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Biomedical subjects

Bernhard R Winkelmann

Publications and source records attributed to Bernhard R Winkelmann.

At least 19 recordsLinked to original sources
PubMed2006

Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study).

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is increased in conditions associated with increased risk of atherosclerosis. We investigated the use of ADMA to predict total and cardiovascular mortality in patients scheduled for coronary angiography. METHODS: In 2543 persons with and 695 without coronary artery disease (CAD) identified by angiography we measured ADMA and recorded total and cardiovascular mortality during a median follow-up of 5.45 years. RESULTS: ADMA was correlated positively to age, female sex, diabetes mellitus, former and current smoking, and C-reactive protein and inversely to HDL cholesterol and triglycerides. ADMA was not associated with body mass index, hypertension, LDL cholesterol, or the presence or absence of angiographic CAD. Glomerular filtration rate and homocysteine were the strongest predictors of ADMA. At the 2nd, 3rd and 4th quartile of ADMA, hazard ratios for all-cause mortality adjusted for age, sex, and cardiovascular risk factors were 1.12 [95% confidence interval (CI) 0.83-1.52], 1.35 (95% CI 1.01-1.81), and 1.87 (95% CI 1.43-2.44), respectively, compared with the 1st quartile. Hazard ratios for cardiovascular death were 1.13 (95% CI 0.78-1.63), 1.42 (95% CI 1.00-2.02), and 1.81 (95% CI 1.31-2.51). ADMA in the highest quartile remained predictive of mortality after accounting for medication at baseline. The predictive value of ADMA was similar to that in the entire cohort in persons with CAD, stable or unstable, but was not statistically significant in persons without angiographic CAD. CONCLUSIONS: ADMA concentration predicts all-cause and cardiovascular mortality in individuals with CAD independently of established and emerging cardiovascular risk factors.

Analysis of Variance↗
PubMed2006

Adiponectin and mortality in patients undergoing coronary angiography.

CONTEXT: The adipokine adiponectin has been suggested to protect against coronary artery disease (CAD). However, studies addressing the association between adiponectin and mortality are sparse. OBJECTIVE: The objective of the study was to elucidate the relationship between adiponectin and mortality. DESIGN, SETTING, AND PARTICIPANTS: Adiponectin was determined in 2473 persons with and 673 persons without angiographic CAD. During a mean follow-up period of 5.45 yr, 427 persons with CAD and 55 persons without CAD died. MAIN OUTCOME MEASURE: Hazard ratios for mortality according to adiponectin levels were measured. RESULTS: Adiponectin was positively related to female gender, age, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, homocysteine, and N-terminal pro-B-type natriuretic peptide. It was inversely related to glomerular filtration rate, body mass index, and triglycerides and was low in diabetes mellitus and CAD. An increase of 1 sd in adiponectin was associated with unadjusted and fully adjusted hazard ratios for death from any cause of 1.31 [95% confidence interval (CI) 1.20-1.42] and 1.22 (95% CI 1.12-1.34), and for death from cardiovascular causes of 1.32 (95% CI 1.19-1.45) and 1.23 (95% CI 1.11-1.37), respectively. In angiographic CAD, stable CAD, and unstable CAD, the predictive value of adiponectin was similar to that in the entire cohort, but it did not attain statistical significance in persons without angiographic CAD. Adiponectin was also positively related to the risk of death from noncardiovascular causes. CONCLUSIONS: Despite the common view about adiponectin as a protective molecule in cardiovascular disease, high adiponectin independently predicts all-cause, cardiovascular, and noncardiovascular mortality in individuals with CAD.

Adiponectin↗
PubMed2006

G-protein beta3 subunit (GNB3) gene polymorphisms and cardiovascular disease: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

A common 825C>T polymorphism in exon 10 of the gene for the beta-3 subunit of heterotrimeric G-proteins, GNB3, has been associated in some studies with traits of the metabolic syndrome as well as coronary artery disease (CAD), but these associations were refuted by other studies. To investigate the role of GNB3 gene variations in CAD and myocardial infarction (MI), we determined five GNB3 polymorphisms (-1429G>A, IVS5 +41G>A, 657T>A, 814G>A and 825C>T) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, including 2575 patients with angiographically documented CAD and 731 individuals in whom CAD had been ruled out by angiography. None of the GNB3 polymorphisms was associated with CAD, MI, diabetes, hypertension, blood pressure, body weight or body mass index. We conclude that a major contribution of GNB3 gene variants to CAD or MI risk is unlikely.

Aged↗
PubMed2006

The angiotensin-I converting enzyme I/D polymorphism is not associated with type 2 diabetes in individuals undergoing coronary angiography. (The Ludwigshafen Risk and Cardiovascular Health Study).

The deletion (D) allele of the angiotensin-I converting enzyme (ACE) is associated with higher ACE activity and has been implicated only recently in the pathogenesis of type 2 diabetes in Caucasian subjects. We have studied the ACE I/D polymorphism in 1054 patients with type 2 diabetes and in 2251 individuals without type 2 diabetes in Caucasians persons undergoing coronary angiography. Further parameters of glucose metabolism (fasting glucose, HbA1c, insulin, C-peptide, pro-insulin, and pancreatic beta-cell function) were analyzed according to the ACE I/D genotype in a subgroup of 2000 individuals in whom an oral glucose challenge was performed. The genotypes ACE II, ID, DD occurred at similar frequencies in patients with type 2 diabetes mellitus (21.0, 50.8, and 28.3%, respectively) compared to non-diabetic individuals (23.3, 49.2, and 27.5%, respectively). There was no association of the ACE D allele with all type 2 diabetes mellitus (OR 1.16, 95%CI, 0.94-1.43), nor with known (OR 1.28, 95% CI, 0.99-1.68) or newly diagnosed diabetes (OR 1.00, 95% CI, 0.75-1.32). These findings were not materially altered when we adjusted for age and gender, cardiovascular risk factors and anti-diabetic or cardiovascular medication. Further the ACE D-allele was not associated with angiographic coronary heart disease or myocardial infarction. The ACE I/D genotype is not associated with type 2 diabetes mellitus, glucose metabolism, coronary heart disease, or myocardial infarction.

Aged↗
PubMed2006

Markers for endothelial dysfunction, but not markers for oxidative stress correlate with classical risk factors and the severity of coronary artery disease. (A subgroup analysis from the Ludwigshafen Risk and Cardiovascular Health Study).

OBJECTIVE: Endothelial dysfunction and oxidative stress are involved in atherogenesis. In the search for predictors of vascular disease markers for endothelial dysfunction and oxidative stress were analyzed. METHODS: Of 208 consecutive patients 22% were controls (CO) without coronary artery disease (CAD), 52% presented with stable angina (SAP) and 26% had acute coronary syndromes (ACS). Nitric oxide (NO), thrombomodulin (TM), von Willebrand factor (vW), sVCAM-1, sICAM-1, sP-selectin, sE-selectin, sL-selectin and C-reactive protein (CRP) were determined as markers for endothelial dysfunction, glutathione (GSH), glutathione peroxidase (Gpx), myeloperoxidase (Mpx), lipid peroxides (Lpx), 8-isoprostane (Iso), superoxide dismutase (SOD), total antioxidant capacity (TAC) and homocysteine (Hc) as markers for oxidative stress. RESULTS: The increases of TM, vW, sVCAM-1, CRP, SOD and Mpx correlated with the CAD status in the order CO < SAP < ACS, whereas NO and sL-selectin were inversely correlated (p < 0.05, resp.). The other markers remained unchanged. For several markers a significant relationship to risk factors was detected. CONCLUSIONS: Markers for endothelial dysfunction rather than those for oxidative stress may serve as indicators for the presence and severity of CAD.

Adult↗
PubMed2005

Adiponectin serum concentrations in men with coronary artery disease: the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study.

BACKGROUND: Adiponectin, the most abundant adipocytokine of adipose tissue cells, has recently been found to be decreased in coronary artery disease (CAD). Data concerning adiponectin in different stages of CAD are rare, and it was not investigated if adiponectin levels are influenced by the severity of angina pectoris. METHODS: Thus, we measured adiponectin serum levels by means of ELISA in 1626 male probands, including 273 control subjects, 367 subjects with silent CAD, 608 patients with stable, and 378 patients with unstable angina. RESULTS: As compared to controls (8.56; 5.85 to 12.85 microg/ml) and subjects with silent CAD (8.60; 5.99 to 12.64 microg/ml), adiponectin was significantly decreased in patients with stable (7.22; 5.06 to 10.41 microg/ml; p < 0.001 for both) and unstable angina (6.72; 4.08 to 10.08 microg/ml; p < 0.001 for both). By a logistic regression analysis, low adiponectin levels were identified as a significant independent predictor for stable and unstable angina (p < 0.001 for both). No significant differences of adiponectin were observed, neither between the stable and unstable angina group, nor between any classes of angina according to the Canadian Cardiovascular Society (CCS) Angina Score for stable angina. CONCLUSIONS: These results suggest, that decreased adiponectin levels are indicative for symptomatic CAD, but are not further influenced by the progression of this disease.

Adiponectin↗
PubMed2005

Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study.

BACKGROUND: Platelet-activating factor acetylhydrolase (PAF-AH), also denoted as lipoprotein-associated phospholipase A2, is a lipoprotein-bound enzyme that is possibly involved in inflammation and atherosclerosis. This study investigates the relationship of PAF-AH activity to angiographic coronary artery disease (CAD), the use of cardiovascular drugs, and other established risk factors. METHODS AND RESULTS: PAF-AH activity, lipoproteins, sensitive C-reactive protein (sCRP), fibrinogen, serum amyloid A, and white blood cell count were determined in 2454 subjects with angiographically confirmed CAD and in 694 control subjects. PAF-AH activity was highly correlated with LDL cholesterol (r=0.517), apolipoprotein B (r=0.644), and non-HDL cholesterol (r=0.648) but not with sCRP or fibrinogen. PAF-AH activity was lower in women than in men and was affected by the intake of lipid-lowering drugs (-12%; P<0.001), aspirin (-6%; P<0.001), beta-blockers (-6%; P<0.001), and digitalis (+7%; P<0.001). Unlike sCRP, fibrinogen, and serum amyloid A, PAF-AH activity was not elevated in unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. When nonusers of lipid-lowering drugs were examined, PAF-AH activity was associated with the severity of CAD and the number of coronary vessels with significant stenoses. In individuals not taking lipid-lowering drugs and after adjustment for use of aspirin, beta-blocker, and digitalis, the odds ratio for CAD associated with increasing PAF-AH activity was 1.39 (95% CI 1.26 to 1.54, P<0.001), a finding that was robust against further adjustments. CONCLUSIONS: PAF-AH activity is not an indicator of the systemic inflammation that accompanies acute coronary syndromes. PAF-AH activity is affected by a number of cardiovascular drugs; however, after such medication use was accounted for, PAF-AH activity was associated with angiographic CAD, complementary to sCRP and independently of established risk factors such as LDL cholesterol.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2004

Association of angiotensinogen haplotypes with angiotensinogen levels but not with blood pressure or coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study.

Angiotensinogen and its cleaved forms angiotensin I and angiotensin II are important regulators of blood pressure. The gene for angiotensinogen (AGT) carries two common polymorphisms, T207M and M268T (previously described as T174M and M235T). To investigate the role of haplotypes formed by these polymorphisms for angiotensinogen levels we examined blood pressure, coronary artery disease (CAD), myocardial infarction (MI), and AGT genotypes and haplotypes in 2,575 patients with angiographically documented CAD and 731 individuals in whom CAD had been ruled out by angiography. Three haplotypes, designated as Hap1 (T207, M268), Hap2 (T207, T268) and Hap3 (M207, T268), accounted for more than 99% of alleles. The AGT Hap2 haplotype was significantly associated with angiotensinogen levels; one additional Hap2 allele accounted for an approx. 8% increase in angiotensinogen. This association was stronger than that of either single polymorphism. AGT genotypes or haplotypes were not related to hypertension, CAD or MI. We conclude that a common haplotype of the angiotensinogen gene is linked to angiotensinogen levels but has no major impact on blood pressure, hypertension, or cardiovascular risk.

Angiotensinogen↗
PubMed2004

Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study.

BACKGROUND: Markers of systemic inflammation and LDL cholesterol (LDL-C) have been considered independent risk factors of coronary artery disease (CAD). We examined whether alterations of LDL metabolism not reflected by LDL-C were associated with low-grade inflammation, vascular injury, and CAD. METHODS AND RESULTS: We studied 739 subjects with stable angiographic CAD and 570 matched control subjects in which CAD had been ruled out by angiography. The association of LDL triglycerides (LDL-TGs) (odds ratio [OR], 1.30; 95% CI, 1.19 to 1.43; P<0.001) with CAD was stronger than that of LDL-C (OR, 1.10; 95% CI, 1.00 to 1.21; P=0.047). The predictive value of LDL-TG for CAD was independent of LDL-C. "Sensitive" C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin 6, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) increased in parallel to LDL-TG. CRP, ICAM-1, and VCAM-1 were inversely related to LDL-C. To examine whether LDL-TGs were associated with the distribution of LDL subfractions, we studied 114 individuals with impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes mellitus. In subjects with high LDL-TG, LDLs were depleted of cholesteryl esters (CEs), and VLDLs, IDLs, and dense LDLs were significantly elevated. CONCLUSIONS: Alterations of LDL metabolism characterized by high LDL-TG are related to CAD, systemic low-grade inflammation, and vascular damage. High LDL-TGs are indicative of CE-depleted LDL, elevated IDL, and dense LDL. LDL-TG may better reflect the atherogenic potential of LDL than LDL-C.

Aged↗
PubMed2004

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.

Adult↗
PubMed2004

G(-30)A polymorphism in the pancreatic promoter of the glucokinase gene associated with angiographic coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of coronary artery disease (CAD). A G(-30)A polymorphism in the beta-cell-specific promoter of glucokinase (GK-30PM) has been implicated in reduced pancreatic beta-cell function. Its impact on CAD has not been examined. METHODS AND RESULTS: The glucokinase G(-30)A variant was determined in 2567 patients with angiographic CAD and in 731 individuals in whom CAD had been ruled out by angiography. In carriers of the A allele, the adjusted OR of CAD was 1.39 (95% CI, 1.15 to 1.70). Corresponding ORs were 1.27 (95% CI, 1.02 to 1.59) and 1.92 (95% CI, 1.26 to 2.93) in individuals without and with T2DM, respectively. The prevalence of the A allele increased in parallel with the Friesinger coronary score. Patients with T2DM were more frequent among carriers of > or =1 A allele (OR, 1.17; 95% CI, 1.00 to 1.28). This association was stronger if CAD patients only were considered. The A allele was associated with higher glucose (fasting, P=0.002; 2 hours after oral glucose, P=0.017) and glycohemoglobin (HbA1c; P=0.002). Furthermore, presence of 1 A allele was negatively related to beta-cell function, estimated by beta percent (P=0.012) and by the ratios of proinsulin to insulin (P=0.025) and proinsulin to C peptide (P=0.019). CONCLUSIONS: The A allele of the pancreatic promoter of glucokinase increases the risk of CAD in individuals with and without T2DM. Furthermore, at least in CAD, it is associated with an augmented prevalence of T2DM.

Aged↗
PubMed2004

Association of RANTES G-403A gene polymorphism with increased risk of coronary arteriosclerosis.

AIMS: Polymorphisms in the RANTES (G-403A), monocyte chemoattractant protein-1 (MCP-1; A-2518G), stromal cell-derived factor-1beta (SDF-1beta; G801A), and C-C chemokine receptor-5 (CCR5; Delta32) genes have been associated with functional effects. These chemokines have been implicated in leucocyte recruitment to arterial lesions. In a case-control study, we explored relations between these polymorphisms and coronary artery disease (CAD), with respect to angiographic abnormalities and acute coronary syndromes (ACS). METHODS AND RESULTS: The LUdwigshafen Risk and Cardiovascular health (LURIC) cohort was genotyped by RFLP-PCR. Based on coronary angiography, individuals were sub-divided into CAD cases (n = 2694) and controls (n = 530). RANTES-403 genotype frequencies were significantly different in cases and controls (chi2 = 4.17, p = 0.041), as were A allele carrier frequencies (36.01% vs. 30.19%, OR = 1.30 [95%-CI = 1.06-1.60], p = 0.010). By multivariate analysis, RANTES A-403 retained significant association with CAD (chi2 = 8.40, p = 0.0038). RANTES A-403 was associated with increased ACS prevalence (OR = 1.36 [95%-CI = 1.08-1.71], p = 0.0073). MCP-1 G-2518, SDF-1beta A801, and CCR5 Delta32 were not associated with CAD. CONCLUSIONS: RANTES A-403 was associated with CAD independently from conventional risk factors and CRP or fibrinogen as inflammatory biomarkers. The association was enhanced in smokers and ACS, conditions where platelet activation and inflammation predominate. RANTES A-403 may increase genetic susceptibility to CAD.

Case-Control Studies↗
PubMed2004

The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study).

BACKGROUND: Statins and cholesterol absorption inhibitors lower the concentration of C-reactive protein (CRP). The genetic polymorphism of apolipoprotein (apo) E is a strong endogenous determinant of sterol homeostasis. We therefore examined the relationship of CRP to the apoE polymorphism. METHODS AND RESULTS: We studied 739 and 570 subjects with or without stable angiographic coronary artery disease (CAD), respectively. In carriers of apoE2, apoB was lower (P<0.001) than in apoE3/3 homozygotes; in individuals with apoE3/4 and apoE4/4, it was higher (P<0.001). Both in the presence and absence of CAD, CRP was higher in carriers of apoE2 (P=0.002) and apoE3/3 homozygotes (P=0.032) than in individuals with apoE3/4 or apoE4/4. Fibrinogen and white cell count were not related to the apoE genotype. CRP was associated with CAD. Compared to the lowest tertile, crude odds ratios were 1.87 (95% confidence interval (CI), 1.43-2.45, P<0.001) and 2.24 (95% CI, 1.71-2.94, P<0.001) in the second and third tertile. In carriers of apoE2, the use of tertiles defined in controls with apoE2 only diminished the odds ratios for CAD. In apoE3/4 heterozygotes or apoE4/4 homozygotes, the use of tertiles specific for this group only slightly increased the odds ratios. CONCLUSIONS: : The concentration of CRP, but not fibrinogen nor white blood cells is associated with the apoE polymorphism. The activity of the mevalonate pathway in the liver may be related to the metabolism of CRP. The predictive value of CRP for CAD may be modified by the apoE polymorphism.

Aged↗
PubMed2004

American Heart Association scientific sessions.

The Annual Scientific Sessions of the American Heart Association is the leading scientific conference in the cardiovascular field, both for basic and clinical research in cardiology and related disclipines. This report covers the outcome of major clinical trials that were presented in the 'late-breaking' clinical trial sessions. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigated the angiotensin receptor blocker valsartan, the angiotensin-converting enzyme inhibitor captopril, and their combination in 14,703 survivors of an acute myocardial infarction with a reduced left ventricular ejection fraction on clinical outcome. The study demonstrated that valsartan and captopril where equally effective, whereas the combination was associated with an increased risk of side effects without further benefit. VALIANT is a landmark trial because it was the first large study that compared the combination of an angiotensin receptor blocker with an angiotensin-converting enzyme inhibitor in the setting of acute myocardial infarction. Other trials that will be summarised in this report are the Na + /H + Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions Trial (EXPEDITION; cariporide in coronary artery bypass graft surgery), the Reversal of Atherosclerosis with Aggressive Lipid Lowering Trial (REVERSAL; atorvastatin and pravastatin for atherosclerosis reversal), the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation V (SPORTIF V; ximelagatran and warfarin for stroke prevention in atrial fibrillation), the Prophylactic Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularisation (PAPABEAR; amiodarone for the prevention of postoperative atrial fibrillation), the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF; vasopressin 2 antagonist tolvaptan in congestive heart failure) and Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT; fosinopril and pravastatin in microalbuminuric subjects without hypertension or hypercholesterolemia).

American Heart Association↗
PubMed2003

The variable number of tandem repeat polymorphism in the P-selectin glycoprotein ligand-1 gene is not associated with coronary heart disease.

Genes involved in inflammatory processes are candidates for predisposition to prothrombotic syndromes. The variable number of tandem repeat (VNTR) polymorphism in the P-selectin glycoprotein ligand (PSGL)-1 gene has been associated with ischemic cerebrovascular disease but not with coronary heart disease (CHD). We assessed the effect of the VNTR polymorphism on CHD in two independent case/control studies. In the first study 281 CHD patients and 397 healthy blood donors were genotyped for the VNTR alleles in PSGL-1. The prevalence of homozygous carriers of the PSGL-1 VNTR allele with 15 repeat units was significantly higher in the CHD patients (5.3% vs. 1.5%) than in controls, suggesting an effect of this marker in CHD. To validate the findings genotyping was performed in a second study including 2,578 CHD patients, 731 patients without CHD, and 1084 healthy blood donors. The larger case control study had a power of 99.9% to detect the initially observed difference but failed to confirm the putative role of PSGL-1 VNTR polymorphism in CHD. Frequencies of the PSGL-1 VNTR 15 repeats for homozygous carriers were 2.2% in healthy blood donors, 2.3% in patients without CHD and 2.7%, in CHD cases, respectively. These results demonstrate that the PSGL-1 VNTR polymorphism is not a genetic risk factor for CHD. Adequately powered studies are prerequisites to obtain reliable results about genotype-phenotype relationships of new candidate genes in complex diseases.

Adult↗