In the present study, the prevalence of MTHFR 677 T was 17.44% and 14.50% in the combined samples and control population respectively, with a lower frequency of TT homozygote (≈4%). These allelic and genotypic frequencies are close to that of Bai Ku Yao (22.6%) whereas much lower than that of Guangxi Han Chinese (39.1%), two neighboring populations we reported recently.
It has been noted that the distribution of the T allele vary substantially across general populations worldwide, with a north-to-south increase in European continent but a reverse gradient in China mainland[19–21]. Zhuang and Bai Ku Yao are typical aboriginal ethnic groups in Southern China, our results thus defer somewhat to this pattern. The underlying mechanism for this great geographical diversity remains unclear, adaptation to external conditions such as climate or nutritional status could be one explanation. Further investigation of gene-gene and gene-environment interaction might help to determine the evolutionary pressures favouring a high prevalence of this variant in certain areas and ethnic groups.
Intriguingly, MTHFR 677 T and its relevant genotypes (CT, TT) were significantly more prevalent in our nonagenarian and centenarian populations, especially in females, as compared with the elder control group (60–75 years). These observations implicate a potential association between MTHFR C677T polymorphism and longevity in Bama area. A question of whether this variant is favorable or deleterious for Bama long-lived individuals therefore emerges. According to most but not all reported data, MTHFR 677 T genotypes have been linked to unfavorable lipid profiles, including greater concentrations of TC, TG, and LDL-C[18, 23–25] and lower level of HDL-C[26, 27], all known risk factors for cardiovascular and metabolic diseases. Herein, the female but not male T-allele carriers in the pooled population and in LG presented greater level of TC, TG and LDL-C than did T noncarriers (Table 3 and Table 5), in agreement with prevailing data as aforementioned, indicating that MTHFR 677 T genotypes may play detrimental rather than beneficial role in lipid modulation and survivorship. However, this influence seems to be limited because the impact of MTHFR 677 T on lipid metabolism remained only in the normolipidemic subgroup of non-LG after further analysis according to lipid status categorization (Table 4). Together, these data suggest that although MTHFR C677T affects the TC and LDL-C metabolism of LG and the overall population studied to varying degree, particularly of the females in LG, these impacts may not be sufficient to cause extremely lipid abnormality.
With regard to the enrichment of deleterious genotypes in long-lived females, it might be partially interpreted by the Buffering Mechanisms in Aging hypothesis proposed recently by Bergman and colleagues who reasoned that in a subpopulation endowed with a favorable longevity genotype(s), the prevalence of a deleterious genotype is expected not to vary or even increase with age because the longevity genotype may buffer out or modulate the harmful effect of deleterious ones, while in a subpopulation lacking longevity genotypes, the prevalence of a deleterious genotype will decrease with age since subjects with this genotype are weeded out due to mortality[28, 29]. Therefore, screening for potential longevity genotypes such as CETP (VV) (rs5882), APOC3 (CC) (rs2542052), AdipoQ (del/del APM1 + 2019) (rs56354395), and FOXO3a (GG), which have been demonstrated in other populations[30–33], will be one of our next efforts in the near future.
Due to the established link among MTHFR C677T polymorphism, Hcy, cardiovascular risk and aging, several investigations have been conducted in some elder cohorts to look at the possible contribution of MTHFR to longevity. However, findings are still inconsistent thus far. For instance, lower frequency of MTHFR C677T +/+genotype, with raised Hcy level, was observed in French cohort with longevity trait (> 90 yrs, n = 564) than in controls (< 70 yrs, n = 374), albeit no statistical significance was reached. Similar observations were made in Swiss (106 elderly, 68–95 yrs vs 118 younger, 21–64 yrs), Japanese (148 oldest, > 80 yrs including 22 nonagenarians vs 311 younger, < 55 yrs) and Jerusalem Ashkenazi (224 elderly, > 75 yrs vs 441 controls, < 22 yrs) populations, while almost equal prevalence of MTHFR C677T genotypes were seen between elderly and younger group in Swede (222 elderly, 80–108 yrs vs 220 newborn), British (282 elderly, > 84 yrs vs 200 younger, < 17 yrs), and Jordanian (130 elderly, > 85 yrs, mean age 90.01 yrs vs 135 younger, 20–50 yrs, mean age 33.34 yrs) population. Conversely, we detected a higher prevalence of MTHFR 677 T in our oldest olds. Although it is known that MTHFR TT might be a risk biomarker against longevity from other perspectives, we cannot exclude the possibility that it may also be in favor of good health or long life span as implicated by Le Marchand et al. that there might be an inverse association between MTHFR 677TT genotype and the development of colorectal cancer. To the best of our knowledge, the nonagenarian population here is the only long-lived cohort that enriches this variant, whose significance deserves further clarification. These discrepancies may arise from factors related to differences in ethnic background of the population studied, recruitment strategy for long-lived and control group, assessment methods or sample sizes.
Despite strengths such as large sample size, highly population genetic homogeneity and well-characterized cases and controls, all the difference of lipid profiles between long-lived individuals and controls cannot completely attribute to MTHFR C677T. The current study should be viewed in the light of some limitations: (1) no determination of folate status, serum MTHFR activity and Hcy levels on baseline data collection due to insufficient funding, which would be more significantly conclusive and would help to interpret the selection and the outcome of MTHFR 677 T[22, 42]; (2) lack of the evaluation of other modifying genetic variants, risk factors such as smoking and alcohol consumption and lifestyle which may interact with MTHFR C677T and change its association with longevity; (3) we could not completely exclude asymptomatic disorders such as atherosclerosis which may create a potentially significant bias due to poor field study condition; (4) it is very much speculative to imagine the controls would have a short life span because of a specific family history, this may also be a significant bias factor. (5) longitudinal follow up is warranted in further interpreting the potential effect of MTHFR C677T polymorphism on lipid metabolism.