The percentages of homozygotes were not different between the young and old age groups (data not shown).

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TABLE 1. Phenotype Frequency of HLA Antigens (%) + Age 20-35 85 Phenotype N = 2444 N = 964 RR X' p Value" Al 30.6 30.8 1.009 0.012 0.877 A2 52.7 49.5 0.890 2.359 0.121 A3 28.7 27.2 0.937 0.581 0.453 A9 19.3 21.8 1, I48 2.171 0.137 A10 6.9 9.2 1.382 5.627 0.017 All 11.5 10.4 0.877 1.132 0.287 A28 10.0 9.2 0.918 0.441 0.514 AW19 20.6 23.5 1.185 3.465 0.059 B5 11.9 12.9 1.091 0.585 0.451 B7 27.4 28.0 1.032 0.140 0.708 B8 22.8 22.5 0.989 0.016 0.869 B12 25.3 27.4 1.131 2.072 0.146 B13 4.4 4.8 1.116 0.383 0.544 B14 2.9 3.5 1.268 1.303 0.252 B15 15.8 15.7 0.968 0.096 0.751 B16 7.2 7.0 0.972 0.038 0.825 B17 6.6 8.0 1.236 2.176 0.136 B18 6.5 8.2 1.297 3.315 0.065 B21 2.2 2.8 1.242 0.828 0.366 BW22 5.8 4.5 0.800 1.644 0.197 B27 6.4 7.7 1.206 1.642 0.197 B35 17.5 16.0 0.908 0.891 0.348 B37 4.1 3.4 0.876 0.441 0.514 B40 17.8 13.2 0.703 10.5 0.002 - B W4 55.2 59.8 1.202 5.695 0.016 BW6 87.8 87.6 0.983 0.023 0.851 CWI 4.8 6.0 1.265 2.053 0.148 c w 2 9.9 9.3 0.921 0.398 0.535 c w 3 32.8 28.6 0.819 5.731 0.016 c w 4 21.0 20.6 0.986 0.022 0.854 c w 5 12.9 16.0 1.311 6.469 0.01 1 CW6 16.5 16.7 1.033 0.092 0.755 c w 7 49.3 51.4 1.078 0.939 0.334 DR 1 19.7 20.0 1.072 0.548 0.466 DR2 28.7 28.3 0.960 0.230 0.637 DR3 25.1 23.1 0.898 1.439 0.228 DR4 28.3 25.0 0.856 3.188 0.071 DR5 19.0 23.4 1.318 8.953 0.003 - DRW6 33.7 31.8 0.913 I .216 0.270 DR7 19.2 22.1 1.204 3.943 0.044 DRW8 5.3 7.5 1.457 6.118 0.013 DR9 2.4 2.7 1.127 0.257 0.619 DRWl0 4.3 2.5 0.588 5.493 0.018 DRW52 69.1 72.6 1.196 4.428 0.033 DRWS3 46.1 47 .O I ,049 0.379 0.546 DQWl 71.2 68.8 0.896 I .740 0.184 DQW2 37.5 36.7 0.965 0.202 0.658 DOW3 50.4 53.0 1.111 1S 89 0.205

TABLE 1. Phenotype Frequency of HLA Antigens (%)

p values uncorrected for number of antigens tested. a

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p values uncorrected for number of antigens tested. a

TABLE 3. Phenotype Frequency of HLA-DR5 and its Splits: DRwll and DRwl2 (%)

Age + Phenotype 20-35 85 RR X2 p Value" + Male female DR5 19.0 23.6 1.318 8.953 0.003 DRwll 14.4 18.4 1.349 8.694 0.004 DRwl2 4.6 4.9 1.067 0.131 0.72 n 2381 954 Males DR5 19.3 21.3 1.141 0.650 0.43 DRwl1 14.9 18.2 1.080 0.180 0.68 DRwl2 4.3 4.9 1.160 0.233 0.64 n 1261 273 Females DR5 18.7 24.5 1.416 8.814 0.003 DRwll 13.8 19.5 1.519 10.45 0.002 DRwl2 4.9 4.9 0.998 0.OOO 0.94 n 1120 681

p values uncorrected for number of antigens tested. a

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Ag frequency % - 40 1 L- 30 - .. . . .. . . .. . . .. .. .. . . . . . . . . . . . . . .. .. . . .. . . .. . , . . . .. .. . . . . .. . . .. . . . . . .. . . . . . .. . .. . . .. .. .. . . .. . . . .. .. A1 0 a + Newborns 20-29 30-39 40-49 50-59 6085 HLA-A1 --CHLA-B40 *HLA-DRS

FIGURE 1. The distribution of HLA-B4O and HLA-DRS in the Dutch-Caucasoid population of Leiden, The Netherlands, in seven age groups, in females. HLA-A1 is shown as an example of an antigen that does not change in frequency with age.

A difference was found in two HLA antigens: the frequency of HLA-B40 was lower and that of HLA-DRS was higher in the age group of 85 years and over. No major disease associations with HLA-B40 or with DRS have been reported. The possibility remains that either of these antigens is in linkage disequilibrium with gene systems, as yet obscure to us, which are involved in controlling life span or which may be associated with diseases or aging processes. Both Dawkins in Australia (personal communication) and Kramer et al. in Hungary** have men- tioned the possible association of HLA-B40 with gene duplication of the fourth component of complement. This could be relevant in the light of our results and it indicates the need for further studies on linkage of the different HLA classes.

Concerning HLA-DRS, no data about age-related differences in class I1 anti- gens in Caucasoids have been reported. HLA-B40, on the other hand, has repeat- edly been found to differ between young and old age groups (FIG.2 ). Macurova et ul.I1 mentioned a marked increase with age, but this study should be regarded critically, as mentioned above. Since then, one study reported an increase'* and two studies found a decrease of HLA-B40 with age.'3.14r2W3 e have not yet suc- ceeded in finding a plausible explanation for this variance in direction of the difference in HLA-B40.

and HLA-B40 is officially listed as being associated with Since in our study, the frequency of HLA-B40 is lower in subjects aged and over, especially in females, it is clear that our data do not support this

LAGAAY et al.: LONGEVITY & HEREDITY

tions (FIG.2). It is well known that within the same race, a considerable variation in HLA antigen frequencies can exist between different populations, for example, between neighboring countries. For the region of Leiden, we have checked this percentage in six other Dutch Caucasoid control groups of the same region and of the same age, containing 101 up to 5490 subjects. The percentage of HLA-B40- positive subjects in these control groups was of the same order of magnitude as in the present study, ranging from 16.8 to 18.0 percent.