain and alters the protein's ability to interact with binding partners involved in apoptosis regulation. Importantly, rs7091565 and rs1049550 are in strong linkage disequilibrium33 strong linkage disequilibrium
LD means the two alleles are inherited together on the same chromosome segment far more often than chance; carriers of one allele almost always carry the paired allele at the other site: the C allele at rs7091565 co-segregates with the C allele at rs1049550 (the arginine/risk haplotype), while the T allele at rs7091565 co-segregates with the T allele at rs1049550 (the cysteine/protective haplotype). This LD relationship makes rs7091565 a proxy marker for the functional R230C variant.

The mRNA expression of ANXA11 is not altered44 mRNA expression of ANXA11 is not altered
This rules out differential transcription as the explanation; the R230C variant changes protein structure and apoptotic function, not expression level by rs1049550 genotype. Instead, the R230C substitution appears to modulate ANXA11's apoptotic activity directly: the arginine-230 (C allele) form is associated with impaired granuloma resolution, while the cysteine-230 (T allele) form may alter calcium-dependent interactions that improve macrophage death signaling and granuloma clearance.

The Evidence

rs7091565 was identified in the first genome-wide association study of sarcoidosis55 first genome-wide association study of sarcoidosis
A GWAS scans ~440,000–1,000,000 common variants across the genome simultaneously, identifying statistical associations without assuming a biological hypothesis in advance by Hofmann et al. (Nature Genetics, 2008). In 499 German cases and 490 controls with validation in 1,649 cases and 1,832 controls, rs7091565 reached p = 1.0×10⁻⁵ in the validation cohort. The lead signal at the ANXA11 locus was rs2789679 (p = 3.0×10⁻¹³), with rs7091565 and the functional R230C variant (rs1049550) in its LD block.

The protective T allele has since been confirmed across multiple independent cohorts. A functional study66 functional study
245 Czech sarcoidosis patients and 254 healthy controls; mechanistic cell biology experiments by Mrazek et al. (Genes & Immunity, 2011) found the T allele significantly less frequent in sarcoidosis cases (35%) versus controls (42%, OR 0.77, p=0.04). The T allele was particularly depleted in patients with pulmonary parenchymal infiltration compared to isolated hilar lymphadenopathy — suggesting it modifies not just susceptibility but disease severity.

The most comprehensive evidence comes from a meta-analysis77 meta-analysis
Pooling data from 6 cohorts including European, African American, and Asian populations by Karakaya et al. (Cells, 2022): T allele protective in both Löfgren's syndrome (OR 0.69, 95% CI 0.52–0.92, p=0.01) and chronic sarcoidosis (OR 0.51, 95% CI 0.36–0.70, p=4×10⁻⁵), with a pooled OR of 0.70 (95% CI 0.66–0.75, p = 3.58×10⁻²⁹) — a highly significant and consistent protective signal. A separate multi-ethnic replication88 multi-ethnic replication
1,689 cases and 1,252 controls in African Americans and European Americans by Levin et al. identified additional ANXA11 variants in African Americans and a significant interaction between rs1049550 and the HLA-DRA locus, pointing to a joint ANXA11–HLA axis in sarcoidosis immunopathology.

Practical Actions

The T allele at rs7091565 is substantially protective against sarcoidosis (approximately 30–50% reduced odds), while CC homozygotes carrying no protective T alleles have the highest risk at this locus. Sarcoidosis most commonly presents with dry cough, shortness of breath, fatigue, and bilateral hilar lymphadenopathy on chest X-ray. Skin involvement (erythema nodosum, lupus pernio), eye inflammation (uveitis), and cardiac arrhythmia are extrapulmonary manifestations.

For C-allele carriers, the most clinically actionable step is awareness: unexplained dry cough lasting more than 8 weeks, eye inflammation, or skin nodules warrant chest imaging, as sarcoidosis is often under-recognized in primary care. Pulmonary function testing and bronchoalveolar lavage can confirm diagnosis. Most cases are self-limited and require only monitoring; severe or progressive disease is treated with corticosteroids.

There is no dietary intervention proven to modify ANXA11-mediated sarcoidosis risk, but the inflammatory granuloma pathology can impair vitamin D metabolism — granuloma macrophages convert 25(OH)D to the active 1,25(OH)₂D form autonomously, leading to hypercalcemia in some patients. This makes calcium-containing supplements potentially contraindicated in active sarcoidosis, unlike most other inflammatory conditions.

Interactions

rs7091565 acts as a proxy for the functional rs1049550 R230C variant, so the two should not be treated as independent signals — they capture the same underlying biological effect. The sarcoidosis-risk haplotype at ANXA11 also includes rs2789679 (the lead GWAS SNP), rs2573346, and rs1953600, all in strong LD.

The interaction with HLA-DRA (rs9268839) is noteworthy: Levin et al. found a significant SNP-SNP interaction between rs1049550 and this HLA locus in African Americans, suggesting that ANXA11 risk is potentiated when combined with certain MHC class II alleles that drive the antigen-presentation arm of granuloma formation. This is biologically coherent — ANXA11 influences the apoptotic fate of macrophages forming the granuloma, while HLA-DRA governs the T-cell activation that recruits them. Risk at both loci simultaneously would amplify the inflammatory cascade from two independent points.

PTPN22 rs2476601 (R620W) is a broad autoimmune susceptibility variant that, while not studied specifically with ANXA11 in sarcoidosis, modulates T-cell receptor signaling and could compound ANXA11-mediated macrophage dysregulation in susceptible individuals.

Genotype Interpretations

What each possible genotype means for this variant.

TT Protective Genotype Normal

Two protective T alleles — lower sarcoidosis susceptibility at the ANXA11 locus

You carry two copies of the T allele at rs7091565, the protective genotype at the ANXA11 sarcoidosis locus. Approximately 23% of people of European descent and 29% of people of South Asian descent share this homozygous genotype (T is more common in African and South Asian populations). The T allele co-segregates with the R230C variant (rs1049550 T allele), which is associated with a roughly 30–50% reduction in sarcoidosis risk in meta-analyses. This does not eliminate sarcoidosis risk — the disease has multiple genetic and environmental contributors — but it means you do not carry the ANXA11 haplotype that appears in excess among sarcoidosis patients.

CT One Risk Allele Intermediate

One C risk allele — modestly elevated sarcoidosis susceptibility through partial loss of ANXA11 protection

The CT heterozygote has one copy of each allele. The protective effect of the T allele operates in a partially additive fashion: the Karakaya 2022 meta-analysis found the per-allele OR for the T allele is approximately 0.70, meaning each T allele reduces risk by ~30% multiplicatively. A CT carrier has approximately 0.70× the risk of a CC carrier but more than the TT carrier's 0.70×0.70 = ~0.49× risk. Sarcoidosis has a lifetime prevalence of approximately 1 in 200 (0.5%) in Europeans and up to 1 in 40 (2.5%) in African Americans — a modest relative elevation from this single locus translates to a still-small absolute risk in most populations.

The classic sarcoidosis presentation is bilateral hilar lymphadenopathy on chest X-ray, often discovered incidentally. Respiratory symptoms (dry cough, dyspnea, chest tightness), ocular inflammation (uveitis), and skin involvement (erythema nodosum) are the most common presentations. In ~50% of cases the disease resolves without treatment within 2–3 years.

CC Two Risk Alleles High Risk

Two C risk alleles — highest ANXA11-linked sarcoidosis susceptibility, associated with more severe pulmonary involvement

CC homozygotes carry no copies of the protective T allele at rs7091565. The protective T allele works in a dose-dependent fashion (per-allele OR ~0.70 from the Karakaya meta-analysis); CC carriers are therefore at approximately 2-fold higher risk compared to TT carriers at this specific locus (OR ~0.70 × 0.70 = ~0.49 for TT vs CC, inverted). The Mrazek 2011 study's observation that the risk allele was specifically depleted in cases with isolated hilar lymphadenopathy (the mild self-resolving form) but not in those with lung parenchymal involvement suggests that ANXA11 genotype may influence disease phenotype as well as susceptibility — CC carriers who develop sarcoidosis may be more likely to develop the chronic pulmonary form requiring treatment.

ANXA11 interacts with the HLA locus in sarcoidosis. Levin 2013 found a statistically significant interaction between ANXA11 rs1049550 and HLA-DRA rs9268839 in African Americans — CC homozygotes who also carry HLA risk alleles may have substantially higher absolute sarcoidosis risk than either locus alone would predict.

Sarcoidosis also impairs vitamin D homeostasis: activated macrophages within granulomas express 1-alpha-hydroxylase, converting 25(OH)D to the active 1,25(OH)₂D form autonomously and independently of renal regulation. This can cause hypercalcemia, hypercalciuria, and kidney stones in active disease. Supplemental calcium and high-dose vitamin D should be approached cautiously if sarcoidosis is suspected or confirmed.