Modulation of nucleotide excision repair in human lymphocytes by genetic and dietary factors.
Gene-environment interactions determine inter-individual variations in nucleotide excision repair (NER) capacity. Oxidative stress was previously found to inhibit NER, thus supplementation with dietary antioxidants could prevent this inhibition, especially in genetically susceptible subjects. To study the effects of genetic polymorphisms in NER-related genes and dietary intake of antioxidants on an individual's NER capacity, lymphocytes of 168 subjects were isolated before and after a 4-week blueberry and apple juice intervention. Twelve genetic polymorphisms in NER genes XPA, XPC, ERCC1, ERCC2, ERCC5, ERCC6 and RAD23B were assessed by multiplex PCR with single base extension. Based on specific genotype combinations, a subset of individuals (n 36) was selected for phenotypical assessment of NER capacity, which was significantly affected by the total sum of low-activity alleles (P = 0.027). The single polymorphism XPA G23A was the strongest predictor of NER capacity (P = 0.002); carriers of low-activity alleles AA had about three times lower NER capacity than XPA GG carriers. NER capacity assessed before and after intervention correlated significantly (R(2) 0.69; P < 0.001), indicating that inter-individual differences in NER capacity are maintained over 4 weeks. Although the intervention increased plasma trolox equivalent antioxidant capacity from 791 (SE 6.61) to 805 (SE 7.90) microm (P = 0.032), on average it did not affect NER capacity. Nonetheless, carriers of twelve or more low-activity alleles seemed to benefit from the intervention (P = 0.013). Among these, carriers of the variant allele for RAD23B Ala249Val showed improved NER capacity upon intervention (P = 0.020). In conclusion, improved NER capacity upon dietary intervention was detected in individuals carrying multiple low-activity alleles. The XPA G23A polymorphism might be a predictor for NER capacity.
Langie
Sabine A S
SA
Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht 6200 MD, The Netherlands.
Wilms
Lonneke C
LC
Hämäläinen
Satu
S
Kleinjans
Jos C S
JC
Godschalk
Roger W L
RW
van Schooten
Frederik J
FJ
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D029798:Blueberry Plants; D002839:Chromans / Q000097:blood; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics*; D004032:Diet; D005260:Female; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D027845:Malus; D008875:Middle Aged; D010641:Phenotype; D028321:Plant Preparations / Q000008:administration & dosage / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D055815:Young Adult
D000975:Antioxidants; D002839:Chromans; D028321:Plant Preparations; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid