DNA repair enzyme gene polymorphisms may alter the function or efficiency of DNA repair and may contribute to stroke susceptibility.3
DNA repair systems are safeguards to maintain genomic integrity in the face of environmental stressors, cumulative effects of age and general DNA replication errors. XRCC1 and APE are thought to play a role in the base excision repair pathway that removes “non‐bulky” base adducts produced by methylation, oxidation, reduction or fragmentation of bases by ionising radiation or oxidative damage.24
XPD is thought to be involved in nucleotide excision repair, which repairs “bulky” lesions such as pyrimidine dimers, other photoproducts and larger chemical adducts.25,26
What this paper adds
- To date, no data on the relationship between DNA repair and stroke in human population studies have been reported, nor are there any reports on the association between DNA repair genes and other neurological diseases such as Alzheimer's or Parkinson's in epidemiological studies.
- Our results suggest that polymorphisms in DNA repair genes may be important in the aetiology of stroke.
- There are no immediate policy implications because these data need to be confirmed in other studies.
- In the future, it is possible that drugs that target DNA repair genes could be tested for stroke.
- Lifestyle factors such as nutritional factors that could possibly stimulate DNA repair capacity might be useful in preventing stroke.
In this prospective study, we observed 118 incident strokes over a 5‐year period in a cohort of 4005 individuals. We found that people with one or more XPD23 variant alleles had a risk of stroke approximately twice as high (RR 2.18, 95% CI 1.14 to 41.7) as those with the wild‐type genotype. In contrast, the individuals with a variant XRCC1*10 allele had approximately 40% fewer strokes (RR 0.59, 95% CI 0.36 to 0.96) than those with the wild‐type genotype. When classified with respect to both polymorphisms, 47% of the population with variant XRCC1*10 and the wild‐type XPD23 had the lowest risk of stroke. The increased risk for individuals with one of the other three genotypes ranged from a little over twofold to a little over fourfold (table 3). We found no association between the risk of stroke and polymorphisms in the APE/ref‐1 or XRCC1*6 genes.
The nutritional status of our subjects may have made them particularly susceptible to genetic inefficiencies in DNA repair. We and others have documented numerous chronic nutritional deficiencies in this population.9,10,14,21,27,28,29
Recently, we have measured pre‐intervention levels of folate, B12
and homocysteine in a random sample of 3000 individuals from our Linxian cohort, and found that 90% of this population had marginal folate status (serum folate <6 ng/l) and 75% had marginal B12
status (serum B12
Consistent with these low serum levels, the serum homocysteine levels were approximately 2–3 times higher than those typically found in women and men in Western populations.15,29
High levels of homocysteine have been found to be associated with increased DNA damage and reduced DNA repair,30,31
and increased rates of stroke both in China 32,33
and in Western populations.34,35
Since the nutrient deficiencies we describe make this Chinese population particularly sensitive for detecting the effect of inefficiencies in DNA repair on stroke, the magnitude of the effects of the polymorphisms in Linxian may be greater than the effects in Western populations where these nutrient deficiencies are rare. Nevertheless, it is quite possible that DNA repair polymorphisms may affect the incidence of stroke in the West as well, possibly owing to the suboptimal intake of dietary folate and B12
vitamins, or independent of nutritional factors. Although there is little direct evidence of a relationship between DNA repair capacity and stroke, recent studies from animal models of expression of proteins in DNA repair pathways suggest that it is important in repairing damage after transient ischaemic events.36,37
The design and execution of our study assure that certain sources of error were avoided. The subjects were from a well‐defined population cohort with ethnic homogeneity. The serum for the genotype measurement and the covariate data was collected at the start of the cohort; this prevents the recall biases that can exist in retrospective studies. Local doctors made end point classification in a timely manner, and the documentation and diagnoses were reviewed by a single panel of expert clinicians.
Our study also had limitations. Although the diagnostic criteria for stroke were consistent, because CT and MRI were not available in this rural area we were prevented from subclassifying the strokes into ischaemic or haemorrhagic categories. Therefore, we cannot address the issue of whether the association of these polymorphisms with stroke might differ by subtype. This probably limits the generalisability of our results, since the ratio between ischaemic and haemorrhagic stroke differs in China and in the West, with more haemorrhagic strokes being diagnosed in China than in the West. Also, this inability to distinguish between the different stroke pathologies probably introduced a conservative bias to our findings, minimising the risk estimates since these estimates must be averages of what are possibly two different associations.
In any case, any misclassification that exists is not related to the DNA polymorphism status, and could not result in false‐positive findings. Our study is also limited by its relatively small number of stroke cases. Although this does not affect the validity of the significant associations we report with XRCC1*10 and XPD23 polymorphisms, it does limit our ability to detect interactions between these two polymorphisms, or to conclude that APE/ref‐1 or XRCC1*6 polymorphisms have no important effect on stroke.
In summary, we found that subjects with a variant XRCC1*10 had a decreased risk of stroke, and those with a variant XPD23 had an increased risk. This is the first population‐based study to suggest that DNA repair, and by extension DNA damage, may play a role in the pathogenesis of stroke in humans. Although the size of this study is too small to be conclusive in any way, it should provide additional impetus for research on DNA damage and stroke in general, and on the relationship of polymorphisms in DNA repair enzymes and stroke in particular. There are no immediate policy implications of this study, because these data need to be confirmed in other studies. In the future, however, it is possible that new research could lead to drugs that target DNA repair genes as a new therapeutic strategy for stroke. In addition, lifestyle factors such as nutritional agents that may stimulate DNA repair capacity might be useful in preventing stroke.