rs11558538
mixedMag 4.5This is a variant in the HNMT gene that changes a threonine to an isoleucine.
Key Literature Trait Associations
Parkinson's disease
Two independent meta-analyses consistently show that rs11558538 T (Ile105) allele carriers have a significantly lower risk of sporadic Parkinson's disease compared to Thr105 homozygotes. The 2016 PRISMA-compliant meta-analysis (n=4,266) reported OR=0.61 (95% CI 0.46–0.81) overall and OR=0.63 in Caucasians. A larger 2022 meta-analysis incorporating IPDGC data (n=88,222) confirmed a log OR of –0.31 for the Ile allele, with protection most evident in non-Chinese populations. The mechanism may involve altered histamine-mediated neuroinflammation in the substantia nigra.
Histamine Intolerance
HNMT (histamine N-methyltransferase) degrades histamine inside cells and in the central nervous system. The rs11558538 variant (Thr105Ile) reduces HNMT stability and protein levels. T allele carriers may clear intracellular histamine less efficiently, potentially contributing to histamine sensitivity symptoms. This variant is sometimes included in histamine-intolerance genetic panels alongside AOC1 variants, though direct GWAS evidence for histamine intolerance symptoms is limited.
Asthma
The rs11558538 T allele has been associated with higher asthma risk in multiple candidate-gene studies, consistent with the role of impaired histamine catabolism in airway inflammation. The original pharmacogenetics study in adult Caucasians found T-allele frequency significantly elevated in asthmatics (0.14 vs 0.08, OR≈1.9, p<0.01). A pediatric case-control study confirmed that the TT genotype and T allele were associated with childhood allergic asthma. However, a 2007 Spanish study of 270 asthma/allergic rhinitis patients found only a non-significant trend, suggesting the association may be modest and population-specific.
Atopic dermatitis
A candidate-gene study in 249 Caucasian children found the T314 (Ile105) allele significantly more frequent in those with atopic dermatitis compared to controls (0.12 vs 0.06, p=0.04), with the CT/TT combined genotype also elevated (p=0.02). Children with HNMT genotypes conferring reduced enzyme activity were approximately twice as likely to have atopic dermatitis, consistent with the hypothesis that histamine accumulation drives skin inflammation. This is a single small study requiring replication; no GWAS data or meta-analyses have been published for this trait.
▶GWAS Catalog Trait Associations (1)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (1)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
HNMT-related disorder; Inherited susceptibility to asthma
View on ClinVar →▶Research that mentions this SNP (2)
▶Polymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatmentAssociationN=237Anssi Solismaa et al.(2014)· Human Psychopharmacology: Clinical and Experimental
This dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.
▶Variability in Ethanol Biodisposition in Whites Is Modulated by Polymorphisms in the Adh1b and Adh1c GenesReviewCarmen Martínez et al.(2010)· Hepatology
A comprehensive review of nutrigenetics and nutrigenomics examining how genetic variants influence individual responses to nutrients and dietary interventions. The paper discusses associations between numerous SNPs (rs9939609 in FTO, rs2287019 in GIPR, rs7903146 in TCF7L2, rs5219 in KCNJ11, and many others) and metabolic traits including obesity, type 2 diabetes, and other chronic diseases, along with epigenetic mechanisms by which phytochemicals (curcumin, resveratrol, lycopene) modulate gene expression. The review synthesizes current evidence for precision nutrition approaches tailored to individual genetic profiles.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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