Results Of Genetic Association Studies Research Articles

Interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events

BackgroundThe PlA1A2 polymorphism of glycoprotein IIIa (GPIIIa), which affects postoccupancy signaling by the platelet fibrinogen receptor IIbIIIa, has been investigated as a potential genetic risk factor for cardiovascular events in numerous studies, without consistent results. We investigated whether the effect of this genetic variant of the platelet fibrinogen receptor on the risk of cardiovascular events is affected by fibrinogen plasma levels. MethodsThe GPIIIa PlA1A2 polymorphism and fibrinogen levels were determined in 455 men with angiographically documented coronary atherosclerosis. ResultsNeither carriership of the rare PlA2 allele nor fibrinogen plasma levels affected the time to cardiovascular event, as assessed in a proportional hazards model. However, there was a significant interaction between PlA2 carriership and fibrinogen plasma levels (P = .002). Carriership of the variant PlA2 allele significantly affected event-free survival only in individuals within the highest fibrinogen quartile (hazard ratio, 2.7; 95% CI, 1.1 to 7.1; P = .03). ConclusionsWe observed a statistically significant interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. This interaction may account for the inconsistent results of genetic association studies investigating this genotype as a genetic risk factor in thrombotic cardiovascular events.

Human population structure and genetic association studies.

Population substructure and recent admixture may confound the results of genetic association studies in unrelated individuals, leading to a potential excess of both false positive and false negative results. The possibility of false associations depends on the population sampled, the trait being studied and the marker being tested. Although family based tests of association avoid the possibility of confounding due to population substructure and admixture, association studies in unrelated individuals may be preferred in many situations due to their feasibility. Unlinked genetic markers may be used to detect confounding in association studies. In addition, the information from unlinked markers may be used to adjust genetic associations.

Correction of bronchial challenge data for age and size may affect the results of genetic association studies in children.

Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose-response slopes (DRS) and PC20 values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7-18 years. Correction of bronchial challenge results, expressed as both DRS and PC20 values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC20 methacholine <8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRSc 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children.

Genetic associations in large versus small studies: an empirical assessment

Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research. We examined the results of 55 meta-analyses (579 study comparisons) of genetic associations and tested whether the magnitude of the genetic effect differs in large versus smaller studies. We noted significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude of the genetic effect differed significantly in large versus smaller studies in ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation, regression on SE, and regression on inverse of variance, respectively. The largest studies generally yielded more conservative results than the complete meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses the proposed association was significantly stronger in the first studies than in subsequent research. Only in nine (16%) meta-analyses was the genetic association significant and replicated without hints of heterogeneity or bias. There was little concordance in first versus subsequent discrepancies, and large versus small discrepancies. Genuine heterogeneity and bias could affect the results of genetic association studies. Genetic risk factors for complex diseases should be assessed cautiously and, if possible, using large scale evidence.

Applying genetic approaches to the treatment of nicotine dependence.

To advance the science of tobacco control, an enhanced understanding of the bio-behavioral basis of nicotine addiction is needed. In this study, we provide an overview of data from investigations of genetic factors in smoking behavior, discuss potential bio-behavioral mechanisms and effect modifiers, and suggest avenues for pharmacogenetics research in the area of smoking cessation treatment. The evidence to date is very consistent with respect to the significance of genetic contributions to smoking behavior. However, attempts to elucidate the role of specific genetic variants have met with mixed success. Explanations for the lack of consistency in the results of genetic association studies include biases in ascertainment, ethnic admixture, lack of attention to co-variates or modifiers of genetic risk, and the need for more refined phenotypes. As the field of genetics and smoking research progresses, increasing attention is being devoted to gene-environment interactions, with particular attention to the identification of genetic variants that may modify the effects of pharmacological treatment for smoking. With advances in molecular biology and genomics technology, individualized tailoring of smoking cessation therapy to genotype is within our grasp. Such research has the potential to improve treatment outcome, thereby reducing morbidity and mortality from smoking-related disease.

Parameters for reliable results in genetic association studies in common disease.

It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.