Browsing by Subject "geneettinen epidemiologia"

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  • Harjutsalo, Valma (Helsingin yliopisto, 2007)
    Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.
  • Tikkanen, Emmi (Helsingin yliopisto, 2013)
    Coronary heart disease (CHD) is a major burden for public health worldwide. Several factors are known to be associated with the disease risk, including high levels of low-density lipoprotein (LDL) cholesterol and blood pressure. The established risk factors do not, however, fully predict an individual s risk for the disease. In recent years, new candidate risk factors, including genetic markers, have been extensively studied. Genome-wide association studies (GWASs) have mapped over 40 genetic regions for CHD risk and hundreds of loci for CHD risk factors. The impact of these findings on public health remains obscure. In this study, we utilized the findings from large-scale GWASs and constructed genetic risk scores (GRSs) based on panels of single-nucleotide polymorphisms (SNPs). The aim was to estimate the joint effects of common genetic markers on CHD and its risk factors, and to evaluate the incremental value of genetic information in CHD risk assessment. In Projects I and II, we studied longitudinal effects of genetic loci associated with lipids and blood pressure, and evaluated the prediction of dyslipidemia and hypertension in young adults by using the genetic information in addition to clinical measurements. Our results show that the GRSs were significantly associated with longitudinal measurements of lipid traits and blood pressure throughout childhood, adolescence and adulthood. For some traits, the genetic effect was not consistent across age groups. For example, the GRS effect for high-density lipoprotein (HDL) cholesterol was considerably larger in children than in adults, and the proportion of variance explained by the SNPs in children was twice as much as in adults. The GRS for triglycerides improved the prediction of dyslipidemia in young adults when added to childhood lipid measurement. The blood pressure GRS increased the risk of hypertension, but did not improve risk discrimination over other risk factors. In Projects III and IV, we found that the GRSs based on CHD SNPs predicted CHD events. The estimated relative risk for the GRS was similar in magnitude to the relative risk of other risk factors such as systolic blood pressure. The genetic effect was independent of family history of the disease, which has been used as a surrogate for genetic risk in many prediction algorithms. The GRS based on 28 SNPs improved the prediction of CHD events beyond traditional risk factors and family history when evaluated with reclassification or discrimination metrics. Genetic screening could be especially useful for individuals in the intermediate-risk group (10-year risk 10-20%), as current preventive strategies are focused mainly on the high-risk group (>20%). In conclusion, these findings suggest that the genetic information obtained from GWASs could be used in early identification of individuals at increased risk for lipid disorders, hypertension and CHD. Keywords: cardiovascular disease, genetic association, genetic epidemiology, risk factor