Recently, haplogroup association studies have been used to define the role of mtDNA mutations in complex diseases and longevity. In this approach, case and control mtDNA sequence sets are assigned to haplogroups, and the distribution of haplogroups is compared. A significant difference is interpreted to indicate that the mtDNA ‘background’ has an effect on expression or penetrance of the phenotypes. Given the inconsis- tency results among the different studies, as observed in Rugao population and Japanese [11,37]; it is difficult to conclude unequivocally that longevity is influenced by mitochondrial haplogroups. The nuclear background in which these mtDNA haplotypes are found is a factor that may contribute to difficulty in detecting and interpreting correlations between mitochondrial haplogroups and longevity. As early as 1996, Guan et al [39] provided biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochon- drial 12S rRNA mutation. However, inconsistency may also be due to population-substructure, lacking of power for small sample size, and possibly different genomic background. Firstly, it is difficult to ‘match’ groups, even when one tries to control gender, ethnicity, and geography. Secondly, the recruitment of cases and control groups from separate population groups is another common source of bias in case-control studies. However, in this study, all cases were recruited from the Han ethnicity of the Rugao City, with a high response rate. The gender ratio of unresponded subjects is similar to the responded ones. Therefore, the representative of the case subjects to source population is guaranteed. The sample frame of our control group was also

In summary, we observed the involvement of mtDNA haplogroups in the prevalence of longevity by using a carefully matched population based case-control design in Rugao, China. The results should lead to increasing understanding of the role of genome maintenance in longevity. Although we selected two control groups to verify our discovery, our finding also needs to be replicated by other independent studies.

Author Contributions

Conceived and designed the experiments: XfW SzY LJ. Performed the experiments: XC SL JQ DgQ FC. Analyzed the data: XC XfW YB SzY. Contributed reagents/materials/analysis tools: SL JQ DgQ FC YjY ZyY JX YB SzY. Wrote the paper: XfW LJ.

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