frequency of DR1 in the centenarians (DRBl*0101: P=0.016, RR=4.300) was also rec- ognized in the present study. However, there was not such a more significant difference between the two groups in this study than that in the serologi- cal study (P=0.0042, RR=12.3) (12), and the fre- quency of DRB1*0901(DR9) was not low in this genotyping study (P=0.086). The high incidence of DR1 in the centenarians is possibly explained in part by the facts that the degree of responsiveness to Cundidu allergen was related to HLA-DR1 in human (13), and that the low frequency or absence of DR1 was associated. with various Japanese autoimmune diseases (12).

Although the possibility of a direct involvement of the non-HLA gene located within, and tightly linked to the class I1 antigen could not be excluded for the favorable influence on their achievement of longevity in centenarians, it is suggested that such * as DRB 1 1401 and/or DQB 1* 0503, favorably re- late to longevity.

Acknowledgments

We thank all the centenarians and their families who have been involved in or have taken part in this study, many officials, technicians and public health nurses in charge, for their help, especially Y. Nohara and R. Zukeran for technical assist- s.€! ance, T. Sato, T. Naruse and Ma for technical advice. This study was partly supported by the Nippon Life Insurance Foundation.

Four alleles, DRB1*1401, DQB1*0503, DQA1*0101=0104 and DQAl*05 were found to be significantly associated with the centenarians. The significantly increased frequencies of HLA- DQB1*0503 and/or DQA1*0101=0104 in the cen- tenarians can be explained by a linkage disequilib- rium with DRBl*1401 or vice versa, which was also significantly frequent in them, because DRB1*1401-DQB1*0503-DQA1*0104 is one of the prominent haplotypes in Okinawan Japanese. Since the frequency of DRB1*1405 in a linkage disequilibrium with DQB1*0503 .was also in- creased, it cannot be determined which of DRB 1* 1401, DQB 1* 0503 and DQAl *0101=0104 is primarily responsible for longevity. Similarly, the low frequency of DQA1*0102 in the centenarians can be explained by linkage disequilibria with DRBl*1302 and/or DQB1*0604, or vice versa (1 4). The frequency of DRB 1* 0403 was relatively low in the centenarians, which may explain the low frequency of DQB1*0302 in them.

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Research Center of Comprehensive Medicine University of the Ryukyus School of Medicine

Uehara Nishihara Okinawa Japan