pp. 70-74 in Intractable Neurological Disorders, Human Genome Research and Society. Proceedings of the Third International Bioethics Seminar in Fukui, 19-21 November, 1993.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.


Copyright 1994, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

Geographical variations in amyloidosis death rate in Japan, 1969-1992

Yoko Imaizumi
Director, Institute of Population Problems, Ministry of Health and Welfare, Tokyo 100, Japan


Introduction

The present study deals with the trends and the geographical variations in the amyloidosis death rate during the period from 1969 to 1992 in Japan. According to McKusick (1), hereditary amyloidosis can be classified into 9 types: amyloidosis I to IX. Familial amyloidosis polyneuropathy (FAP) corresponds to amyloidosis I of McKusick (1). In Japan, there are two large foci of FAP: Arao district (2, 3) and Ogawa Village (4, 5). The latter focus is the second largest aggregation of the disease in the world (4). According to Itoga and Kito (5), and Sakoda et al (3), FAP in the above two areas is transmitted in an autosomal dominant mode as in Portuguese and Swedish families (6, 7).

The amyloidosis death rate in Japan increased gradually year by year during 1969 to 1985 (8). The death rate of amyloidosis (ICD 277.3) in Japan have now been analyzed using mortality statistics for 1969-1992. The amyloidosis death rate has increased gradually year by year for both sexes. Recently, the techniques of DNA diagnosis of FAP have been developed and gradually spread out over the whole of Japan. The changing patterns of the mortality might be explicable by a steady improvement in the identification of death by DNA diagnosis of amyloidosis. Geographical variations in the amyloidosis death rate were also observed with the highest death rate in Kumamoto and Nagano prefectures for both sexes. The mean age at death from amyloidosis has steadily increased for both sexes, being 11-23 years shorter for males and about 20 years shorter for females compared to the general population during that period. The results from the present paper indicate the basic data on genetic counseling for amyloidosis patients and provide useful data for planning health care facilities and research centres.

Materials and Methods

Data consisting of 2,396 deaths from amyloidosis reported for 1969-1992 inclusive were obtained from the death certificate records kept at the Ministry of Health and Welfare, Japan. The certificate includes information on sex, place of residence, dates of birth and death, and cause of death. Data on the general population were taken from the annual volumes of the "Vital Statistics of Japan for the Years 1969-1992" (9), which covers the entire population.

In computing the amyloidosis death rates, the number of deaths from amyloidosis in each sex were divided by the population size of each sex during the same period. On the other hand, in computing the regional amyloidosis death rates, the population size as the denominator in each prefecture was the average of that of the five census years from 1970 to 1990.

Trends in the amyloidosis mortality rate

Table 1 shows changes in the amyloidosis death rates for each sex during the period from 1969 to 1992. The death rate is similar for both sexes during the period. The male amyloidosis death rates were 0.022 per 100,000 of the population in 1969 and 0.178 in 1992. The latter is 8 times as high as the former. Similarly, the corresponding female death rates were 0.021 and 0.167, respectively, and the rate in 1992 is also 8 times higher than 1962 (9). The linear regression coefficients of the amyloidosis death rate on the year (per 100,000 years) are 0.00760.0003 for males and 0.00740.0004 for females. These values were significant at the 0.1% level. Namely, the diagnosis of amyloidosis has improved year by year, and the reported number of deaths due to amyloidosis are approaching the real values.

Age-specific mortality rate of amyloidosis

Figure 1 shows the death rate for age groups by sex during the period from 1969 to 1992. For both sexes, the death rate from amyloidosis per 100,000 of the population is nearly constant up to the 25-29 age group and gradually increased thereafter up to the 70-74 age group for males and the 65-69 age group for females, and thereafter decreased.


Table 1: Secular change in amyloidosis death rate by sex during 1969-1992

Columns across page: Year; Number of Deaths (Males; Females; Total); Amyloidosis Death Rate per 100,000 Population (Males; Females; Total);

1969 11 11 22 0.022 0.021 0.022
1970 7 8 15 0.014 0.015 0.015
1971 6 7 13 0.012 0.013 0.013
1972 15 6 21 0.029 0.011 0.020
1973 17 14 31 0.032 0.025 0.029
1974 24 14 38 0.045 0.025 0.035
1975 25 22 47 0.046 0.039 0.042
1976 33 16 49 0.060 0.028 0.044
1977 29 15 44 0.052 0.026 0.039
1978 28 37 65 0.050 0.064 0.057
1979 41 29 70 0.072 0.050 0.061
1980 38 36 74 0.066 0.061 0.064
1981 54 45 99 0.094 0.076 0.085
1982 50 67 117 0.086 0.112 0.099
1983 65 66 131 0.111 0.109 0.110
1984 66 63 129 0.112 0.104 0.108
1985 75 69 144 0.127 0.113 0.120
1986 84 70 154 0.141 0.114 0.127
1987 73 85 158 0.122 0.138 0.130
1988 95 72 167 0.159 0.116 0.137
1989 86 100 186 0.143 0.161 0.152
1990 97 104 201 0.161 0.166 0.164
1991 113 95 208 0.187 0.152 0.169
1992 108 105 213 0.178 0.167 0.173


Geographical variation

The amyloidosis death rate was computed in each prefecture during the periods from 1969 to 1985, 1986 to 1992, and 1969 to 1992 (Table 2). In order to look at the geographical variations in the death rate, the coefficient of variations in the death rate in each period calculated, being 0.61, 0.46, and 0.50, respectively. This shows the geographical variation has decreased in recent years, reflecting more uniform and standard diagnosis of amyloidosis in each prefecture.


Figure 1: Deaths by amyloidosis in age groups by sex, during 1969-1992

Figure 2: Geographical distribution in the amyloidosis death rate during 1969-1992

Table 2: Deaths due to amyloidosis per 100,000 population in prefectures,1969-1992

Columns across the page: Prefecture; Number of Deaths (1969-85; 1986-92; 1969-92); Death Rate (1969-85; 1986-92; 1969-92; 1986-1992/1969-1985);

Whole of Japan 1,109 1,287 2,396 0.057 0.151 0.086 2.6

Hokkaido 32 54 86 0.035 0.137 0.065 4.0
Aomori 15 11 26 0.059 0.105 0.073 1.8
Iwate 10 12 22 0.042 0.121 0.065 2.9
Miyagi 15 24 39 0.044 0.155 0.079 3.5
Akita 13 19 32 0.061 0.220 0.107 3.6
Yamagata 21 16 37 0.100 0.182 0.124 1.8
Fukushima 13 19 32 0.038 0.130 0.066 3.4
Ibaraki 19 23 42 0.046 0.118 0.069 2.6
Tochigi 10 15 25 0.034 0.113 0.059 3.3
Gunma 16 22 38 0.052 0.162 0.087 3.1
Saitama 22 40 62 0.026 0.093 0.049 3.6
Chiba 31 39 70 0.042 0.104 0.064 2.5
Tokyo 104 108 212 0.053 0.132 0.076 2.5
Kanagawa 62 59 121 0.056 0.109 0.074 2.0
Niigata 35 40 75 0.085 0.231 0.129 2.7
Toyama 11 8 19 0.060 0.102 0.073 1.7
Ishikawa 12 11 23 0.065 0.136 0.087 2.1
Fukui 14 7 21 0.105 0.123 0.111 1.2
Yamanashi 2 8 10 0.015 0.136 0.052 9.2
Nagano 68 53 121 0.195 0.353 0.244 1.8
Gifu 15 13 28 0.046 0.091 0.060 2.0
Shizuoka 30 40 70 0.053 0.158 0.085 3.0
Aichi 44 65 109 0.043 0.142 0.074 3.3
Mie 13 13 26 0.046 0.105 0.065 2.3
Shiga 10 10 20 0.057 0.121 0.078 2.1
Kyoto 25 18 43 0.060 0.101 0.073 1.7
Osaka 39 60 99 0.028 0.100 0.050 3.6
Hyogo 33 41 74 0.039 0.111 0.061 2.9
Nara 11 12 23 0.057 0.128 0.081 2.2
Wakayama 4 11 15 0.022 0.146 0.058 6.7
Tottori 13 8 21 0.129 0.186 0.147 1.4
Shimane 13 14 27 0.098 0.255 0.144 2.6
Okayama 23 26 49 0.074 0.194 0.111 2.6
Hiroshima 18 29 47 0.040 0.147 0.073 3.7
Yamaguchi 22 17 39 0.083 0.155 0.104 1.9
Tokushima 5 9 14 0.036 0.154 0.071 4.3
Kagawa 10 10 20 0.061 0.140 0.085 2.3
Ehime 12 19 31 0.048 0.179 0.087 3.8
Kochi 5 7 12 0.036 0.121 0.061 3.3
Fukuoka 65 92 157 0.087 0.277 0.146 3.2
Saga 21 17 38 0.144 0.277 0.184 1.9
Nagasaki 39 36 75 0.145 0.327 0.198 2.3
Kumamoto 59 57 116 0.197 0.443 0.272 2.3
Oita 10 29 39 0.049 0.334 0.134 6.9
Miyazaki 19 11 30 0.100 0.134 0.111 1.3
Kagoshima 14 22 36 0.047 0.174 0.085 3.7
Okinawa (1973-1992) 12 13 25 0.072 0.155 0.138 2.14

Figure 3: Trends in the mean age of death by amyloidosis by sex, during 1969-1992.


Overall death rates per 100,000 population were 0.057 in the former period and 0.151 in the latter period. The ratio of the death rate in the latter to that in the former was 2.6. The ratios in different prefectures ranged from 1.2 in Fukui Prefecture to 9.2 in Yamanashi Prefecture. Accordingly, it seems that inaccurate determination of death due to amyloidosis in the former period was especially common in Yamanashi, Wakayama, and Oita prefectures.

Figure 2 shows the geographical distribution in the amyloidosis death rate during the period from 1969 to 1992. The overall amyloidosis death rate per 100,000 population was 0.086. The highest amyloidosis death rate was seen in Kumamoto Prefecture (0.272), followed by Nagano Prefecture (0.244). The amyloidosis death rate in the above two prefectures is 2.8-3.2 times higher than the national average. The third highest amyloidosis death rate was seen in Nagasaki Prefecture (0.198) and followed by Saga (0.184) Prefecture. The lowest amyloidosis death rate was in Saitama Prefecture (0.049), followed in order by Osaka (0.050), Yamanashi (0.052), and Wakayama (0.058) prefectures. The regression coefficient of the amyloidosis death rate on the latitude of the prefectural capital (per 100,000 degree) was -0.00500.0027, which is not significant from zero. However, the death rate was higher in the southwest than in the northeast.

Mean age at death

Figure 3 shows the trends in the mean age at death from amyloidosis in each sex during the period from 1969 to 1992. The mean ages at death from amyloidosis were 46.7 years for males and 52.8 years for females in 1969-1970, and in 1991-1992 they were 65.1 years and 64.6 years, respectively. The mean age at death for both sexes gradually increased with time. The mean age at death was similar for both sexes after 1975.

Discussion

FAP is an autosomal dominant character, and almost all patients are heterozygote. Half of the children will have the FAP gene, but do not know whether they have it or not until the onset of the disease. Recently, predictive, or presymptomatic, testing for FAP has become possible, as for some other late onset diseases such as Huntington's disease. There is still no treatment for these diseases, so predictive testing raises many problems and ethical issues (10). The reported amyloidosis death rate has increased year by year in Japan (Table 1). The increased amyloidosis death rate might be explicable by a constant improvements in diagnosis of amyloidosis as cause of death, and by some environmental factors.

The Ogawa Village and the Arao district are located in Nagano and in Kumamoto prefectures, respectively. As shown in Table 2, the amyloidosis death rate was the highest in Kumamoto Prefecture. The second highest death rate was seen in Nagano Prefecture, followed by Nagasaki, Saga, Tottori, and Fukuoka prefectures. Therefore, some ancestral patients with FAP from the Arao focus might have moved to Nagasaki, Saga, and Fukuoka prefectures because these prefectures are located in the neighbourhood of Kumamoto Prefecture. These geographical distributions in the amyloidosis death rate were also observed with the highest death rate in Kumamoto and Nagano prefectures for both sexes during the period from 1969 to 1985 (8).

Recently, the prevalence rates of amyloidosis were examined in five areas during the period from 1977 to 1981 (Ministry of Health and Welfare Primary Amyloidosis Research Committee) (11). These areas, except Hokkaido, had average annual prevalence rates of amyloidosis in the range from 0.26 (Yamagata Prefecture) to 0.83 (Miyazaki City) per 100,000 of the population for the five years, whereas the corresponding rate in Hokkaido was 0.06. The ratios of the prevalence rate to the death rate of amyloidosis ranged between 1.7 (Hokkaido) and 13.1 (Hiroshima City). The ratio for Kumamoto Prefecture was 3.7. Similarly, a national-wide statistical analysis was carried out on patient numbers and the prevalence rate per 100,000 population during the period from 1987 to 1988 by Miyamoto (12). The highest rate is observed in Nagano (1.77), Nagasaki (1.07), Kumamoto (0.92), and Fukuoka (0.71) prefectures, whereas the overall rate was 0.28 in 1988. The ratios of the prevalence rate in Nagano and Kumamoto prefectures to the overall rate are 6.3 and 3.3, respectively, with these data. Therefore, these are consistent with the results of the present study of geographical distributions in the amyloidosis death rate.

The Japanese life expectancy in 1969 was 69.2 years for males and 74.7 years for females, and the corresponding value in 1992 was 76.1 and 82.2 years, respectively (13). In the present study, the mean age at death from amyloidosis in 1969-1970 was 46.7 years for males and 52.8 years for females, and the corresponding value in 1991-1992 was 65.1 and 64.6 years, respectively. Accordingly, for the last 22 years, the mean age at death from amyloidosis was 11-23 years shorter for males, and 18-22 years shorter for females, compared with the overall Japanese life expectancy.


References

1. McKusick, V.A., Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes, 9th ed. (Baltimore: The Johns Hopkins University Press 1992).
2. Araki, S., Mawatari, S., Ohta, M., Nakajima, A. & Kuroiwa, Y. (1968) Polyneuritic amyloidosis in a Japanese family. Arch Neurol 18: 593-602.
3. Sakoda, S., Suzuki, T., Higa, S., Ueji, M., Kishimoto, S., Hayashi, A., Yasuda, N., Takaba, Y., & Nakajima, A. (1983) Genetic studies of familial amyloid polyneuropathy in the Arao district of Japan: I. The genealogical survey. Clin Genet 24: 334-338.
4. Kito, S., Fujimori, N., Yamamoto, M., Itoga, E., Toyoizumi, Y., Kakizaki, T., Mitsui, Z., Ichikawa, H., Morinaga, T., Wakatsuki, K., Satoh, S., and Iwasaki, I. (1973) A focus of familial amyloid polyneuropathy. Nippon Rinsho 31: 2326-2388 (in Japanese).
5. Itoga, E. and Kito, S. (1982) Genetic aspects of familial amyloid polyneuropathy in Ogawa Village, Japan. Jpn J Human Genet 27: 319-334.
6. Andrade, C., Canijo, M., Klein, D. and Kaelin, A. (1969) The genetic aspect of the familial amyloidotic polyneuropathy. Humangenetik 7: 163-175.
7. Andersson, R. (1976) Familial amyloidosis with polyneuropathy. Acta Med Scand [Suppl] 590: 1-64.
8. Imaizumi, Y. (1989) Mortality rate of amyloidosis in Japan: Secular trends and geographical variations. Amer J Med Genet 34: 562-568.
9. Japan, Ministry of Health and Welfare (1971-1991) Vital Statistics, 1969- 1992. (Health and Welfare Statistics and Information Department, Ministry of Health and Welfare, Tokyo) (in Japanese).
10. Holtzman, N. (1988) Recombinant DNA technology, genetic tests, and public policy. Amer. J. Human Genetics 42: 624.
11. Japan, Ministry of Health and Welfare (1983-1984) Annual Report of the Ministry of Health and Welfare Primary Amyloidosis Research Committee, 1982-1983. (Ministry of Health and Welfare, Tokyo) (in Japanese).
12. Miyamoto, H. (1990) Statistical analysis of 3 intractable diseases associated with amyloid in national and prefectural data, pp. 150-158 in Annual Report of the Ministry of Health and Welfare Primary Amyloidosis Research Committee, 1989. (Ministry of Health and Welfare of Japan, Tokyo) (Summary in English).
13. Japan, Ministry of Health and Welfare (1993) Abridged Life Table for Japan 1992. (Health and Welfare Statistics and Information Department, Ministry of Health and Welfare, Tokyo) (in Japanese).


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