level. Our finding of a possible association between ) a polymorphism in position 110 in the 5¢UTR of the HSP70-1 gene and self-rated health (P-value 0.0046) nevertheless requires corroboration with further studies.

was unfavourable to longevity in women. In order to avoid various confounding factors discussed earlier, we in our study, have introduced a model where we took a group of 400 individuals, aged 70–91 years, from LSADT, who have been scored for parameters which are characteristic of suc- cessful/unsuccessful aging. These parameters have been studied for their association with polymor- ) phism at 110 of HSP70-1. Of all the parameters studied, self-rated health (scored both in absolute terms and in relation to others of the same age) shows a striking association (P-value 0.0046 and 0.018, respectively). This self-rated health, an ordinal trait with multifactorial etiology, repre- sents an individual’s overall sense of physical well being and has been shown to be both a predictor of survival at older ages (McCallum et al. 1994), and a better indicator of future survival than objectively measured health status (Mossey and Shapiro 1982). In our series we observed lower health score in the heterozygous individuals. This seems somewhat surprising, first because Altomare et al. found lower survival in the females homo- zygous for allele A (AA genotype), and second because it is difficult to envision a molecular mechanism causing phenotypic domination in heterozygotes. We also did a gender-specific anal- ysis for the association of ‘self-rated health’ with ) 110A > C polymorphism, but did not find any sex specificity for this association (data not

Standard statistical methods require indepen- dent observations. In this study we use twins and it is known that twins correlate for many phenotypes including a number of health outcomes such as self- rated health (Christensen et al. 1999, 2000). This leads to an underestimation of the standard error but has no impact on the mean and hence does not bias the results (Holm 1983). However, this is pri- marily a problem while using monozygotic twin pairs and for highly heritable traits such as ‘height’; but not for moderately heritable traits and dizy- gotic twins, where the problem is negligible.

extending the investigation to include other markers in the region. There are 14 polymorphic sites within the three MHC-linked HSP70, and the present study does not rule out a more significant association of human longevity with one of these polymorphisms. Moreover, this polymorphism at ) position 110, and other polymorphic sites within HSP70-1, HSP70-2 and HSP70-Hom are shown to be in linkage disequilibrium with the other markers in the MHC region, which have been studied for their association with human longevity. For example, in Caucasian populations, Proust et al. (1982) and Rea and Middleton (1994) have reported a positive association of haplotype A1B8Cw7DR3 with longevity in male nonage- narians. Similarly, haplotypes bearing DR3 were increased in male nonagenarians (Ivanova et al. 1998). Effects of genetic variation at the HLA-DR locus were found on survival beyond age 90 years, whenever sex was taken into account. Also, allelic combinations from three HSP70 genes have been defined in the context of MHC ancestral haplotype in the Caucasian population (Kok et al. 1999). In this study the polymorphism at HSP70-Hom, HSP70-2 and HSP70-1 gene has been shown to be associated with HLA-DR3 antigen which confirms the result from the previous study (Casino et al. 1993). The present study can therefore also be extended by defining haplotypes and using them instead of single nucleotide polymorphisms SNPs.

A genetic component for the variation in the self-rated health can be demonstrated by genetic factors for those who are more than 70 years old (Christensen et al. 1999). In a follow-up, it was investigated if low self-rated heath score could be due to depression (McGue and Christensen 2003), by including the depression score for the individ- uals, assessed using an adaptation of the depres- sion section of the Cambridge Mental Disorders of Elderly Examination (CAMDEX), but we could not find any association to it (P-value 0.47), thus excluding this possibility. Although the two P-values obtained for self-rated health are quite low, the possibility of type 1 error due to multiple testing cannot be disregarded. Doing a Bonferroni correction, and taking into account that some of the parameters are dependant, revealed that a P-value should be below 0.0048 before type 1 error can be disregarded on the 5% level of significance

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