Genetic Variation and Mendelian Randomization Approaches.

While genome-wide association studies (GWAS) on levels of nuclear receptors are sparse, the genetics of ligands of these receptors (steroid hormones, thyroid hormones, and liposoluble vitamins) have been extensively studied in GWAS of predominantly European populations. Hundreds of genetic variants across the genome have been associated with serum levels of nuclear receptor ligands, shedding light on the physiology of hormone metabolism. These GWAS findings have been used to explore causal associations of these hormones with complex human traits and diseases in Mendelian randomization (MR) studies, and in studies using polygenic risk scores to quantify the genetic predisposition to higher/lower hormone levels. As such, besides providing insights into hormonal pathophysiology and its causal relationship with clinical complications, GWAS-identified genetic markers could ultimately play an important role in the daily clinical management of patients. As large trans-ethnic GWAS on levels of nuclear receptor ligands emerge, and with the fast advances in genotyping techniques and constant decrease of the genotyping costs, studying an individual's genetically predicted hormonal profile could be the next step in personalizing the management of patients with pathologies related to nuclear receptors and their ligands.

Role of interleukin 6 signaling pathway in the anti-inflammatory effects of statins on coronary artery disease: Evidence from Mendelian randomization analysis.

BACKGROUND: Statins are currently widely used in the prevention of coronary artery disease (CAD) primarily for lipid-lowering with a potential anti-inflammatory effect. However, it is not clear if their potential anti-inflammatory effects are mediated through the interleukin 6 (IL-6) signaling pathway. METHODS: Using the Mendelian randomization (MR) approach followed by multivariable MR analyses, we examined the extent to which the effects of statins on CAD might be mediated through the IL-6 signaling pathway. RESULTS: Our observations showed that HMG-CoA reductase, using LDL levels as a proxy, had a significant effect on upstream IL-6 (ßMR = 0.47, P-IVW = 0.01) and nominally significant effects on IL-6RA (ßMR = 0.22, P-IVW = 0.047) and APOB (ßMR = 0.82, P-IVW = 1.8 × 10-33). While the IL-6 signaling cascade (IL-6RA ßMR = -0.06, P-IVW = 3.45 × 10-20 and IL-6 ßMR = -0.03, P-IVW = 0.09) and the anti-inflammatory effect of HMG-CoA reductase (ßMR = -0.31, P-IVW = 0.01) was found to influence the risk of CAD, the multivariable MR (MVMR) model indicated that the anti-inflammatory effect of HMG-CoA reductase is not likely to be mediated through the IL-6 signaling cascade, including APOB and IL-6RA (MVMRß = 0.23, P = 0.688). CONCLUSIONS: Our findings suggest that statins may use inflammatory mechanisms independent of the IL-6 signaling pathway to prevent CAD. This result could potentially affect the definition of the target population for statin use.

Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause.

BACKGROUND: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR). METHODS: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause. CONCLUSIONS: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.

Mendelian randomization identifies circulating proteins as biomarkers for age at menarche and age at natural menopause.

Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Secondary analysis of publicly available data reveals superoxide and oxygen radical pathways are enriched for associations between type 2 diabetes and low-frequency variants.

Genome-wide association studies explain at most 5%-10% of the heritable components of type 2 diabetes. Some of the "missing type 2 diabetes heritability" could be explained by low-frequency variants. We examined the associations between low-frequency variants and type 2 diabetes, using data from 2538 diabetic and 2977 nondiabetic subjects in the publicly available database of Genotypes and Phenotypes. We applied two approaches. First, we combined information from all low-frequency (1%-5%) variants at a locus in a gene-centric analysis of associations with diabetes. Next, we searched for gene ontology (GO) biological processes that were enriched for gene-centric associations, after correcting for multiple testing to control the false discovery rate (FDR). We found three GO biological processes that were significantly enriched for associations to diabetes: "response to superoxide" (FDR-adjusted p=2.7×10(-3)), "response to oxygen radical" (FDR-adjusted p=2.7×10(-3)), and "heart contraction" (FDR-adjusted p=2.6×10(-2)). There were three genes that contributed to "response to superoxide" and "oxygen radical" pathways, including the SOD1 gene. Gene-centric tests of association with low-frequency variants, followed by analysis to evaluate which biological pathways are enriched for these associations has the potential to recover, at least some proportion of, the "missing heritability" of type 2 diabetes.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

A frequent variant in the ABCA1 gene is associated with increased coronary heart disease risk and a better response to statin treatment in familial hypercholesterolemia patients.

AIMS: Statins are essential for the reduction of risk of coronary heart disease (CHD) in familial hypercholesterolemia (FH). One of many genes influenced by statin treatment is the ATP-binding cassette transporter A1 (ABCA1) gene, which plays an important role in metabolism of high-density lipoprotein (HDL). The present aim was to test if the ABCA1 C69T polymorphism influences CHD risk and response to statin treatment. METHODS AND RESULTS: In a large cohort of 1686 FH patients without a history of CHD before 1 January 1990, we analysed statin-ABCA1 C69T polymorphism interaction by comparing treated and untreated patients. We used a Cox proportional hazard model adjusted for sex, birth year, and smoking. In analyses restricted to untreated patients, the TT genotype was associated with 1.7 times higher CHD risk than the CC genotype (hazard ratio (HR) =1.65, 95% confidence interval (95% CI): 1.08-2.53; P = 0.02). Conversely, in statin-treated FH patients, CHD risk in TT individuals was not increased (HR: 0.65, 95% CI: 0.35-1.24; P = 0.2). Formal testing confirmed this interaction (P = 0.03). HDL-cholesterol levels were significantly more raised in statin-treated patients with the TT than with the CC genotype (two-way ANOVA, P = 0.045). CONCLUSION: In untreated FH patients, the TT genotype of the ABCA1 C69T polymorphism was associated with increased CHD risk. However, in statin-treated patients, CHD risk was no longer significantly different between genotypes, at least partially explained by a higher rise in HDL-cholesterol levels during statin treatment in TT individuals.

Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study.

Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit ß2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1ß (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and α1-3-N-acetylgalactosaminyltransferase and α1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets.

Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study.

OBJECTIVE: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS: We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 × 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 × 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 × 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006). CONCLUSIONS: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.

The risk of tendon xanthomas in familial hypercholesterolaemia is influenced by variation in genes of the reverse cholesterol transport pathway and the low-density lipoprotein oxidation pathway.

AIMS: The presence of tendon xanthomas is a marker of high risk of cardiovascular disease (CVD) among patients with familial hypercholesterolaemia (FH). Therefore, xanthomas and atherosclerosis may result from the same pathophysiological mechanisms. Reverse cholesterol transport (RCT) and low-density lipoprotein (LDL) oxidation are pathophysiological pathways of atherosclerosis, and it is well established that genetic variation in these pathways influences CVD risk. We therefore determined whether genetic variation in these pathways is also associated with the occurrence of tendon xanthomas in FH patients. METHODS AND RESULTS: Four genetic variants in each pathway were genotyped in 1208 FH patients. We constructed a gene-load score for both pathways. The odds of xanthomas increased with the number of the risk alleles in the RCT pathway (OR 1.21, 95% CI 1.08-1.36, P(trend) = 0.0014). Similarly, higher numbers of risk alleles in the LDL oxidation pathway were associated with the presence of xanthomas (OR 1.24, 95% CI 1.08-1.41, P(trend) = 0.0015). CONCLUSION: The presence of tendon xanthomas in FH patients is associated with genetic variation in the RCT and LDL oxidation pathways. These results support the hypothesis that xanthomas and atherosclerosis share pathophysiological mechanisms.

Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct GLB1-related phenotype.

BACKGROUND: Morquio B disease (MBD) is a distinct GLB1-related dysostosis multiplex presenting a mild phenocopy of GALNS-related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). OBJECTIVES AND METHODS: With the aim to further describe patterns of MBD-related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1-related dysostosis multiplex living and diagnosed in Brazil. RESULTS: About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age-dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. CONCLUSION: Our study extends the phenotypic spectrum of GLB1-related conditions by describing a cohort of patients with MBD and GM1-gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1-related conditions is warranted.

Genetic polymorphisms in the DRD2, DRD3, and SLC6A3 gene in elderly patients with delirium.

Dopamine excess appears to be critical in the final common pathway of delirium. The aim of this study was to investigate whether genetic polymorphisms in three dopamine-related genes (the dopamine receptor 2 (DRD2), dopamine receptor 3 (DRD3), and the dopamine transporter (SLC6A3) gene) were associated with delirium. Patients aged 65 years and older acutely admitted to the medical department or to the surgical department following hip fracture were included. Delirium was diagnosed by the Confusion Assessment Method. Sixteen single nucleotide polymorphisms (SNPs) and one variable number of tandem repeats in the SLC6A3 gene, nine SNPs in the DRD2 gene, and six SNPs in the DRD3 gene were genotyped. Fifty percent of the 115 surgical patients and 34% of the 605 medical patients experienced delirium. Delirious patients were older and had more frequently pre-existing functional and cognitive impairment (P < 0.001). After correction for multiple testing, one SNP in the SLC6A3 gene (rs393795) was associated with reduced risk of delirium (P = 0.032). Adjusted for age, cognitive impairment, and functional impairment, three SNPs in the DRD2 gene and seven SNPs in the SLC6A3 gene were associated with delirium; none of these associations was significant after correction for multiple testing. Variations in the SLC6A3 gene and possibly the DRD2 gene were associated with delirium. Although validation of these results is needed our results support a role for the dopamine transporter and dopamine receptor 2 in the pathogenesis of delirium.

The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis.

Delirium is the most common neuropsychiatric syndrome in elderly ill patients. Previously, associations between delirium and the dopamine transporter gene (solute carrier family 6, member 3 (SLC6A3)) and dopamine receptor 2 gene (DRD2) were found. The aim of this study was to validate whether markers of the SLC6A3 and DRD2 genes are were associated with delirium in independent populations. Six European populations collected DNA of older delirious patients. Associations were determined per population and results were combined in a meta-analysis. In total 820 medical inpatients, 185 cardiac surgery patients, 134 non-cardiac surgery patients and 502 population-based elderly subjects were included. Mean age was 82 years (SD 7.5 years), 598 (36%) were male, 665 (41%) had pre-existing cognitive impairment, and 558 (34%) experienced delirium. The SLC6A3 rs393795 homozygous AA genotype was more frequent in patients without delirium in all populations. The meta-analysis showed an Odds Ratio (OR) for delirium of 0.4 (95% confidence interval (C.I.) 0.2-0.6, P = 0.0003) for subjects with AA genotype compared to the AG and GG genotypes. SLC6A3 marker rs1042098 showed no association with delirium. In meta-analysis the DRD2 rs6276 homozygous GG genotype showed an OR of 0.8 for delirium (95% C.I. 0.6-1.1, P = 0.24). When subjects were stratified for cognitive status the rs6276 GG genotype showed ORs of 0.6 (95% C.I. 0.4-1.0, P = 0.06) and 0.8 (95% C.I. 0.5-1.5, P = 0.51) for delirium in patients with and without cognitive impairment, respectively. In independent cohorts, a variation in the SLC6A3 gene and possibly the DRD2 gene were found to protect for delirium.

Genetic variation in the renin-angiotensin system and arterial stiffness. The Rotterdam Study.

We studied the associations of three renin-angiotensin system polymorphisms, angiotensin-converting enzyme (ACE) I/D, angiotensinogen 235 M/T, and angiotensin II receptor type I 573 C/T, with arterial stiffness. The study was embedded in the Rotterdam Study, a population-based study older adults. The association of the polymorphisms with pulse wave velocity, the carotid distensibility, and pulse pressure was investigated in 3706 subjects. We found no association of the ACE I/D polymorphism with pulse wave velocity, but the D-allele was associated with a lower distensibility coefficient (p = 0.05) and higher pulse pressure (p = 0.01). For the angiotensinogen 235 M/T polymorphism, no significant associations with either pulse wave velocity (p = 0.71), the distensibility coefficient (p = 0.16) or pulse pressure (p = 0.34) were found. Also, we found no significant associations of pulse wave velocity (PWV) (p = 0.32), the distensibility coefficient (p = 0.08), and pulse pressure (p = 0.09) with the angiotensin II receptor type 1 573 C/T polymorphism. No epistatic effects were observed between the three renin-angiotensin system (RAS) genes with arterial stiffness. Our findings suggest that genetic variation in the renin-angiotensin system may play a role in determining carotid distensibility and pulse pressure.

Gene-load score of the renin-angiotensin-aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin-angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of importance in determining the CHD risk in FH, because of their involvement in CHD. We investigated the association between CHD risk and combined genetic variation in the RAAS and adrenalin/noradrenalin system. METHODS AND RESULTS: In 2190 FH patients, we genotyped six RAAS polymorphisms and five adrenalin/noradrenalin polymorphisms. For each patient, we calculated two gene-load scores by counting the number of risk genotypes within each pathway. Four of the six RAAS polymorphisms and none of the polymorphisms in the adrenalin/noradrenalin system were significantly associated with CHD (P < 0.05). The RAAS gene-load score was significantly associated with CHD (P(linear trend) < 0.001): in patients with a gene-load score of 5 or 6, the CHD risk was 2.3 times as high as in patients with a score of 0 or 1. The gene-load score of the adrenalin/noradrenalin system was not associated with CHD. CONCLUSION: Genetic variation in the RAAS contributes gene-dose dependently to CHD risk in patients with FH, whereas genetic variation in the adrenalin/noradrenalin system is not associated with CHD.

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia.

AIMS: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. METHODS AND RESULTS: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). CONCLUSION: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes.

We examined the association between alpha-adducin 1 (ADD1) gene polymorphism (Gly460Trp) with macrovascular complications and mortality in type 2 diabetes in a Caucasian population aged >or=55 years. The study was part of the Rotterdam Study, a prospective population-based cohort study. ADD1 polymorphism was determined in 6,471 participants, including 599 patients with type 2 diabetes at baseline. The prevalence of hypertension in type 2 diabetic patients was 2.57 times higher in ADD1 TT carriers compared with GG carriers (95% CI 1.05-6.32, P = 0.03). Homozygous T carriers also had a higher mean common carotid intima media thickness (IMT) compared with GG carriers (mean difference 0.05 mm, P for trend = 0.03). In diabetic patients with hypertension, the risk of mortality was 1.83 times higher in homozygous T carriers compared with the GG genotype group (95% CI 1.07-3.16, P = 0.03). The increased risk was only present among TT carriers who did not use antidiabetes medication (hazard ratio 2.18 [95% CI 1.12-4.24], P = 0.02). The results of this population-based cohort study suggest that the ADD1 gene contributes to the risk of hypertension and increases mean common carotid IMT in patients with type 2 diabetes. Furthermore, the study indicates that the ADD1 polymorphism could be useful in identifying hypertensive type 2 diabetic patients with a high risk of mortality.

Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.

OBJECTIVE: To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. METHODS: All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed. RESULTS: Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). CONCLUSION: Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.

Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk.

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.