We have previously found an association between longevity and food availability during the paternal grandfather's SGP.11 In this study we have looked specifically at cardiovascular deaths, including diabetes mellitus.

The number of probands with diabetes on their death certificates was very small and does not really allow for the multivariable control of a large number of possible confounders. However, the bivariate influence of overfeeding during the paternal grandfather's SGP was, in itself, indicative of some effect on the proband.

For 22 individuals from the older generations, we found only the year of birth and not the date of birth. A sensitivity analysis excluding them, however, changed results very little (data not shown). In order to establish the period of slow growth velocity, we used a modern cohort and determined the SGP from the growth velocity in cm/year. We then added 1 year because puberty occurred about 1 year later in the older generations. Furthermore, age at puberty for this older group is known to have had a more skewed distribution to the right than it does today.18 However, we did not consider this. Consequently, our delineation of the SGP is approximate, which might mean that some effects of different nutrition could not be detected.

The attrition rate was 25%, the samples included 320 probands and we followed 239. Another 7–22% of parents or grandparents had been exposed to both a famine and a year with surfeit of food during their SGP, which could be seen as a type of attrition as well. Hence, we assigned them ‘zero’ in the analyses. The high attrition rate could have distorted the results. We do not know what the older generations actually received from the available food supplies. The individual's social class coupled with the socio-economic circumstances of the area contributes independently to health outcomes.19

Furthermore, the availability of food was determined for the province as a whole, not just for our small research area, but that means that access to relief supplies within 200–300 km was unlikely. Food relief from farther away was impossible for people living in the 19th century because there were no railways or roads, and in the winter the frozen Baltic Sea prevented any transport over water.

The outcome parameter, that is, cardiovascular and diabetes mortality, was collected from parish registers and was based on death certificates that are known to be less than accurate with respect to cardiovascular causes. The number of probands in each of the three cohorts was small. Diabetes mellitus, for instance, was a cause of death in only 19 cases, and we do not know whether they suffered from type-1 or type-2 diabetes. The small sample of probands might have left real effects undiscovered.

The probands' own nutrition during embryonic and foetal life might have had significant bearing on stroke in adulthood.9 Childhood experiences, social environment, circumstances of the adult life,19 and psychological circumstances might have had a long-term influence on the probands' management of risks for cardiovascular disease. None of these possible effects was taken into account.

Interesting results

The most intriguing result is that nutrition-related circumstances of the social environment had transgenerational associations with cardiovascular and diabetes-related deaths, and that transmissions were down the male line.

When the father (P=0.05) and perhaps the paternal grandmother (P=0.11) were exposed to a famine during their SGP, the proband was protected against cardiovascular causes of death. Furthermore, if the paternal grandfather lived through a famine during his SGP it tended to protect the proband from diabetes (P=0.09). Most interesting, however, was the finding that if the paternal grandfathers had access to a surfeit of food during their SGP, the probands (their grandchildren) had a fourfold over-risk for death of diabetes mellitus according to the point estimate (P=0.01).

Selection and fitness

Ancestors of the proband were surviving cohorts and it is possible that genetic selection through differential survival/fertility might explain the findings. The variation around the (similar) average ages at death did not decrease over the three generations, which might mean that selection had not occurred (Table 2). The paternal grandfathers exposed to poor or good availability of food during their infancy were nearly the same average age at death. The paternal grandfather's age when the father of the proband was born was not coherent with the exposure during his SGP. In addition, the father's age at the birth of his firstborn child was not coherent with the exposure during his SGP. If exposure during the SGP had revealed selection based on survival/fertility, then such selection should be detectable in others and not just in the paternal grandfathers. One indication, which is difficult to interpret, was the fact that the number of children in the probands' sibship was higher when the grandfather ‘starved’ during the SGP and when the father had been exposed to a surfeit of food during his SGP.

Analogies as to mechanisms

Genomic imprinting in its classical genetic sense is not applicable here as it can only happen at the time of fertilisation. The lack of support for genetic selection as a mechanism raises the question, however, as to whether the nutrition-related transgenerational effect down the male line involves direct epigenetic modification of DNA and/or the associated histones. Epigenetic inheritance has been described in mice20,21 and in proposing a feed-forward loop linking grandparental nutrition with their grandchildrens growth Pembrey argued that imprinted genes are good candidates for mediating such transgenerational effects.14 The question remains if such inheritance will turn out to happen during the SGP.

The over-risk found for death with diabetes directs our speculations to variation at the variable number tandem repeat (VNTR) minisatellite 5′ of the insulin gene which is associated with type-1 diabetes. Variation, most plausible in the VNTR, influences type-2 diabetes susceptibility. This effect is mediated exclusively by the paternally derived allele, which implicates an imprinted gene (possibly IGF2) in the pathogenesis of type-2 diabetes.22 Ins2 in mice and IGF2 in the yolk sac are likewise expressed solely from the paternal allele hinting at later insulin and growth related diseases.23

Nutrition affects ovaries and testes from the moment they form during foetal life through maturity.24 Too little is known to speculate on how food availability during the SGP might impact epigenetically on the maturing male germ line, but in mice new parental-specific genomic imprints are introduced when sperm and oocytes begin to mature.25

The probands had a tendency to be protected from cardiovascular death if the mother lived through a year or years with a surfeit of food during her SGP (P=0.05). That result points not only to the DNA of the mother's allele but also to the cytoplasm of the ovum and the influence of nutrition on the height of the mother and size of her pelvis, – both of which influence the probands' risk for cardiovascular disease. Therefore, this finding is not easy to interpret. Many other environmental influences might have been at work as nutrition is coherent with other determinants such as infections.26

In conclusion, these epidemiological findings draw attention to transgenerational effects down the male line of nutrition-related circumstances during a period of childhood with a bearing on over-risks for cardiovascular disease and diabetes.