M = male; F = female. Data are presented as a percentage with the number of individuals given in parentheses.

2. Estimated Relative Risks of the Genotypes at the Three Loci in Females

Genotype Frequency Risk p-value 
HSPA1A AA 0.398 3.864 0.016 
AC 0.484 2.577 0.056 
CC 0.118 1 - 
HSPA1B AA 0.359 2.764 0.039 
AG 0.478 1.932 0.188 
GG 0.163 1 - 
HSPA1L* C allele carriers 0.359 1.913 0.328 

*Analysis was not possible due to the low frequency of the C allele.

Fig. (1). Survival of genotypes in HSPA1A (left) and HSPA1B (right) among females.

Also, female carriers of genotype HSPA1B-AA (RR=2.764; p=0.039) had a shorter survival duration than carriers of HSPA1B-GG [Fig.(1)]. These results on the association of genotypes with female survival were maintained when Kaplan-Meiers test of survival was performed [Fig.(2)]. No significant results were obtained in analyzing male subjects.

DISCUSSION

The conventional method for performing the genetics of human longevity, in population-based association studies, is the cross-sectional design. In this method, gene, genotype, or haplotype frequencies are compared between a group of old cases and young controls. This methodology, though inexpensive and straightforward, suffers from a drawback that the observed differences in the frequencies in the two groups can be due to secular changes in population demographic and genetic parameters of the two groups and not necessarily age. An alternative to this approach is the longitudinal cohort design for studying the effects of genes on human survival in a cohort of long-lived individuals. In this, a group of individuals is genotyped for polymorphisms in the candidate genes, and then followed up for studying their survival. This methodology mitigates the drawbacks thus encountered by the case-control design. In the present study, we have applied the longitudinal cohort design for studying relative risk of haplotypes and genotypes on human survival in a cohort of individuals born in Denmark in the year 1905 [21].

In our study, we found that female carriers of genotype HSPA1A-AA survived for a shorter duration than non-carriers. Our result is consistent with the observations of Altomare et al. from a case-control study done on Italian subjects where they found that the frequency of allele A was unfavorable for female longevity [11]. However, the current survival study,Longevity is a complex trait. Statistical approaches that take into account a group of genetic variants (haplotypes) are crucial in mapping genes that modulate human survival. In our analyses on the association of haplotypes on human survival, we observed that female carriers of haplotype G-C-T were longer survivors compared to non-carriers. Our current results are consistent with our earlier observations of haplotype survival analysis in the cross-sectional study design (manuscript in preparation). Moreover, in the cross-sectional study design, we had also seen that allele HSPA1L-T was favorable, whereas allele HSPA1L-C was unfavorable for female longevity. From the current results on the 1905 cohort individuals, we see that allele HSPA1L-T is defined in the haplotype G-C-T, which is shown to have a longer survival duration for females. We also observed a trend towards shorter survival duration of carriers of HSPA1L-C as compared to non-carriers (Table 2).

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