CONCLUSIONES Y RECOMENDACIONES

International (D.E.R.I.) group has compared the results of all studies of the incidence of Type 1 diabetes for the years 1979-80, using comparable definitions of the disease, and with some form of independent validation of the levels of ascertainment achieved (Diabetes Epidemiology Research International Group, 1988). They were able to include results from both the southern and northern hemispheres and found a significant positive correlation between latitude and the incidence of Type 1 diabetes on both sides of the equator; thus diabetes is more common in Northern Europe than the Mediterranean and in the South Island of New Zealand than in the North Island. They went on to establish that there was a significant negative correlation between the incidence of the disease and average temperature, i.e. that the disease is more common in colder countries. The distribution of participating centres was however very uneven, with most studies in western, developed nations and few in the lower incidence countries of the Mediterranean and Third World. Although all centres undertook some form of validation of their methodology, it remains possible that differences in the quality of the component studies may have been a confounding factor. These initial differences do however suggest the need for more detailed study of the variation between populations.

4.4.2 Type 1 diabetes In Europe: There is enormous variation in the frequency of insulin dependent diabetes in different countries in Europe. The results of incidence studies between 1970-90 are shown in Table 4.1. These suggested that a child in Finland appeared about 6 times more likely to develop Type 1 diabetes than one in France. A north-south gradient in disease frequency was suggested (Vaandrager

et al. 1984). Many of the studies performed in Europe were subject to the problems outlined above for British studies and comparable incidence studies performed in well defined populations using independently validated methods of ascertainment were needed. This has recently been possible in the EURODIAB project, in which 26 centres (including the Oxford Region) carried out prospective incidence studies in Europe and Israel. This confirmed the existence of major differences in the incidence of Type 1 diabetes but refuted the idea of a simple north-south gradient (Green et ai. 1992b) (Table 4.2). The incidence is generally higher in the Scandinavian countries than in the Mediterranean countries but the incidence in Sardinia is second only to that in Finland. A second, east-west gradient has also become apparent; the annual incidence in all the participating eastern and central European countries is below 10 cases/100,000, even in relatively northern countries such as Poland. In another comparative study the incidence in Estonia between 1980-1988 was 10.7 cases/100,000 per year (95% Cl 10.0- 11.7), compared with a contemporary incidence of 32.8 (31.6-34.0) in Finland, a country with a common ethnic and linguistic background (Tuomilehto et al. 1991b). Identification of differences in incidence between countries provokes a series of questions: is the disease the same in all countries, or is there significant heterogeneity? Are there variations in the clinical features, mode of inheritance and evidence of autoimmunity? If no differences are found, then to what extent can differences in the genetic susceptibility of the background population account of differences in incidence and what is the role of variation in environmental exposure? Efforts are currently under way to establish a network of population-based studies throughout Europe which will allow detailed comparisons between low and high incidence populations with respect to genetic markers and environmental conditions. This will allow hypotheses to be generated and tested before more complex and expensive case-

control or prospective cohort studies are undertaken.

Table 4.1 Variation in incidence of Type 1 diabetes in Europe

Country Study Age Annual Incidence/100,000 Reference

period range male female total

Finland 1970-86 0-14 32.5 29.1 30.8 (Akerblom et al. 1985)

Sweden 1977-83 0-14 23.6 (Dahlquist etal. 1982)

Nonway 1973-77 0-14 18.8 16.4 17.6 (Joner et al. 1981 )

Netherlands 1978-80 0-19 11.6 10.4 (Vaandrager et al. 1984)

Midwestern

Poland 1982-84 0-16 6.7 6.6 6.6 (Rewers et al. 1987)

Scotland 1977-83 0-19 21.7 20.2 (Patterson et al. 1983)

France 1970-79 0-15 5.1 4.8 5.0 (Hours etal. 1984)

France 1988 0-14 7.13 (Levy-Marchal etal. 1990)

Italy 1981-82 0-19 11.6 (Pagnano et al. 1987)

Hungary 1978-87 0-14 6.1 (Soltesz et al. 1990)

Catalonia 1987-90 0-14 11.4 11.6 11.5 (Goday et al. 1992)

Table 4.2 Standardized incidence rates age 0-14 years (EURODIAB ACE 1989-90)

COUNTRY Males Females All

Austria (whole nation) 7.9 7.5 7.7

Belgium (Antwerp region) 9.2 10.4 9.8

Denmark (3 counties) 21.5 21.4 21.5

Finland (2 regions) 47.0 38.8 42.9

France (4 regions) 7.8 7.8 7.8

Greece (Athens region) 10.9 7.7 9.3

Greece (5 northern regions) 5.3 3.8 4.6

Hungary (18 counties) 7.7 7.5 7.6

Israel (whole nation) 4.4 6.7 5.5

Italy (Lombardia region) 7.6 5.9 6.8

Italy (Lazio region) 7.2 5.8 6.5

Italy (Sardinia) 33.5 26.9 30.2

Italy (eastern Sicily) 11.2 9.0 10.1

Luxembourg (whole Nation) 12.1 12.6 12.4

Netherlands (5 regions) 11.2 10.8 11.0

Norway (8 counties) 22.3 19.3 20.8

Poland (9 western provinces) 5.3 5.8 5.5

Poland (3 cities) 5.7 6.0 5.8

Portugal (3 regions combined) 10.1 4.9 7.5

Romania (Bucharest region) 4.6 5.7 5.1

Slovenia 5.2 7.7 6.5

Spain (Catalonia region) 10.5 10.6 10.6

UK (Northern Ireland) 17.8 15.4 16.6

UK (Oxford region) 17.8 14.9 16.4

4.4.3 Correlation with genetic differences: Attempts have been made to relate the incidence of diabetes to the frequency of genes known to be associated with diabetes. The prevalence of the HLA class II antigens, DR3 and DR4, does not differ significantly amongst populations with very different rates of Type 1 diabetes (LaPorte et al. 1985). These antigens are however relatively crude markers of genetic risk, since they are present in a large proportion of the non-diabetic population. With the identification of more precise markers such as DR4 subtypes, DO loci and the presence or absence of an aspartate in position 57 in the DO beta chain (Todd et ai. 1987), further studies of this type can be undertaken. Dorman and colleagues estimated the relative risk associated with Non-Asp 57 alleles from case-control studies in a number of populations. They also calculated the genotype specific risk by linking the relative risk and overall incidence of disease in their own population in Allegheny County, Pennsylvania. Finally they applied the genotype specific risk and the relative risk in the different populations. They reported good correlation between the resulting 'expected' incidence with that actually observed

in four other low, medium and high risk populations (Dorman etal. 1990). In some high risk populations 'novel' diabetes-associated haplotypes have been described (Tuomilehto-Wolf etal. 1989; Carcassi et al. 1990).

4.4.4 Variation in incidence within countries: The incidence of Type 1 diabetes may also vary considerably within a given country. Studies in Scotland have found a marked variation in different counties with the lowest rates in the central lowlands which include the cities of Glasgow and Edinburgh. An inverse association was found between the incidence and population density. Even within the city of Glasgow the incidence in each city ward was inversely related to the average number of people per room (Patterson et al. 1988). In Norway, however, the incidence is highest in the more highly populated southern part of the country (Joner et al. 1989) and in Tasmania a higher prevalence of the disease was found in the urban, as opposed to the rural sector of the community (King et al. 1988). These differences remain unexplained, but are certainly partially explained by differences in the level of social deprivation. Deprivation appears to confer protection from diabetes (Patterson et al. 1992).