Is HLA the cause of the high incidence of type 1 diabetes in the Canary Islands? Results from the Type 1 Diabetes Genetics Consortium (T1DGC).

INTRODUCTION: Incidence of childhood-onset type 1 diabetes mellitus in the Canary Islands is the highest reported so far in Spain, and among the highest worldwide. The HLA region accounts for approximately half the genetic risk of type 1 diabetes. Our aim was to assess distribution of high-risk and protective HLA haplotypes in the Canarian families included in the T1DGC, as compared to the rest of Spain. METHODS: The T1DGC study, an international project to study the genetics and pathogenesis of type 1 diabetes, enrolled more than 3000 families with type 1 diabetes worldwide. Spain provided 149 of these families, of whom 42 were from Tenerife and Gran Canaria. HLA was genotyped centrally using a PCR-based, sequence-specific oligonucleotide probe system. Haplotypes were reconstructed using the deterministic algorithm alleHap in the R programming environment. Based on prior T1DGC results in Caucasian population, haplotypes DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB1*0302, DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0402-DQA1*0301-DQB1*0302 and DRB1*0404-DQA1*0301-DQB1*0302 were considered high-risk. DRB1*0701-DQA1*0201-DQB1*0303, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*1104-DQA1*0501-DQB1*0301, DRB1*1303-DQA1*0501-DQB1*0301, DRB1*1301-DQA1*0103-DQB1*0603 and DRB1*0403-DQA1*0301-DQB1*0302 were considered protective. The distribution of protective, high-risk, and other haplotypes in the (first two) affected siblings and unaffected parents from Canarian and non-Canarian Spanish families was compared (Chi-square test). RESULTS: No significant differences were found between the regions in distribution of the HLA haplotypes in the affected siblings or in the non-affected parents. CONCLUSIONS: The high incidence of childhood-onset type 1 diabetes in the Canarian population does not appear to be explained by a greater prevalence of high-risk class II HLA haplotypes in families with the disease. However, sample size limits the differences that can be detected in this study.

Is HLA the cause of the high incidence of type 1 diabetes in the Canary Islands? Results from the Type 1 Diabetes Genetics Consortium (T1DGC) / ¿Es el HLA la causa de la alta incidencia de diabetes tipo 1 en las Islas Canarias? Resultados del Consorcio de Genética de la Diabetes tipo 1 (T1DGC)

Introduction: Incidence of childhood-onset type 1 diabetes mellitus in the Canary Islands is the highest reported so far in Spain, and among the highest worldwide. The HLA region accounts for approximately half the genetic risk of type 1 diabetes. Our aim was to assess distribution of high-risk and protective HLA haplotypes in the Canarian families included in the T1DGC, as compared to the rest of Spain. Methods: The T1DGC study, an international project to study the genetics and pathogenesis of type 1 diabetes, enrolled more than 3000 families with type 1 diabetes worldwide. Spain provided 149 of these families, of whom 42 were from Tenerife and Gran Canaria. HLA was genotyped centrally using a PCR-based, sequence-specific oligonucleotide probe system. Haplotypes were reconstructed using the deterministic algorithm alleHap in the R programming environment. Based on prior T1DGC results in Caucasian population, haplotypes DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB1*0302, DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0402-DQA1*0301-DQB1*0302 and DRB1*0404-DQA1*0301-DQB1*0302 were considered high-risk. DRB1*0701-DQA1*0201-DQB1*0303, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*1104-DQA1*0501-DQB1*0301, DRB1*1303-DQA1*0501-DQB1*0301, DRB1*1301-DQA1*0103-DQB1*0603 and DRB1*0403-DQA1*0301-DQB1*0302 were considered protective. The distribution of protective, high-risk, and other haplotypes in the (first two) affected siblings and unaffected parents from Canarian and non-Canarian Spanish families was compared (Chi-square test). Results: No significant differences were found between the regions in distribution of the HLA haplotypes in the affected siblings or in the non-affected parents. Conclusions: The high incidence of childhood-onset type 1 diabetes in the Canarian population does not appear to be explained by a greater prevalence of high-risk class II HLA haplotypes in families with the disease. However, sample size limits the differences that can be detected in this study (AU)

Introducción: La incidencia de diabetes tipo 1 infantil en Canarias es la más alta descrita hasta el momento en España y una de las mayores a nivel mundial. La región HLA explica aproximadamente el 50% del riesgo genético de la diabetes tipo 1. Nuestro objetivo fue comparar la frecuencia de haplotipos de HLA de riesgo y protectores en familias españolas canarias y peninsulares incluidas en el T1DGC. Métodos: El T1DGC es un proyecto internacional que estudia la genética y patogenia de la diabetes tipo 1, para el que fueron inluidas más de 3000 familias con la enfermedad. Un total de 149 familias provenían de España, y 42 de ellas, de Tenerife y Gran Canaria. El HLA fue genotipado en un laboratorio central, utilizando un método basado en PCR y sondas específicas de secuencia. Los haplotipos fueron reconstruidos utilizando el algoritmo determinista alleHap en el entorno de programación R. En base a los resultados previos del T1DGC en población caucásica, los haplotipos DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB1*0302, DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0402-DQA1*0301-DQB1*0302 y DRB1*0404-DQA1*0301-DQB1*0302 fueron definidos como de alto riesgo. DRB1*0701-DQA1*0201-DQB1*0303, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*1104-DQA1*0501-DQB1*0301, DRB1*1303-DQA1*0501-DQB1*0301, DRB1*1301-DQA1*0103-DQB1*0603 y DRB1*0403-DQA1*0301-DQB1*0302 fueron considerados protectores. La distribución de haplotipos de riesgo, protectores y otros en los (dos primeros) hermanos afectos y en los padres no afectos fue comparada entre las familias canarias y no canarias (chi cuadrado). Resultados: No se encontraron diferencias significativas en la distribución de haplotipos HLA entre las regiones estudiadas, ni en los hermanos afectos ni en los padres no afectos. Conclusiones: La alta incidencia de la enfermedad en la población canaria no parece ser explicada por una mayor prevalencia de haplotipos de HLA de clase II de riesgo en los casos con agregación familiar, aunque el tamaño de la muestra limita las diferencias detectables en este estudio (AU)

Fertility is reduced in women and in men with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium (T1DGC).

AIMS/HYPOTHESIS: A recent Finnish study described reduced fertility in patients with childhood-onset type 1 diabetes. The Type 1 Diabetes Genetics Consortium (T1DGC) is an international programme studying the genetics and pathogenesis of type 1 diabetes that includes families with the disease. Our aim was to assess fertility, defined as number of offspring, in the affected and unaffected siblings included in the T1DGC. METHODS: Clinical information from participants aged ≥18 years at the time of examination was included in the present analysis. The number of offspring of affected and unaffected siblings was compared (in families including both) and the influence of birth year, disease duration and age of onset was assessed, the last in affected siblings only, using Poisson regression models. RESULTS: A total of 3010 affected and 801 unaffected adult siblings that belonged to 1761 families were assessed. The mean number of offspring was higher in the unaffected than in the affected individuals, and the difference between the two groups was more pronounced in women than men. Poisson regression analysis showed that both sex and birth cohort significantly affected the differences between groups. In the affected siblings, adult onset (≥18 years), female sex and older birth cohort were associated with higher fertility. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes have fewer children than their unaffected siblings. This effect is more evident in women and in older birth cohorts. Onset of type 1 diabetes as an adult rather than a child is associated with a higher number of offspring, even after accounting for birth cohort and disease duration.