Isaacs, A.J.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease (Article)

2010-08-01T00:00:00Z

Aims The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. Methods and resultsIn 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5 of the patients [hazard ratio (HR) 0.67; 95 confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5 (HR 1.26; 95 CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. Conclusion The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.

A genome-wide association study of optic disc parameters (Article)

2010-06-01T00:00:00Z

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p =6.72*10-19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p=2.67*10-33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p =6.15*10-11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p=2.93*10-10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N=3,612), and the TwinsUK cohort (N=843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. © 2010 Ramdas et al.

Genome-wide linkage analysis of serum creatinine in three isolated European populations (Article)

2009-08-01T00:00:00Z

There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans.Kidney International advance online publication, 22 April 2009; doi:10.1038/ki.2009.135.

Familial aggregation of preeclampsia and intrauterine growth restriction in a genetically isolated population in The Netherlands (Article)

2008-07-10T00:00:00Z

Preeclampsia and intrauterine growth restriction are related, pregnancy-specific disorders with a substantial genetic influence, which may have a joint genetic aetiology. We investigated familial aggregation, consanguinity and parent-of-origin effects for preeclampsia and IUGR. Fifty women with previous preeclampsia and 56 with previous pregnancies complicated by intrauterine growth restriction were recruited from a recent genetically isolated population in the Netherlands. Their relationships were estimated by means of a large genealogy database that contains information on more than 110000 individuals from the isolate over 23 generations. Relationships were quantified using kinship and inbreeding coefficients. Parent-of-origin effects were evaluated by comparing parental kinships. Eighty-six women (39 preeclampsia and 47 intrauterine growth restriction) could be linked to one common ancestor within 14 generations. The proportion of related women with previous preeclampsia (95.6%) or pregnancies complicated by intrauterine growth restriction (95.1%) was significantly greater than expected by chance (P<0.001). Combined analysis of both disorders did not change the magnitude of familial aggregation. The proportion of women born from consanguineous marriages was increased in women with previous preeclampsia (81.8%) and those with intrauterine growth restriction (78%) compared to a random sample (P<0.001). Maternal and paternal kinships were not significantly different in both disorders. We demonstrate cosegregation of preeclampsia and intrauterine growth restriction, supporting a common genetic aetiology. The high proportion of parental consanguineous marriages suggests the possibility of an underlying recessive mutation. No evidence was found for a parent-of-origin effect either in preeclampsia or in intrauterine growth restriction.

The apolipoprotein E gene and its age-specific effects on cognitive function (Article)

2008-01-01T00:00:00Z

The E4 allele of the apolipoprotein E gene (APOE) is a well-established determinant of Alzheimer's disease but its relation to cognitive function is much less understood. We studied the age-specific effects of the APOE*E4 allele on cognitive function and cardiovascular risk factors in 2208 related individuals. APOE*E4 allele was significantly associated with reduced test scores for Adult Verbal Learning Test, particularly on the memory and learning sub domains, in persons older than 50 years of age. The effect of APOE*E4 was independent of the effect of APOE*E4 on vascular risk factors and most pronounced on learning ability. Our findings suggest that APOE*E4 has an effect on cognitive function predominantly in the elderly, independent of vascular risk factors.

Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology (Article)

2007-10-01T00:00:00Z

BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

Genetic Epidemiology and Lipids: A Pattern So Grand and Complex (Doctoral Thesis)

2007-05-16T00:00:00Z

Intensive research over the course of the last several decades led to dramatic improvements in understanding, treating, and preventing cardiovascular disease. Despite this progress, cardiovascular disease remains the leading cause of mortality in both high- and low-income countries, and the leading source of morbidity in high-income countries. Lipids are well known determinants of cardiovascular disease risk; epidemiological evidence was published long ago. Total cholesterol and low-density lipoprotein cholesterol (LDL), which tend to be strongly correlated, are associated with increased disease risk. LDL can be readily oxidized, which causes inflammation and atherosclerosis to occur, and small, dense LDL particles are considered the most atherogenic lipid particles. High-density lipoprotein cholesterol (HDL), by contrast, is associated with beneficial effects, in terms of cardiovascular disease risk. Several mechanisms are likely to account for the protective consequences of increased HDL concentrations. HDL exhibits anti-inflammatory properties. Additionally, it is thought to be an anti-oxidant, helping to offset the deleterious effects of oxidized LDL. HDL is also involved in reverse cholesterol transport (i.e. the sequestration of cholesterol to the liver for metabolism), which helps to reduce the amount of circulating lipid.

Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk (Article)

2006-12-01T00:00:00Z

BACKGROUND AND PURPOSE: Carriers of the 460Trp allele of the alpha-adducin gene (ADD1) show higher rates of sodium reabsorption compared with homozygous carriers of the Gly460 allele and were found to have an increased risk of hypertension and cardiovascular disease. We studied the association between the Gly460Trp polymorphism and atherosclerosis, cardiovascular disease, and cerebrovascular disease. METHODS: Intima-media thickness of the common carotid artery, as well as incident stroke and myocardial infarction, were studied within 6471 subjects of the Rotterdam Study. Within 1018 subjects of the Rotterdam Scan Study, prevalent silent brain infarcts and cerebral white matter lesions were studied. Subjects were grouped into 460Trp carriers (variant carriers) and homozygous carriers of the Gly460 allele (reference). RESULTS: Intima-media thickness of the common carotid artery was 0.80 mm in variant carriers compared with 0.79 mm in the reference group (P=0.04). Variant carriers had an increased risk of any stroke (hazard ratio [HR], 1.22; 95% CI, 1.02 to 1.45), ischemic stroke (HR, 1.29; 95% CI, 1.02 to 1.63), hemorrhagic stroke (HR, 1.07; 95% CI, 0.59 to 1.92), and of myocardial infarction (HR, 1.33; 95% CI, 1.05 to 1.69). For any ischemic stroke, there was a significant interaction between the Gly460Trp polymorphism and hypertension. Variant carriers more often had a silent brain infarct (odds ratio, 1.36; 95% CI, 0.98 to 1.88) and had more subcortical white matter lesions than the reference group (1.45 vs1.24 mL; P=0.22). CONCLUSIONS: The Gly460Trp polymorphism is associated with atherosclerosis, cardiovascular disease, and cerebrovascular disease, especially in hypertensive subjects.

The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis. (Article)

2004-08-01T00:00:00Z

Investigations of the -514 C-->T single nucleotide polymorphism (SNP) in the hepatic lipase (HL) gene promoter region (LIPC) have yielded contradictory results regarding its association with changes in plasma lipids. The current study is a meta-analysis of 25 publications on this SNP, comprising over 24,000 individuals, and its relationship with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and HL activity. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype [weighted mean difference (WMD), -5.83 mmol/liter.h (95% confidence interval, -8.48, -3.17) and -11.05 mmol/liter.h (95% confidence interval, -14.74, -7.36), respectively]. Moreover, significant increases in HDL were found; the CT to CC comparison showed an increase in WMD of 0.04 mmol/liter (95% confidence interval, 0.02, 0.05) mmol/liter, and the increase in the TT vs. CC difference was WMD of 0.09 mmol/liter (95% confidence interval, 0.07, 0.12). These changes appear to be stepwise, implying an allele dosage effect. All P values for these associations were less than 0.001. This meta-analysis demonstrates the importance of the -514C-->T SNP in determining HL activity and plasma HDL concentration and helps quantify the role that hepatic lipase plays in the metabolism of HDL.