3.3. The effect of gender on the association of mtDNA variation with longevity

Table 1

The characteristics in 738 Chuang subjects in China.

Longevity Control p value (n=367) (n=371) Age (yr) 95.34±4.75 46.75±4.79 b0.001 Gender (M/F) 98/269 107/264 – BMI (kg/m2) 18.69±3.21 24.03±2.69 b0.001 SBP (mm Hg) 146.31±21.94 117.21±13.71 b0.001 DBP (mm Hg) 80.13±11.38 75.27±9.38 b0.001 FBG (mmol/l) 5.34±1.54 4.83±0.59 b0.001 TC (mmol/l) 4.91±1.24 4.62±0.72 0.001 HDL-c (mmol/l) 1.51±0.61 1.52±0.33 0.970 LDL-c (mmol/l) 2.85±0.92 2.27±0.64 b0.001 TG (mmol/l) 1.37±0.93 1.51±0.44 0.022

Sex differences exist in longevity, with women living longer than men. When we stratified the Bama cohort by gender we found signif- icant association of longevity in females for haplogroup F (p=0.003, OR: 2.01, 95%CI: 1.263–3.197) and the three mtSNPs (m.3970CNT, m.13928GNC and m.10310GNA) that defined haplogroup F (p=0.001, OR: 1.970, 95%CI: 1.305–2.976; p=0.004, OR: 1.799, 95%CI: 1.204–2.689 and p=0.003, OR: 2.010, 95%CI: 1.263–3.197). However, there was no such significant association found in males (Table 3). Additionally, subhaplogroup F3 and one mtDNA variant (m.10320GNA) in subhaplogroup F3 were slightly associated with

Note: Values are given as means±SDs. BMI = body mass index, SBP = systolic blood pressure, DBP = diastolic blood pressure, FBG = fasting blood glucose, TG = serum total triglyceride, TC = serum total cholesterol, HDL-c = high density lipoprotein- cholesterol, LDL-c = low density lipoprotein- cholesterol.

3.4. mtDNA variation associated with longevity-related phenotype

To attain supporting evidence for the association of mtDNA variations withlongevity,wetestedtherelationshipof FBG,TG, TC,HDL-candLDL-c levelswithmtDNAhaplogroupFamongtheBamapopulation.Theresults showed that mtDNA haplogroup F was associated with markedly higher HDL-c levels (pb0.05), but only in long-lived subjects, as shown in

(13.5%). There was significantly statistical difference for haplogroup F between the long-lived and control groups for the two genders com- bined (p=0.010, OR: 1.703, 95%CI: 1.153–2.514, see Table 2), and the power was 85.5% by the statistical power calculator (http://www. dssresearch.com/toolkit/sscalc/size_p2.asp). To further determine the influence of haplogroup F on longevity, every mtDNA variant (m.3970CNT, m.13928GNC or m.10310GNA) in haplogroup F was ana- lyzed by the association study. The three mtDNA variants were found to be consistently associated with longevity for the two genders com- bined (p=0.009, OR: 1.602, 95%CI: 1.134–2.262; p=0.021, OR: 1.507, 95%CI: 1.075–2.114 and p=0.010, OR: 1.703, 95%CI: 1.153– 2.514, respectively, see Table 2).

4. Discussion

Although the mechanism by which mtDNA variation influences mitochondrial function, longevity and successful aging are unknown, the present study provides evidence of association between mtDNA haplogroups and longevity. At present, there are three methods in longevity studies (Christensen et al., 2006), i.e. case–control studies (Kleindorp et al., 2003; Li et al., 2009; Pan et al., 2011), linkage anal- ysis and longitudinal studies. The linkage studies require very large sample size while longitudinal studies are difficult to be carried out based on practical issues. Although case–control studies have the pri- marily methodological shortcoming of appropriate control groups, the advantage of this method is that variants with small effects can be detected (Christensen et al., 2006).

Table 2

Distribution of mtDNA haplogroups and variants between long-lived subjects and con- trols in Chuang population, Bama.

Haplogroups Longevity % Controls % p value OR 95%CI (n=367) (n=371) M8 6.3 9.7 0.116 0.624 0.362–1.075 ⁎ C 5.2 4.6 0.845 1.133 0.580–2.216 M7 17.2 15.4 0.575 1.141 0.771–1.689 ⁎ M7b′c 17.2 14.6 0.383 1.217 0.819–1.810 ⁎ M7b1′2 16.1 13.2 0.316 1.261 0.837–1.900 D 8.7 9.7 0.733 0.888 0.539–1.462 ⁎ D4 8.2 7.3 0.744 1.137 0.662–1.951 ⁎ D4a 1.6 1.9 0.980 0.867 0.289–2.604 F 21.0 13.5 0.010 1.703 1.153–2.514 ⁎ F3 4.9 2.8 0.109 2.085 0.922–4.714 #Others 46.8 51.7 0.212 0.823 0.616–1.098 Variants 10400CNT 43.1 47.7 0.238 0.830 0.621–1.110 15487ANT 6.3 9.7 0.116 0.624 0.362–1.075 13263ANG 5.2 4.6 0.845 1.133 0.580–2.216 6455CNT 17.2 15.4 0.575 1.141 0.771–1.689 4071CNT 17.2 15.4 0.575 1.141 0.771–1.689 4048GNA 17.2 15.1 0.503 1.167 0.788–1.729 12811TNC 16.1 12.9 0.266 1.291 0.855–1.950 5178CNA 8.7 10.0 0.641 0.861 0.524–1.414 3010GNA 8.2 7.3 0.744 1.137 0.662–1.951 14979TNC 1.6 1.9 0.980 0.867 0.289–2.604 3970CNT 27.5 19.1 0.009 1.602 1.134–2.262 13928GNC 28.3 20.8 0.021 1.507 1.075–2.114 10310GNA 21.0 13.5 0.010 1.703 1.153–2.514 10320GNA 4.9 2.4 0.109 2.085 0.922–4.714 5585GNA 5.2 3.2 0.261 1.632 0.780–3.415