Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population

Abstract

We report new results from the re-analysis of 672 complete mitochondrial (mtDNA) genomes of unrelated Japanese individuals stratified into seven equal sized groups by the phenotypes: diabetic patients, diabetic patients with severe angiopathy, healthy non-obese young males, obese young males, patients with Alzheimer's disease, patients with Parkinson's disease and centenarians. Each phenotype had 96 samples over 27 known haplogroups: A, B4a, B4b, B4c, B*, B5, D*, F1, F2, M*, M7a, M7b, M8, M9, D4a, D4b1, D4b2, D4d, D4e, D4g, D4h, D5, G, Z, M*, N9a, and N9b. A t-test comparing the fraction of samples in a haplogroup to healthy young males showed a significant enrichment of haplogroups D4a, D5, and D4b2 in centenarians. The D4b2 enrichment was limited to a subgroup of 40 of 61 samples which had the synonymous mutation 9296C > T. We identified this cluster as a distinct haplogroup and labeled it as D4b2b. Using an exhaustive procedure, we constructed the complete list of "mutation patterns" for centenarians and showed that the most significant patterns were in D4a, D5, and D4b2b. We argue that if a selection for longevity appeared only once, it was probably an autosomal event which could be dated to after the appearance of the D mega-group but before the coalescent time of D4a, D5, and D4b2b. Using a simple procedure, we estimated that this event occurred 24.4 +/- 0.9 kYBP.

Longevity-associated mitochondrial DNA 5178 C/A polymorphism and its interaction with cigarette consumption are associated with pulmonary function in middle-aged Japanese men

“…The frequency of the Mt5178A genotype, a genetic marker of mitochondrial haplogroup D, is significantly higher in Japanese centenarians than in the general population (Alexe et al 2007;Tanaka et al 1998) and it is reported that individuals with Mt5178A (mitochondrial haplogroup D) are less susceptible to lifestyle-related adult-onset diseases, for example hypertension (Kokaze et al 2007), diabetes (Wang et al 2001), metabolic syndrome ), myocardial infarction (Mukae et al 2003;Takagi et al 2004), and cerebrovascular diseases (Ohkubo et al 2002), than those with Mt5178C. Mt5178 C/A polymorphism is, moreover, also reported to be associated with blood pressure (Kokaze et al 2004a(Kokaze et al , 2007, serum lipid levels (Kokaze et al 2001(Kokaze et al , 2003a, fasting plasma glucose levels and glucose tolerance (Kokaze et al 2005a), serum uric acid levels (Kokaze et al 2006), intraocular pressure (Kokaze et al 2004b), hematological data (Kokaze et al 2005b), and serum protein fraction levels (Kokaze et al 2002(Kokaze et al , 2003b, and its interaction with smoking habits is associated with serum triglyceride levels (Kokaze et al 2003a), intraocular pressure (Kokaze et al 2004b), red blood cell counts (Kokaze et al 2005b), and serum protein fraction levels (Kokaze et al 2003b).…”

The mitochondrial‐derived peptide MOTS‐c: a player in exceptional longevity?

“…reporting no association between mtDNA haplogroups and EL (Pinos et al ., 2012) but Dominguez‐Garrido and co‐workers finding that the Caucasian haplogroup J (which would be associated with lower mtDNA damage) might confer a higher chance to attain high longevity (85+years) compared with other haplogroups in Northern Spaniards (Domínguez‐Garrido et al ., 2009). On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes (Fuku et al ., 2007), they are linked with EL in Japanese population (Alexe et al ., 2007; Bilal et al ., 2008). We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population (Alexe et al ., 2007).…”

“…On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes (Fuku et al ., 2007), they are linked with EL in Japanese population (Alexe et al ., 2007; Bilal et al ., 2008). We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population (Alexe et al ., 2007). …”

“…Among long‐lived individuals, those who reach exceptional longevity (EL, i.e ., centenarians (≥100 years) and supercentenarians (SCs, ≥110 years)) are arguably the paradigm of successful aging (Andersen et al ., 2012). Several genetic factors might contribute to EL, as suggested by the differences found in the frequency distribution of several genetic variants among centenarians compared with their ethnic‐matched referents of younger ages (Alexe et al ., 2007; Ruiz et al ., 2012; Garatachea et al ., 2014). Factors related to inflammation (Basile et al ., 2012), metabolism (Emanuele et al ., 2014) or nutrition (Pareja‐Galeano et al ., 2015), among others, can also influence the likelihood of reaching EL.…”

Mitochondrial Haplogroups A and M7a Confer a Genetic Risk for Coronary Atherosclerosis in the Japanese Elderly: An Autopsy Study of 1,536 Patients

“…We previously reported significant associations between specific mitochondrial haplogroups and myocardial infarction 6) , atherosclerotic cerebral infarction 7) , metabolic syndrome 8) and longevity among the Japanese 9,10) , and type 2 diabetes among both Japanese and the Koreans 11) . A recent study also indicated significant associations between haplogroup T and coronary artery disease and diabetic retinopathy in Middle European Caucasians 12) .…”