**5. Seasonal variation at onset and birth**

The first report of seasonal variation in the manifestation of T1DM was presented by Franklin Adams in 1926[32] although a consistent picture on the real seasonality of the disease has not been established. The increased incidence of T1DM diagnosis during

Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents 329

A seasonal variation of birth has been also observed in children who developed T1DM later in life in many countries, which suggests that environmental factors during pregnancy, in the neonatal period or very early in life play a role in its development. Several studies from Europe [35-37] and Israel [38] showed higher rates of T1DM among youth born in spring and lower rates among youth born in winter. Although McKinney maintained that there is no relationship between T1DM diagnosis and date of birth[39]. It has been suggested that seasonability pattern may be explained by reduced vitamin D production [40] during the

The genetics of T1DM cannot be classified according to a specific model of inheritance. Susceptibility to autoimmune T1DM is determined by multiple genes with HLA genes having the strongest known association. HLA antigens are present on the surface of the leucocytes and participate in some immune reactions. The genes coding for these antigens are located on chromosome 6. The class II sub region of HLA consists of the DR, DQ, and DP loci. These class II molecules are involved to the immune destruction of the pancreatic beta cells because they participate in the presentation of the antigen to the helper T cell,

Inheritance of HLA-DR3 and HLA-DR4 appears to confer a 2 to 3 fold increased risk for the development of T1DM. When both HLA-DR3 and HLA-DR4 are inherited the relative risk for the development of T1DM is increased by 7-10 folds. It is estimated that 48 percent of the familial aggregation can now be ascribed to known loci, and the Major Histocompatibility Complex (MHC) contributes 41 percent [41]. As an example, siblings with the highest risk HLA DR and DQ alleles, who inherit both HLA regions identical by descent to their diabetic sibling, may have a risk of developing anti-islet autoimmunity as high as 80 percent and a similar long-term risk of diabetes[42]. Moreover HLA DR2 and HLA DR5 are both protective in most studies. Furthermore, stronger associations of DM1 have been reported

In our effort to detect the genetic susceptibility of Greek Cypriot population to DM1, we studied 101 DM1 patients with age of onset less than 15 years through HLA serological typing for the DR and DQ1 alleles and compared them to 209 healthy controls. Our findings support the strong association of HLA-DR4 and DR3 with DM1. The most frequent allelic combination was that of HLA-DR3/DR4 (27%) followed by that of DR2/DR4 (21.6%). The percentage of HLA antigens in patients with DM1 and controls are shown in figure 4. The protective role of HLA-DR5 was shown, whereas the presence of HLA-DR2 is neutral, in contrast with most findings among Caucasian population where DR2 is protective. In addition, high resolution testing of the DR4 and DR3 alleles revealed the predominant presence of the DRB1\*0403 (0% vs 36%), similar frequency of the DRB1\*0402 in both groups (19% vs 14%) and that the DRB1\*301 was the only DR3 allele detected. The DQB1 alleles present in our T1DM patients as shown in figure 5 were nearly exclusively DQB1\*0201 and DQB1\*0302 [44]. The relative risk of developing T1DM in children carrying the DQB1\*0201 and the DQB1\*0302 alleles is 5.05 and 2.56 respectively whereas the protective role of

Furthermore, although most T1D cases occur in individuals without a family history of the disease, T1D is strongly influenced by genetic factors. The lifelong risk of T1DM is markedly

critical intrauterine and neonatal periods of life.

which initiates the immune reaction.

DQB1\*0301 is documented.

with other MHC loci: HLA-DQA1 and DQB1 antigens[43].

**6. Genotype** 

Fig. 3. Ratio of males and females in relation to year of diagnosis (at 2-yr intervals).

Autumn and Winter months could support the hypothesis that infections may act as participating factors in the clinical onset of the disease, possibly accelerating an autoimmune process that may have been initiated months or years before [33]. Based on the average temperature record in our island, the newly diagnosed cased were grouped according to the month of diagnosis as follow: November, December, January, and February were defined as cold months, October, March, April and May as neutral months and, June, July , August and September, as warm months. More children were significantly diagnosed with T1DM during the cold months compared to those who manifested the disease during the warm months (p<0.001), whereas no difference was observed in the incidence between neutral and cold months ((p>0.05) throughout the study period (1990-2009) as depicted in Table 2. A recent study on seasonal variation in DM in 53 countries has suggested that seasonality in the diagnosis of T1DM occurs and that the pattern of seasonality appears to be related to the geographical position, at least as far as the northern/southern hemisphere dichotomy is concerned [34].


Table 2. Percentage of children diagnosed with T1DM at cold months, neutral months and warm months. Binomial test performed to compare proportions compared to "Cold Months" group: \* NS (p>0.05), \*\* p<0.05, \*\*\* p<0.01, \*\*\*\*p<0.001

A seasonal variation of birth has been also observed in children who developed T1DM later in life in many countries, which suggests that environmental factors during pregnancy, in the neonatal period or very early in life play a role in its development. Several studies from Europe [35-37] and Israel [38] showed higher rates of T1DM among youth born in spring and lower rates among youth born in winter. Although McKinney maintained that there is no relationship between T1DM diagnosis and date of birth[39]. It has been suggested that seasonability pattern may be explained by reduced vitamin D production [40] during the critical intrauterine and neonatal periods of life.
