DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span

► hOGG1 Ser326Cys and APE1 Gln51His showed associations with general cognitive function, reasoning, cognitive control and speed of processing, with genotype by age interactions in the cross-sectional analysis and a main effect on longitudinal decline. ► Dispersed association effects involving MutYH, PolB, and NEIL2 were also detected when APOE or CHRNA4, which have been proposed to modulate cognitive aging, were included in the statistical model. ► The results support the notion that polymorphisms in BER genes are associated with cognitive performance and decline in normal elderly individuals. To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20–75 years. SNPs examined included PolB Pro242Arg, hOGG1 Ser326Cys, MutYH Met22Val, MutYH His324Gln, APE1 Gln51His, APE1 Glu148Asp, XRCC1 Lys298Asn, XRCC1 Arg7Leu, NEIL1 Asp252Asn, and NEIL2 Arg257Leu. XRCC1 Arg7Leu and PolB Pro242Arg were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1 Ser326Cys (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH His324Gln (His/Gln37%/Gln/Gln 6.0%) and APE1 Glu148Asp (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH Met22Val, APE1 Gln51His and NEIL2 Arg257Leu occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1 Ser326Cys and APE1 Gln51His had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH His324Gln, MutYH Met22Val, PolB Pro242Arg and NEIL2 Arg257Leu were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.