rs2244012 — RAD50 RAD50 Intron 2 Variant

Intronic variant in RAD50 on chromosome 5q31.1 that was the top GWAS hit for asthma at this locus (P=3.04×10⁻⁷); the G allele tags a regulatory haplotype in the Th2 locus control region and is associated with elevated serum IgE and susceptibility to asthma and atopic disease through amplified IL-4/IL-13 output

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RAD50 Intron 2 — The Genome's Top Asthma Signal at the Th2 Cytokine Hub

The RAD50 gene11 RAD50 gene
RAD50 (RAD50 double-strand break repair protein) encodes an ATPase component of the MRN complex involved in DNA damage repair — but at chromosome 5q31.1, its introns house the locus control region that coordinates IL-4, IL-5, and IL-13 expression in Th2 immune cells, making it a key regulatory scaffold for the Th2 cytokine cluster sits at one of the most replicated atopy-susceptibility loci in the human genome. At position chr5:132,565,533, rs2244012 lies within intron 2 of RAD50, 5q31.1 — a chromosomal address that genomicists have been tracking since the first genome-wide scans for IgE and asthma susceptibility. The Li et al. (2010) GWAS22 Li et al. (2010) GWAS
genome-wide association study of 473 patients with severe or difficult-to-treat asthma versus 1,892 general population controls; 292,443 SNPs genotyped; top hit rs2244012 in intron 2 of RAD50 reached P=3.04×10⁻⁷ at the 5q31 locus identified rs2244012 as the top GWAS hit at this locus — the single SNP with the strongest genome-wide association signal for asthma in the 5q31 region. The G allele tags a regulatory haplotype in the Th2 locus control region that amplifies the output of IL-4, IL-5, and IL-13 — the cytokines that collectively orchestrate allergic inflammation.

The Mechanism

The introns of RAD50 are not just splice-junction filler. A landmark study by Lee et al. (2003)33 Lee et al. (2003)
Lee GR et al. Immunity 2003; BAC transgenic mice carrying IL4-luciferase reporters showed that a 25 kb fragment within the RAD50 gene confers Th2-specific, copy-number-dependent expression of IL-4 and IL-13 — defining this region as a locus control region (LCR) governing the adjacent Th2 cytokine gene cluster identified a 25 kb region within RAD50 as the Th2 locus control region (TH2-LCR)44 Th2 locus control region (TH2-LCR)
a cluster of four DNase I hypersensitive sites (RHS4–RHS7) that loop chromosomally to simultaneously activate IL-4, IL-5, and IL-13 transcription when a T cell commits to the Th2 lineage; mechanistically analogous to the beta-globin LCR that governs globin gene switching during red blood cell development — a regulatory element that coordinates simultaneous transcription of IL-4, IL-5, and IL-13 when T cells commit to the Th2 lineage.

Within this control region, the rs2244012 G allele tags a haplotype that includes functional regulatory variants. One such neighbor, rs2240032 in the RHS7 element of the TH2-LCR, shows allele-specific binding of SMAD3 and SP155 allele-specific binding of SMAD3 and SP1
Kretschmer et al. Allergy 2014; differential transcription-factor binding at RHS7 alters methylation of the IL13 promoter and shifts IL4 and RAD50 expression in an allele-specific manner and alters DNA methylation at the IL13 promoter beginning in cord blood and persisting into childhood — a mechanism that links genotype at birth to measurable epigenetic differences in Th2 cytokine regulation years later. When this regulatory hub is in the more active state, Th2-committed T cells produce higher pulses of IL-13 and IL-4 on allergen stimulation. IL-13 then acts directly on airway epithelium and smooth muscle to drive mucus hypersecretion and airway hyperresponsiveness; IL-4 drives B-cell class switching to IgE, sensitizing mast cells to allergens systemically.

The Evidence

rs2244012 rose to the top of the 5q31 GWAS signal in the Li et al. (2010)66 Li et al. (2010)
Li X et al. J Allergy Clin Immunol 2010; 292,443 SNPs genotyped; 473 TENOR patients with severe asthma vs 1,892 Illumina general population controls study — the first large-scale GWAS to genotype the RAD50-IL13 region at the density needed to resolve the 5q31 signal. Multiple SNPs in the region reached significance, but rs2244012 carried the strongest p-value at P=3.04×10⁻⁷, implicating intron 2 of RAD50 as the locus index variant for asthma in this cohort.

Fine-mapping by Sharma et al. (2014)77 Sharma et al. (2014)
Sharma V et al. Allergy 2014; 64 polymorphisms across three IgE loci (1q23, 5q31, 12q13) in >1,300 German children; 5q31 confirmed as a major IgE determinant; risk alleles at all three loci together elevate IgE risk fourfold in more than 1,300 German children confirmed 5q31 (RAD50-IL13 and IL4) as one of three major determinants of total serum IgE. Associations at this locus are primarily with mild-to-moderate IgE elevation — the 5q31 signal reflects a common population-level Th2 amplifier rather than a rare high-penetrance risk factor.

The atopic spectrum of this locus extends beyond asthma. The 5q31.1 region maps to the IL4/KIF3A locus in a meta-analysis by Marenholz et al. (2015)88 meta-analysis by Marenholz et al. (2015)
Nature Commun 2015; 12 populations, 2,428 cases of infantile eczema progressing to childhood asthma, 17,034 controls; seven genome-wide significant loci for the atopic march identified; IL4/KIF3A at 5q31.1 confirmed identifying seven loci for the atopic march — the progression from eczema to food allergy to asthma to allergic rhinitis — confirming that the 5q31 signal drives not just asthma risk but the full sequential atopic phenotype.

Replication has been mixed by population: the Li et al. finding was replicated in Pakistani children (Ghani et al. 2025, PMID 41001556), while a Han Chinese pediatric study (Li et al. 2016, PMID 26365633) found no association — population-specific genetic backgrounds and differing LD structures likely explain the discrepancy. The G allele shows dramatically higher frequency in African ancestry (~61%) compared to European (~22%) and East Asian (~18%) populations, consistent with a common regulatory haplotype that is ancestrally enriched in African populations.

Practical Implications

The G allele at rs2244012 lowers the threshold at which allergen exposure triggers sensitization and sustained allergic inflammation. The mechanism is upstream Th2 cytokine amplification — each G allele shifts the IL-13/IL-4 output capacity of Th2 cells upward, raising baseline IgE and making mast cell sensitization faster and more durable. Children carrying the G allele who develop early eczema face elevated biological risk for the full atopic march; adults who have never developed overt atopy may still carry subclinically elevated IgE that sensitizes them to new occupational or environmental allergens more readily than AA individuals.

Therapeutically, the biology is increasingly tractable: dupilumab (anti-IL-4Rα, blocking both IL-4 and IL-13), tralokinumab (anti-IL-13), and cendakimab (anti-IL-13Rα1) directly counter the cytokine output amplified by this genotype. G allele carriers with refractory atopic disease are biologically well-matched to this drug class.

Interactions

rs2244012 lies within the same 5q31.1 RAD50/TH2-LCR haplotype block as rs2040704 and rs2240032 — these variants are in strong linkage disequilibrium and collectively tag the Th2 locus control region regulatory haplotype. The rs2040704 G allele at the TH2-LCR enhancer hub and rs2244012 G allele in RAD50 intron 2 likely co-segregate on the same risk haplotype, making their combined effect equivalent to carrying a single high-activity TH2-LCR configuration.

Carriers who also carry rs20541-A (IL13 R130Q, increased IL-13 bioavailability) face a double hit: elevated IL-13 production from this locus control region variant, combined with reduced IL-13 decoy receptor clearance from the downstream coding variant. The combination of rs1801275 (IL-4Rα R576Q) with the G allele at this locus creates a production × receptor synergy that is particularly relevant to dupilumab pharmacogenomics.

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal

Two reference A alleles — baseline Th2 locus control region activity and population-average asthma and atopy risk

You carry two copies of the A allele at rs2244012 — the GRCh38 plus-strand reference allele and the population-major allele globally (~67% frequency). Your Th2 locus control region at 5q31 operates within the typical regulatory range. IL-4 and IL-13 induction from this enhancer hub is not amplified by this variant, and your IgE setpoint from this locus is not elevated above baseline. Approximately 45% of the global population carries this AA genotype; it is more common in Europeans (~60%) and East Asians (~66%) than in individuals of African ancestry (~24%).

AG Intermediate

One G allele — moderately amplified Th2 enhancer output with elevated IgE tendency and increased atopic sensitization susceptibility

rs2244012 sits in intron 2 of RAD50 within the 5q31.1 Th2 locus control region — a hub of regulatory elements (RHS4–RHS7) that coordinate simultaneous IL-4, IL-5, and IL-13 expression when T cells commit to the Th2 lineage. The G allele is in strong linkage disequilibrium with functional regulatory variants in this region, including rs2240032 in the RHS7 element, which shows allele-specific SMAD3/SP1 binding and differential methylation of the IL13 promoter beginning in cord blood (Schieck et al., 2014).

As a heterozygote you carry one risk haplotype and one reference haplotype. The 5q31 signal operates additively — each G allele contributes an increment to Th2 cytokine output capacity. Fine-mapping studies in German children confirmed that the 5q31 associations are primarily with mild-to-moderate IgE elevation rather than extreme atopic phenotypes, meaning heterozygotes like you are the most common recipients of this risk signal.

GG High Risk

Two G alleles — maximally amplified Th2 locus enhancer activity with highest IgE tendency and greatest susceptibility to asthma and the full atopic march

The GG genotype places both copies of the 5q31 TH2-LCR in the more active enhancer state. With both alleles driving higher IL-13 and IL-4 output in Th2-committed T cells, the immune system is primed for allergic sensitization from multiple entry points: skin (eczema, environmental allergens), gut (food sensitization), and airway (inhaled allergens). The additive effect across both alleles produces the highest IgE level attributable to this locus.

The regulatory mechanism involves the TH2-LCR elements RHS4–RHS7 within RAD50 introns. Functional variants in LD with rs2244012-G alter SMAD3/SP1 binding at RHS7, shifting DNA methylation of the IL13 promoter and increasing allele-specific expression of both IL4 and RAD50. At the GG level, both chromosomes are in the methylation-permissive, expression-elevated configuration — a gene-regulatory state set in cord blood that persists through childhood.

From a therapeutic standpoint, this genotype directly implicates the IL-4/IL-13 axis: dupilumab (anti-IL-4Rα, blocking both IL-4 and IL-13 signaling), tralokinumab (anti-IL-13), and cendakimab (anti-IL-13Rα1) all counteract the upstream cytokine amplification that this genotype drives. GG carriers who develop refractory atopic dermatitis, moderate-severe asthma, or eosinophilic esophagitis have mechanistic grounds for biologic therapy targeting this axis.