rs1800975 — XPA A23G

XPA A23G — Your DNA's Damage Inspector and Cancer Defense

The XPA gene encodes a zinc-finger protein¹¹ zinc-finger protein
XPA is a 31 kDa protein that acts as a scaffold for assembling the nucleotide excision repair complex at sites of DNA damage that serves as the central damage verifier in the nucleotide excision repair (NER) pathway²² nucleotide excision repair (NER) pathway
NER is the primary system for removing bulky DNA lesions caused by UV radiation, tobacco carcinogens, and platinum-based chemotherapy drugs. Without functional XPA, the NER complex cannot properly assemble at damage sites — complete loss of XPA function causes xeroderma pigmentosum group A³³ xeroderma pigmentosum group A
XP-A is the most severe form of xeroderma pigmentosum, characterized by extreme UV sensitivity and >1,000-fold increased skin cancer risk, one of the most dramatic DNA repair disorders known. The rs1800975 variant (A23G) is a common polymorphism in the 5' untranslated region that subtly modulates how much XPA protein your cells produce, with measurable effects on DNA repair efficiency and cancer susceptibility.

The Mechanism

The rs1800975 variant sits at position -4 from the ATG start codon, directly within the Kozak sequence⁴⁴ Kozak sequence
The Kozak sequence is the consensus nucleotide context surrounding the start codon that controls how efficiently ribosomes initiate translation of an mRNA into protein. This position influences how effectively the 40S ribosomal subunit recognizes and binds to XPA mRNA, directly controlling the rate of XPA protein production. The A allele (T on the plus strand, the minor allele) results in a less optimal Kozak context, leading to reduced XPA protein levels⁵⁵ reduced XPA protein levels
Functional studies show individuals with the A allele have lower DNA repair capacity compared to G allele carriers and consequently diminished NER efficiency. The G allele (C on the plus strand, the major allele) maintains a more favorable translational context, supporting higher XPA expression and more robust DNA repair.

The Evidence

The most comprehensive assessment comes from a meta-analysis of 71 case-control studies⁶⁶ meta-analysis of 71 case-control studies
Yuan et al. Cancer Cell International 2020 — 19,257 cancer cases and 30,208 controls from 52 publications examining rs1800975 across multiple cancer types. The findings reveal a complex, tissue-specific pattern. For skin cancer, particularly basal cell carcinoma⁷⁷ basal cell carcinoma
BCC is the most common human cancer, strongly linked to UV-induced DNA damage that NER normally repairs in Caucasian populations, the A allele (plus-strand T) significantly increases risk: homozygous AA carriers face 36% higher odds (OR=1.36, 95% CI 1.17–1.57) compared to GG carriers. A similar pattern emerges for colorectal cancer⁸⁸ colorectal cancer
Homozygous AA carriers showed OR=1.68 (95% CI 1.15–2.44) for colorectal cancer.

For lung cancer, the picture inverts in an interesting way. A case-control study of 695 matched pairs⁹⁹ case-control study of 695 matched pairs
Wu et al. Carcinogenesis 2003 found that the G allele (plus-strand C) reduced lung cancer risk in Caucasians (OR=0.69, 95% CI 0.53–0.90) and Mexican-Americans (OR=0.32, 95% CI 0.12–0.83). Carriers of the G allele demonstrated measurably higher DNA repair capacity. A subsequent meta-analysis¹⁰¹⁰ subsequent meta-analysis
Lou et al. Tumour Biology 2014 confirmed that in East Asian populations, the AA genotype (plus-strand TT) increases lung cancer risk under a recessive model (OR=1.30, 95% CI 1.08–1.56), with the strongest effect in squamous cell carcinoma subtype (OR=1.42).

The variant also predicts response to platinum-based chemotherapy. A study of 115 advanced NSCLC patients¹¹¹¹ study of 115 advanced NSCLC patients
Cheng et al. Technology in Cancer Research & Treatment 2013 found that carriers of the G allele (plus-strand C) treated with platinum-based regimens had significantly longer progression-free survival (10.6 vs 6.0 months) and overall survival (20.8 vs 11.2 months, HR=0.65). This may seem paradoxical — better DNA repair should mean more resistance to platinum drugs — but the relationship between NER capacity and chemotherapy outcome is complex, involving both tumor-cell repair of drug damage and host-tissue resilience.

Practical Implications

The clinical relevance of this variant operates on two levels. First, it modulates baseline cancer susceptibility: carriers of the T allele (literature's A) have reduced NER capacity, making their cells less efficient at repairing DNA damage from UV exposure, environmental carcinogens, and oxidative stress. This is most consequential for sun-exposed skin and tissues exposed to dietary or inhaled carcinogens. Second, the variant influences how cancer patients respond to platinum-based chemotherapy, which works by creating DNA lesions that NER would normally repair.

Interactions

XPA functions within the broader NER pathway alongside several other genes with common functional variants. The ERCC2/XPD helicase (rs13181, rs1799793) unwinds DNA around damage sites, while XRCC1 (rs25487) coordinates base excision repair that handles overlapping substrate damage. XPA rs1800975 and ERCC2 rs13181 have been studied together in platinum chemotherapy response, with combined genotyping showing stronger predictive power than either variant alone. The NER pathway also interacts with base excision repair through shared substrates — oxidative DNA damage can be processed by either pathway depending on lesion chemistry. When combined with impaired XPD helicase function (rs13181 GG genotype), reduced XPA expression could compound NER deficiency, though the specific combined risk has not been quantified in large studies.