Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Association of type D personality with unhealthy lifestyle, and estimated risk of coronary events in the general Icelandic population.

BACKGROUND: Type D personality is associated with an increased morbidity and mortality risk in cardiovascular disease patients, but the mechanisms explaining this risk are unclear. We examined whether Type D was associated with coronary artery disease (CAD) risk factors, estimated risk of developing CAD, and previous cardiac events. DESIGN: Cross-sectional study in the general Icelandic population. METHODS: A random sample of 4753 individuals (mean age 49.1 ± 12.0 years; 49% men) from the REFINE-Reykjavik study completed assessments for Type D personality and conventional CAD risk factors. Ten-year risk of developing CAD was estimated with the Icelandic risk calculator. RESULTS: Type D personality (22% of sample) was associated with a higher prevalence of hypertension (35 vs. 31%, p = 0.009), but less use of hypertension medication (58 vs. 65%, p = 0.013) in hypertensives, more diabetes (6 vs. 4%, p = 0.023), wider waist circumference (p = 0.007), and elevated body mass index (p = 0.025) and blood lipids (p < 0.05). Type D individuals reported less physical exercise (p = 0.000) and more current (26 vs. 21%, p = 0.003) and former smoking (48 vs. 44%, p = 0.036). Estimates of 10-year risk of CAD were higher in Type D individuals (12.4%, 95% CI 1.9 to 23.8%), and Type Ds reported more previous cardiac events than non-Type Ds (5 vs. 3%, p < 0.01; OR 1.71, 95% CI 1.21 to 2.42). CONCLUSIONS: In the general Icelandic population, Type D personality was associated with differences in lifestyle-related CAD risk factors, a higher estimated risk of developing CAD, and higher incidence of previous cardiac events. Unhealthy lifestyles may partly explain the adverse cardiovascular effect of Type D personality.

Type D personality is associated with impaired psychological status and unhealthy lifestyle in Icelandic cardiac patients: a cross-sectional study.

BACKGROUND: Type D (distressed) personality has been associated with adverse cardiac prognosis and poor emotional well-being in cardiac patients, but it is still unclear what mechanisms link Type D personality with poor clinical outcomes in cardiac patients. In the present cohort of Icelandic cardiac patients, we examined potential pathways that may explain this relationship. The objectives were to examine 1) the association between Type D personality and impaired psychological status, and to explore whether this association is independent of disease severity; and 2) the association between Type D personality and an unhealthy lifestyle. METHODS: A sample of 268 Icelandic coronary angiography patients (74% males (N = 199); mean age 62.9 years (SD 10.5), range 28-85 years) completed the Type D Scale (DS14), Hospital Anxiety and Depression Scale (HADS), and Perceived Stress Scale (PSS) at hospitalization. Health-related behaviors were assessed 4 months following angiography. Clinical data were collected from medical files. RESULTS: Type D personality was associated with an increased risk of anxiety (OR 2.97, 95% CI:1.55-5.69), depression (OR 4.01, 95% CI:1.42-11.29), and stress (OR 5.99, 95% CI:3.08-11.63), independent of demographic variables and disease severity. Furthermore, fish consumption was lower among Type Ds, as 21% of Type Ds versus 5% of non-Type Ds consumed fish < 1 a week (p < 0.001). Type D patients were also more likely to smoke at follow-up (22% versus 10%, p = 0.024) and to use antidepressants (17% versus 9%, p = 0.049) and sleeping pills (49% versus 33%, p = 0.019) compared to non-Type Ds. Type D personality was not associated with other health-related behaviors, aside from trends towards less fruit and vegetable consumption, and more weight gain. CONCLUSION: Type D personality was associated with psychological distress and an unhealthy lifestyle in Icelandic cardiac patients. Future studies should further investigate the association between Type D personality and health-related behaviors.

Validity of Type D personality in Iceland: association with disease severity and risk markers in cardiac patients.

Type D personality has been associated with poor prognosis in cardiac patients. This study investigated the validity of the Type D construct in Iceland and its association with disease severity and health-related risk markers in cardiac patients. A sample of 1,452 cardiac patients completed the Type D scale (DS14), and a subgroup of 161 patients completed measurements for the five-factor model of personality, emotional control, anxiety, depression, stress and lifestyle factors. The Icelandic DS14 had good psychometric properties and its construct validity was confirmed. Prevalence of Type D was 26-29%, and assessment of Type D personality was not confounded by severity of underlying coronary artery disease. Regarding risk markers, Type D patients reported more psychopharmacological medication use and smoking, but frequency of previous mental problems was similar across groups. Type D is a valid personality construct in Iceland, and is associated with health-related risk markers, but not cardiac disease severity.