rs2303065 — SPINK5 SPINK5 His396His (c.1188T>C)

SPINK5 His396His — An LD Marker for the Skin Barrier Risk Haplotype

The SPINK5 gene encodes LEKTI¹¹ LEKTI
Lympho-Epithelial Kazal-Type Inhibitor, a 15-domain serine protease inhibitor expressed in skin, thymus, and mucosal surfaces; it acts as the primary brake on kallikrein proteases that drive epidermal desquamation, the protease inhibitor central to skin barrier integrity. Genetic variants across SPINK5 have been associated with atopic dermatitis since the landmark Walley et al. study²² Walley et al. study
Gene polymorphism in Netherton and common atopic disease. Nat Genet, 2001 identified the gene's role in common allergic disease. rs2303065 sits in exon 13 of SPINK5 and changes the codon for histidine at position 396 from CAT to CAC — a synonymous substitution that does not alter the LEKTI protein sequence (His396=).

The Mechanism

The c.1188T>C change at rs2303065 does not alter any amino acid in LEKTI and has no known direct functional consequence on protease inhibitor activity. ClinVar classifies this variant as benign based on submissions from multiple independent clinical testing laboratories with no conflicts. The T allele's clinical relevance arises entirely from its physical proximity to the functional rs2303067 variant³³ rs2303067 variant
SPINK5 p.Lys420Glu, 843 bp downstream in the same exon 13 region; Lys420 increases furin-mediated cleavage of the LEKTI D6–D7 linker, impairing the potent D6–D9 inhibitory fragment and elevating KLK5/KLK7 kallikrein activity in the skin. These two variants are in tight linkage disequilibrium within the exon 13 risk haplotype: the T allele of rs2303065 and the A (Lys420) allele of rs2303067 are inherited together more often than chance would predict.

The consequence of impaired LEKTI function — the mechanism tagged by this haplotype — is well characterised: KLK5 and KLK7 kallikreins run with reduced inhibition, cleaving desmoglein-1 and accelerating corneodesmosomes breakdown, increasing transepidermal water loss. Simultaneously, elevated kallikrein activity upregulates TSLP⁴⁴ TSLP
thymic stromal lymphopoietin, a cytokine that polarises dendritic cells toward Th2 immune responses and initiates the atopic sensitisation cascade in keratinocytes, lowering the threshold for IgE-mediated sensitisation to environmental allergens.

The Evidence

The rs2303065 T allele was among seven of eight SPINK5 polymorphisms found to be significantly associated with atopic dermatitis in a Japanese cohort of 124 AD patients and 110 healthy controls by Kato et al.⁵⁵ Kato et al.
Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol, 2003. This finding was extended by Nishio et al.⁶⁶ Nishio et al.
Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immun, 2003 using transmission disequilibrium tests, which confirmed SPINK5 haplotype-level association with AD but not asthma, and noted cross-ethnic consistency.

A large European analysis by Weidinger et al.⁷⁷ Weidinger et al.
Analysis of SPINK5, KLK7, and FLG polymorphisms and eczema risk. J Allergy Clin Immunol, 2008 (2,774 AD cases, 10,607 controls) found that SPINK5 variants showed only modest association at the population level, primarily through maternal transmission — a finding consistent with an LD proxy effect that varies in strength across populations with different haplotype structures. Because rs2303065 tags rather than causes the LEKTI impairment, the magnitude of its association with AD depends on how tightly it co-segregates with the functional rs2303067 variant in a given population — an LD parameter that differs between Japanese, European, and African cohorts.

The overall evidence is best classified as moderate: replicated across independent Japanese cohorts using different statistical methods, with a plausible mechanistic explanation via LD, but attenuated in large European studies and with no independent functional pathway.

Practical Actions

Because rs2303065 has no protein-altering effect, its actionability derives entirely from the underlying LEKTI pathway impairment it tags. Carrying the T allele — particularly in homozygous form — signals an increased likelihood of also carrying the risk haplotype at rs2303067. The practical implications are the same as for impaired LEKTI activity: supporting the skin barrier proactively, identifying allergen sensitisers that exploit a more permeable barrier, and monitoring for early atopic features in childhood.

Interactions

LD relationship with rs2303067: This is the primary interaction. Carriers of the TT genotype at rs2303065 are enriched for the Lys420/Lys420 (AA) genotype at rs2303067, the directly functional variant. For users who have results for both SNPs, the rs2303067 result provides the mechanistic information; rs2303065 provides LD-based corroboration.

SPINK5 × FLG variants: SPINK5 haplotype risk and filaggrin (FLG) loss-of-function variants operate through parallel mechanisms — protease over-activity vs. structural scaffold loss — and their effects on AD risk appear additive rather than synergistic, as documented in the Weidinger 2008 analysis.