Risk Factors For Intracranial Aneurysms Research Articles

Incidence and risk factors of intracranial aneurysm: A national cohort study in Korea.

Background Estimations of the intracranial aneurysm incidence require long-term follow-up of a relatively large at-risk population; as a result, the incidence remains largely unknown. Aims To investigate the national incidence of intracranial aneurysm in a Korean population. Methods After excluding 18,604 potential subjects with a previous history of stroke (I6x.x), 998,216 subjects were included in this observational cohort. The primary endpoint was the earliest date of diagnosis of either unruptured intracranial aneurysm (UIA; I67.1) or subarachnoid hemorrhage (SAH; I60.x). We collected anthropometric data, blood pressure measurements, laboratory data, and smoking, drinking, and physical exercise habits of 132,355 subjects for whom healthcare screening data were available. Factors influencing intracranial aneurysm were evaluated via multivariate Cox regression. Results The overall observation size was 8,792,214 person-years. During follow-up, 4346 subjects were diagnosed with intracranial aneurysm (SAH, 1960; UIA, 2386). The crude incidence of intracranial aneurysm was 49.4/100,000 person-years. The hazard ratio for women was 1.56 ( p < 0.01), and older subjects had an increased hazard ratio. Subjects with hypertension had an approximately 1.5-fold higher risk of intracranial aneurysm. A history of heart disease and family history of stroke were associated with respective hazard ratios of 2.08 and 1.77. Conclusions In this Korean population study, the standardized incidence of intracranial aneurysm was 52.2/100,000 person-years. Older age, female sex, hypertension, history of heart disease, and family history of stroke were independent risk factors for intracranial aneurysm.

Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.

Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.

Prevalence of Intracranial Aneurysms in Patients with Aortic Aneurysms.

Previous studies have suggested an association between aortic aneurysms and intracranial aneurysms with a higher prevalence of intracranial aneurysms in patients with aortic aneurysms. The aims of the present study were to evaluate the incidence of intracranial aneurysms in a large cohort of patients with aortic aneurysms and to identify potential risk factors for intracranial aneurysms in this population. We included all patients with aortic aneurysms (either abdominal and/or thoracic) who had available cerebral arterial imaging and were seen at our institution during a 15-year period. We identified patients with intracranial aneurysms. Patient demographics, comorbidities, and aortic aneurysm and intracranial aneurysm sizes and locations were analyzed. Univariate analysis was performed with a χ(2) test for categoric variables and a Student t test or ANOVA for continuous variables. A total of 1081 patients with aortic aneurysms were included. Of them, 440 (40.7%) had abdominal aortic aneurysms, 446 (41.3%) had thoracic aortic aneurysms, and 195 (18.0%) had both abdominal aortic and thoracic aortic aneurysms. The overall prevalence of associated intracranial aneurysms in patients with aortic aneurysms was 11.8% (128/1081), with 12.7% (56/440), 10.8% (48/446), and 12.3% (24/195), respectively, in patients with abdominal aortic aneurysms, thoracic aortic aneurysms, and both thoracic aortic aneurysms and abdominal aortic aneurysms. Female patients had a higher risk of associated intracranial aneurysms (OR = 2.08; 95% CI, 1.49-3.03; P = .0002). There was a slight association between abdominal aortic aneurysm size and the prevalence of intracranial aneurysms (OR = 1.02; 95% CI, 1.01-1.03; P = .045). There was no significant association between the locations of the aortic and intracranial aneurysms (P = .93). The prevalence of intracranial aneurysms is high in patients with aortic aneurysms. Further studies examining the role and cost-effectiveness of intracranial aneurysm screening in patients are warranted.

Hypertension and Estrogen Deficiency Augment Aneurysmal Remodeling in the Rabbit Circle of Willis in Response to Carotid Ligation.

Increased cerebral blood flow has been shown to induce pathological structural changes in the Circle of Willis (CoW) in experimental models. Previously, we reported flow-induced aneurysm-like remodeling in the CoW secondary to flow redistribution after bilateral common carotid artery (CCA) ligation in rabbits. In the current study, we tested the hypothesis that loading rabbits with biological risk factors for vascular disease would increase flow-induced aneurysmal remodeling in the CoW. In the same series as the previously-reported bilateral CCA-ligation-alone (n = 6) and sham surgery (n = 3) groups, eight additional female rabbits (the experimental group in this study) were subjected to two risk factors for intracranial aneurysm (hypertension and estrogen deficiency) and then bilateral CCA ligation. Upon euthanasia at 6 months, vascular corrosion casts of the CoW were created and analyzed by scanning electron microscopy for morphological changes and aneurysmal damage. In rabbits with hypertension and estrogen deficiency, arterial caliber increased throughout the CoW, similar to rabbits with CCA ligation alone. However, aneurysmal remodeling (i.e., local bulging) in the CoW was significantly greater than in CCA-ligation-only rabbits and was more widespread, presenting in regions that did not show aneurysmal changes after CCA ligation alone. Furthermore, hypertension and estrogen deficiency caused greater increases in vessel length and tortuosity. These results suggest that hypertension and estrogen deficiency make the CoW more vulnerable to flow-induced aneurysmal remodeling and tortuosity. We propose they do so by lowering the tolerance of vascular tissue to hemodynamic forces caused by CCA ligation, thus lowering the threshold necessary to incite vascular damage.

Genetic Determinants of Unruptured Intracranial Aneurysms in the General Population.

Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for intracranial aneurysms in clinical samples. In addition, SNPs have been discovered for blood pressure, one of the strongest risk factors for intracranial aneurysms. We studied the role of these genetic variants on occurrence and size of unruptured intracranial aneurysms, discovered incidentally in a general community-dwelling population. In 4890 asymptomatic participants from the Rotterdam Study, 120 intracranial aneurysms were identified on brain imaging and segmented for maximum diameter and volume. Genetic risk scores (GRS) were calculated for intracranial aneurysms (10 SNPs), systolic blood pressure (33 SNPs), and diastolic blood pressure (41 SNPs). The GRS for intracranial aneurysms was not statistically significantly associated with presence of aneurysms in this population (OR, 1.16; 95% CI, 0.96-1.40; P=0.119), but showed a significant association with both maximum diameter (difference in log-transformed mm per SD increase of GRS, 0.10; 95% CI, 0.02-0.19; P=0.018) and volume (difference in log-transformed µL per SD increase of GRS, 0.21; 95% CI, 0.01-0.41; P=0.040) of aneurysms. GRSs for blood pressures were associated with neither presence nor size of aneurysms. Genetic variants previously identified for intracranial aneurysms in clinical studies relate to the size rather than the presence of incidentally discovered, unruptured intracranial aneurysms in the general population.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Sex-related clustering of intracranial aneurysms within families.

Family history is important risk factor for intracranial aneurysms (ICA), but the pattern of inheritance is unsettled. If ICA within families would cluster according to sex, this may have implications for risk prediction and screening advice within families. We assessed the relationship between the sex of probands and their affected first-degree relatives (FDRs) within families with ICA. We used data from our prospectively collected database of families with known familial ICA. We calculated relative risks for a female affected proband having a female affected FDR as compared with a male affected proband having female affected FDR with corresponding 95% confidence intervals. We included 148 families with 376 affected FDR. For a female proband the relative risk for having a female affected FDR compared with a male proband having an affected female FDR was 1.2 (95% confidence interval, 1.0-1.6). The clustering of ICA within families is greater in women than in men, with an excess of affected female FDR in female probands. However, because this excess is modest, our findings indicate that sex is not a relevant factor in risk prediction or screening advice in families with ICA.

Intracranial Aneurysms In Autosomal Dominant Polycystic Kidney Disease: A Nephrologist’s Perspective

Autosomal dominant polycystic kidney disease (ADPKD) belongs to the most common genetic disorders, and affects approximately 1 in 1,000 people in the general population. It is well-known risk factor for intracranial aneurysms (IAs). However, universal screening for IAs in ADPKD patients remains controversial. Nevertheless, to improve patients’ outcomes, patients at risk for IAs should be identified, screened, and prophylactically treated if required. From the point of view of a nephrologist, it is crucial to answer two questions: (1) which ADPKD patients should undergo screening for IAs; and (2) how this screening should be done. These issues are discussed in the paper.

Intracranial aneurysm risk factor genes: relationship with intracranial aneurysm risk in a Chinese Han population.

Few studies have examined the genes related to risk fac-tors that may contribute to intracranial aneurysms (IAs). This study in Chinese patients aimed to explore the relationship between IA and 28 gene loci, proven to be associated with risk factors for IA. We recruited 119 patients with aneurysms and 257 controls. Single factor and logistic regression models were used to analyze the association of IA and IA rup-ture with risk factors. Twenty-eight single nucleotide polymorphisms (SNPs) in 22 genes were genotyped for the patient and control groups. SNP genotypes and allele frequencies were analyzed by the chi-square test. Logistic regression analysis identified hypertension as a factor that increased IA risk (P = 1.0 x 10(-4); OR, 2.500; 95%CI, 1.573-3.972); IA was associated with two SNPs in the TSLC2A9 gene: rs7660895 (P = 0.007; OR, 1.541; 95%CI, 1.126-2.110); and in the TOX gene: rs11777927 (P = 0.013; OR, 1.511; 95%CI, 1.088-2.098). Subsequent removal of the influence of family relationship identified between 12 of 119 patients enhanced the significant association of these SNPs with IA (P = 0.001; OR, 1.691; 95%CI, 1.226-2.332; and P = 0.006; OR, 1.587; 95%CI, 1.137-2.213 for rs7660895 and rs11777927, respectively). Fur-thermore, the minor allele of rs7660895 (A) was also associated with IA rupture (P = 0.007; OR, 2.196; 95%CI, 1.230-3.921). Therefore, hypertension is an independent risk factor for IA. Importantly, the TSL-C2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of IAs, and rs7660895 may be associated with IA rupture.

A variant in the endoglin gene is associated with the development of sporadic intracranial aneurysms.

Intracranial aneurysms (IAs) are acquired lesions in the brain and can pose potential risk of rupture leading to subarachnoid hemorrhage. Endoglin plays a pivotal role in the vascular development and disease. Variations of endoglin gene have been shown to be risk factors for IAs in different racial population. In the present study, we investigated the correlation between polymorphism in the endoglin gene with IAs in Chinese Han population. The association of endoglin D366H variant (rs1800956) with sporadic IAs was tested in 313 patients with intracranial aneurysms, and 450 controls. The difference in allelic frequency between patients and control group was evaluated with the chi-square test. The frequency of the GG+CG genotype of rs1800956 was significantly higher in patients with IAs than in controls [22.0% vs 15.3%, P = .018; crude OR(odds ratio), 1.56; 95% CI(confidence interval), 1.08-2.26]. Multivariate analysis showed that rs1800956G conferred a risk to IAs [adjusted OR, 1.56 [95% CI, 1.08-2.26]; P=.019], independent of conventional factors, including age, sex, blood pressure, smoking, and alcohol consumption. The variant rs1800956 of endoglin might raise the risk of sporadic IAs among individuals of Chinese Han ethnicity.

Association of Kallikrein gene polymorphisms with sporadic intracranial aneurysms in the Chinese population

Variants of Kallikreins have been shown to be risk factors for intracranial aneurysm (IA) in a Finnish population. In the present study, the authors investigated the correlation between polymorphisms in the Kallikrein gene cluster and IAs in the Chinese population. The association of Kallikrein variants (rs1722561 and rs1701946) with sporadic IAs was tested in 308 cases and 443 controls. The differences in allelic frequencies between patients and the control group were evaluated with the chi-square test. The C allele of rs1722561 showed a significant reduction in the risk of sporadic IA (OR 0.71, 95% CI 0.53-0.95; p = 0.023). However, no association of the variant rs1701946 with sporadic IA was found (OR 0.78, 95% CI 0.57-1.06; p = 0.115). The variant rs1722561 of Kallikreins might reduce the risk of sporadic IAs among individuals of Chinese Han ethnicity. This study confirms the association between Kallikreins and IAs.

Vascular endothelial growth factor: Genetic polymorphisms in patients with intracranial aneurysm and its relation to hypertension and diabetes mellitus

Background: Vascular Endothelial Growth Factor (VEGF) is an important regulator and genetic marker of vasculogenesis and angiogenesis. VEGF polymorphisms are/INS; considered as risk factors for intracranial aneurysm (IA). Objective/INS;: Analize VEGF polymorphism, lifestyle and comorbidities in the Brazilian casuistic with IA.

The Association Between Genetic Risk Factors and the Size of Intracranial Aneurysms at Time of Rupture

Genetic risk factors for intracranial aneurysms may influence the size of aneurysms. To assess the association between genetic risk factors and the size of aneurysms at the time of rupture. Genotypes of 7 independent single-nucleotide polymorphisms (SNPs) of the 6 genetic risk loci identified in genome-wide association studies of patients with intracranial aneurysms were obtained from 700 Dutch patients with an aneurysmal subarachnoid hemorrhage (1997-2007) previously genotyped in the genome-wide association studies; 255 additional Dutch patients with an aneurysmal subarachnoid hemorrhage (2007-2011) were genotyped for these SNPs. Aneurysms were measured on computerized tomography angiography or digital subtraction angiography. The mean aneurysm size (with standard error) was compared between patients with and without a genetic risk factor by the use of linear regression. The association between SNPs and size was assessed for single SNPs and for the combined effect of SNPs by using a weighted genetic risk score. Single SNPs showed no association with aneurysm size, nor did the genetic risk score. The 6 genetic risk loci have no major influence on the size of aneurysms at the time of rupture. Because these risk loci explain no more than 5% of the genetic risk, other genetic factors for intracranial aneurysms may influence aneurysm size and thereby proneness to rupture.

Independent Risk Factors for Intracranial Aneurysms and Their Joint Effect: A Case-Control Study: Vlak M, Rinkel G, Greebe P, Algra A. Stroke 2013;44:984–7.

Independent Risk Factors for Intracranial Aneurysms and Their Joint Effect: A Case-Control Study: Vlak M, Rinkel G, Greebe P, Algra A. Stroke 2013;44:984–7.

Genetic risk factors for intracranial aneurysms

There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain. We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses. Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31). Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status).

Independent Risk Factors for Intracranial Aneurysms and Their Joint Effect

Three percent of the population has an unruptured intracranial aneurysm (UIA). We aimed to identify independent risk factors from lifestyle and medical history for the presence of UIAs and to investigate the combined effect of well-established risk factors. We studied 206 patients with an UIA who never had a subarachnoid hemorrhage and 574 controls who were randomly retrieved from general practitioner files. All participants filled in a questionnaire on potential risk factors for UIAs. With logistic regression analysis, we identified independent risk factors for UIA and assessed their combined effect. Independent risk factors were current smoking (odds ratio [OR], 3.0; 95% confidence interval [CI], 2.0-4.5), hypertension (OR, 2.9; 95% CI, 1.9-4.6), family history of stroke other than subarachnoid hemorrhage (OR, 1.6; 95% CI, 1.0-2.5), hypercholesterolemia (OR, 0.5; 95% CI, 0.3-0.9), and regular physical exercise (OR, 0.6; 95% CI, 0.3-0.9). The joint risk of smoking and hypertension was higher (OR, 8.3; 95% CI, 4.5-15.2) than the sum of the risks independently. Current smoking, hypertension, and family history of stroke increase the risk of UIA, with smoking and hypertension having an additive effect, whereas hypercholesterolemia and regular physical exercise decrease this risk. A healthy lifestyle probably reduces the risk of UIA and thereby possibly also that of aneurysmal subarachnoid hemorrhage. Whether smoking and hypertension increase the risk of aneurysmal subarachnoid hemorrhage only through an increased risk of aneurysm formation or also through an increased risk of rupture remains to be established.

A functional variant of the collagen type III alpha1 gene modify risk of sporadic intracranial aneurysms

Abnormalities in type III collagen in the arterial walls cause certain familial intracranial aneurysms (IAs); however, it remains unknown whether COL3A1 variants contribute to the risk of sporadic IAs. To study whether COL3A1 variants are associated with sporadic IAs, the association of COL3A1 variants with sporadic IAs was tested in 298 cases and 488 controls, replicated in an independent population of 192 cases and 1,690 controls, and further verified in 633 patients with intra-cerebral hemorrhage, 1,074 hypertensives, and 1,883 controls. We found that allele A of SNP rs1800255 conferred a 1.71-fold increased risk for IAs (adjusted odds ratio: OR = 1.71, 95% confidence interval: CI 1.19-2.45, P = 0.004) and results in an amino acid change of Ala698Thr, which led to a lower thermal stability of the peptide. These results were confirmed in the independent study. The associations were independent of the presence of hemorrhagic stroke and hypertension. These results support the view that the functional variant of COL3A1 is genetic risk factors for IAs in the Chinese population.

Relationship between polymorphism of methylenetetrahydrofolate reductase gene and plasma homocysteine level with Intracranial aneurysm

0bjective To explore relationship between plasma homocysteine(Hcy) level and polymorphism of methylenetetrahydrofolate reductase gene(MTHFR) with intracranial aneurysm.Methods The genotyes of MTHFR were determined by PCR-based assay and their plasma Hcy levels were determined in 76 patients with intracranial aneurysm and 77 healthy controls. Results There were significant differences in the CT genotype frequenceies of MTHFR mutations between the patients and central groups(P＜0.01). Mean total plasma Hcy concentrations were significantly higher in intracranial aneurysm patients than those in the normal subjects. Conclusion Hyperhomocysteinemia may be independent risk factors for intracranial aneurysm and MTHFR CT genotype may be independent risk factors for intracranial aneurysm. Key words: Homocysteine; Methylenetetrahydrofolate reductase; Intracranial aneurysm; Polymorphism

From GWAS to the clinic: risk factors for intracranial aneurysms

Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating subset of stroke, occurring in relatively young people (mean age around 50 years) of whom around a third die within the initial weeks after the bleed. Environmental and genetic risk factors both have a role in SAH. A recent genome-wide association study of intracranial aneurysms in Finnish, Dutch and Japanese cohorts totaling 5,891 cases and 14,181 controls identified three new loci strongly associated with intracranial aneurysms on chromosomes 18q11.2 and 10q24.32, and replicated two previously found loci on chromosomes 8q11.23-q12.1 and 9p21.3. However, these five intracranial aneurysm risk loci identified so far explain only up to 5% of the familial risk of intracranial aneurysms, which makes genetic risk prediction tests currently unfeasible for intracranial aneurysms. New approaches, including identification of causal variants, rare variants and copy number variants, such as insertions and deletions, may improve genetic risk prediction for SAH and intracranial aneurysms. This may lead to diagnostic tools for identifying individuals at increased risk for aneurysm formation and rupture of aneurysms. In this way, genetic diagnostic tools will identify the people who will benefit most from screening by imaging studies for aneurysms and those who are most likely to benefit from preventive treatment of incidentally discovered aneurysms.

Systematic review of reviews of risk factors for intracranial aneurysms

Systematic reviews of systematic reviews identify good quality reviews of earlier studies of medical conditions. This article describes a systematic review of systematic reviews performed to investigate factors that might influence the risk of rupture of an intracranial aneurysm. It exemplifies the technique of this type of research and reports the finding of a specific study. The annual incidence of subarachnoid haemorrhage resulting from the rupture of intracranial aneurysms is estimated to be nine per 100,000. A large proportion of people who have this bleed, will die or remain dependent on the care of others for some time. Reliable knowledge about the risks of subarachnoid haemorrhage in different populations will help in planning, screening and prevention strategies and in predicting the prognosis of individual patients. If the necessary data were available in the identified reviews, an estimate for the numerical relationship between a particular characteristic and the risk of subarachnoid haemorrhage was included in this report. The identification of eligible systematic reviews relied mainly on the two major bibliographic databases of the biomedical literature: PubMed and EMBASE. These were searched in 2006, using specially designed search strategies. Approximately 2,000 records were retrieved and each of these was checked carefully against the eligibility criteria for this systematic review. These criteria required that the report be a systematic review of studies assessing the risk of subarachnoid haemorrhage in patients known to have an unruptured intracranial aneurysm or of studies that had investigated the characteristics of people who experienced a subarachnoid haemorrhage without previously being known to have an unruptured aneurysm. Reports which included more than one systematic review were eligible and each of these reviews was potentially eligible. The quality of each systematic review was assessed. In this review, 16 separate reports were identified, including a total of 46 eligible systematic reviews. These brought together research studies for 24 different risk factors. This has shown that the following factors appear to be associated with a higher risk of subarachnoid haemorrhage: being a woman, older age, posterior circulation aneurysms, larger aneurysms, previous symptoms, "non-white" ethnicity, hypertension, low body mass index, smoking and alcohol consumption of more than 150 g per week. The following factors appear to be associated with a lower risk of subarachnoid haemorrhage: high cholesterol, diabetes and use of hormone replacement therapy.