The search for gene variants associated with human longevity has turned up only two reliable correlations to date, with a couple more in the tentative bucket awaiting further confirmation. The effects of all of these are not large; individually, each represents only a small increase in the odds of a longer life. The emerging picture of the genetics of longevity is one of thousands of tiny influences, near all of which are highly conditional on circumstances and other variants. The vast majority of correlations observed in any one study population are not seen in others. One of the variants still in the tentative bucket is 5q33.3, first noted a couple of years ago, and this paper is illustrative of the sort of work required in the ongoing investigation of such correlations:
The search for major longevity genes in humans has so far had limited success and only the APOE and FOXO3A genes have been found to consistently associate with human longevity. Recently, however, a third longevity locus was proposed based on the results of a genome-wide association meta-analysis including 12,736 long-lived individuals older than 85 years and 76,268 controls younger than 65 years of European descent. In this study, the single nucleotide polymorphism (SNP) rs2149954 on chromosome 5q33.3 was found to associate with survival to beyond 90 years of age. This association has afterwards been confirmed in a genome-wide association study of exceptional longevity in Han Chinese centenarians. Investigation of the effect of rs2149954 on prospective survival in the meta-analysis showed a significant association with lower all-cause mortality as well. Further investigation of cause-specific mortality in a sub-group analysis revealed that the lower mortality seen in rs2149954 minor allele carriers was partly conferred by a decreased mortality risk for cardiovascular disease, primarily due to protection from stroke. However, a protective effect of the rs2149954 minor allele on mortality independent of cardiovascular disease was also found.
Previous studies in middle-aged individuals have revealed a significant association between the rs2149954 minor allele and a decreased risk for coronary artery disease, and lower diastolic and systolic blood pressure. Also, two SNPs on chromosome 5q33.3 in high linkage disequilibrium with rs2149954, rs9313772 and rs11953630, have been reported to be associated with blood pressure and hypertension. In individuals older than 75 years the association between rs2149954 and all-cause mortality was, however, not found to be influenced by blood pressure. So, although there is an established connection between rs2149954 and different cardiovascular phenotypes, there also seems to be an effect of the variant in mechanisms other than those associated with cardiovascular disease and blood pressure regulation, at least in long-lived individuals. The role of the 5q33.3 locus in survival and longevity is therefore still partly unknown.
To further explore this, we investigated the influence of rs2149954 on age-related phenotypes previously shown to predict survival in the oldest-old: cognitive function (evaluated by a 5-item cognitive composite score and the Mini-Mental State Examination (MMSE)), physical function (evaluated by an activity of daily living (ADL) strength score, hand grip strength, gait speed, and chair stand), ADL disability, depression symptomatology, and self-rated health. In addition, self-reported diseases related to cancer and cardiovascular disease, which are among the leading causes of death, were explored. The apparent age-dependent pleiotropy in the role of the 5q33.3 locus was addressed by analyzing long-lived as well as middle-aged and elderly individuals.
In the middle-aged and elderly individuals, we found a nominally significant association between the minor allele of rs2149954 and a lower risk of hypertension. This is supported by an analysis of the diastolic and systolic blood pressure measured in the middle-aged individuals at a later follow-up assessment. Here we find that homozygous carriers of the rs2149954 minor allele have lower diastolic and systolic blood pressure, which is in line with the previously found association between rs2149954 and lower diastolic and systolic blood pressure in middle-aged individuals. Overall, our results support a role of rs2149954 in cardiovascular health, and we confirm the previously found association between rs2149954 and a lower risk of hypertension in middle-aged as well as in elderly individuals. The 5q33.3 locus thus appears to play a persistent role in cardiovascular health throughout the entire age-span investigated here, although we see a shift with age from a role in hypertension to a role in heart attack and heart failure. This shift is supported by a number of studies indicating that while high blood pressure is disadvantageous in midlife it appears to be advantageous at higher ages where it is associated with better physical and cognitive health and lower all-cause mortality. This reversal of risk has been suggested to take place around the age of 75 to 85 years and it is thus consistent with the age-related attenuation that we see for the association between rs2149954 and hypertension.
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