rs1800975 — XPA A23G

5' UTR variant in the XPA DNA damage recognition gene that modulates nucleotide excision repair capacity, influencing cancer susceptibility and platinum-based chemotherapy response

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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.

Drug Interactions

cisplatin reduced_efficacy literature
carboplatin reduced_efficacy literature
oxaliplatin reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Robust Repair Normal

Optimal XPA expression supporting efficient nucleotide excision repair

You have two copies of the C allele (literature's G allele), which maintains the most favorable Kozak sequence context for XPA protein production. Your cells produce optimal levels of XPA protein, supporting efficient nucleotide excision repair of UV-induced and carcinogen-induced DNA damage. This is the most common genotype globally, carried by about 43% of people across all ancestries. Studies show this genotype is associated with the highest DNA repair capacity and the lowest risk for several cancer types including skin basal cell carcinoma and lung cancer.

CT Intermediate Repair Intermediate

Moderately reduced XPA expression with intermediate DNA repair capacity

The heterozygous state produces both optimal and suboptimal Kozak sequence contexts for XPA translation, resulting in intermediate XPA protein levels. While the NER pathway remains functional, the slightly reduced XPA availability means DNA damage recognition and repair complex assembly proceed less efficiently under high-damage conditions. This matters most in tissues with high carcinogen exposure — sun-exposed skin, the colorectal epithelium, and lung tissue in smokers. The effect is modest in absolute terms but consistent across multiple large studies.

TT Reduced Repair Reduced

Reduced XPA expression diminishes nucleotide excision repair capacity, increasing susceptibility to DNA damage

With both alleles producing suboptimal XPA translation initiation, your cells have the lowest expression of this critical NER scaffold protein. XPA protein levels directly determine how efficiently your NER pathway can assemble at sites of DNA damage — fewer XPA molecules mean slower damage recognition and fewer active repair complexes per cell at any given time. Under normal conditions, this reduced capacity is generally sufficient for baseline DNA maintenance. However, under conditions of elevated DNA damage — intense UV exposure, tobacco carcinogen exposure, or dietary carcinogen intake — the repair system may become saturated more quickly than in individuals with higher XPA expression, allowing more damage to persist and accumulate. The elevated cancer risks seen in multiple meta-analyses reflect this reduced damage tolerance over decades of exposure.