Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.

BACKGROUND: The management of unruptured intracranial aneurysms is controversial. Investigators from the International Study of Unruptured Intracranial Aneurysms aimed to assess the natural history of unruptured intracranial aneurysms and to measure the risk associated with their repair. METHODS: Centres in the USA, Canada, and Europe enrolled patients for prospective assessment of unruptured aneurysms. Investigators recorded the natural history in patients who did not have surgery, and assessed morbidity and mortality associated with repair of unruptured aneurysms by either open surgery or endovascular procedures. FINDINGS: 4060 patients were assessed-1692 did not have aneurysmal repair, 1917 had open surgery, and 451 had endovascular procedures. 5-year cumulative rupture rates for patients who did not have a history of subarachnoid haemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2. 6%, 14 5%, and 40% for aneurysms less than 7 mm, 7-12 mm, 13-24 mm, and 25 mm or greater, respectively, compared with rates of 2 5%, 14 5%, 18 4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. These rates were often equalled or exceeded by the risks associated with surgical or endovascular repair of comparable lesions. Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes. INTERPRETATION: Many factors are involved in management of patients with unruptured intracranial aneurysms. Site, size, and group specific risks of the natural history should be compared with site, size, and age-specific risks of repair for each patient.

Geographical, linguistic, and cultural influences on genetic diversity: Y-chromosomal distribution in Northern European populations.

We analyzed 10 Y-chromosomal binary markers in 363 males from 8 populations in Northern Europe and 5 Y microsatellites in 346 of these individuals. These populations can be grouped according to cultural, linguistic, or geographical criteria, and the groupings are different in each case. We can therefore ask which criterion best corresponds to the distribution of genetic variation. In an AMOVA analysis using the binary markers, 13% of the Y variation was found between populations, indicating a high level of differentiation within this small area. No significant difference was seen between the traditionally nomadic Saami and the neighboring, historically farming, populations. When the populations were divided into Uralic speakers and Indo-European speakers, 8% of the variation was found between groups, but when they were divided according to geographical location, 14% of the variation was between groups. Geographical factors have thus been the most important in limiting gene flow between these populations, but linguistic differences have also been important in the east.

Y-chromosomal diversity in Europe is clinal and influenced primarily by geography, rather than by language.

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift.

Manganese-containing superoxide dismutase signal sequence polymorphism associated with sporadic motor neuron disease.

An alanin-9valin (Ala-9Val) polymorphism in the mitochondrial targeting sequence of manganese-containing superoxide dismutase (Mn-SOD) has recently been described. We studied this polymorphism in 72 Swedish patients with sporadic motor neuron diseases (MND) and controls using an oligonucleotide ligation assay. There were significant differences in genotype between MND patients and controls (P = 0.025), and between male and female MND patients (P = 0.009). Individuals homozygous for the Ala allele had a higher risk for MND [odds ratio, 2.9; 95% confidence interval (CI), 1.3-6.6], which was increased when including only females in the analysis (odds ratio, 5.0; 95% CI, 1.8-14.0). In classical amyotrophic lateral sclerosis, the odds ratio was 3.8 (95% CI, 1.3-10.0), and 5. 5 (95% CI, 1.5-19.9) when including only females. The results suggest that mutations influencing the cellular allocation of Mn-SOD may be a risk factor in MND, especially in females, and that MND may be a disease of misdistribution of the superoxide dismutase enzymes.

Ethnic variation in the mitochondrial targeting sequence polymorphism of MnSOD.

In contrast to CuZn superoxide dismutase (SOD), only a very limited number of mutations have been described in MnSOD. One interesting example is a polymorphism (Ala-9Val) in the mitochondrial targeting sequence of this radical-scavenging enzyme. We have studied the Ala-9Val polymorphism in various ethnic groups by means of the oligonucleotide ligation assay. There were significant variations in this unique polymorphism between three different language groups: Baltic (Lithuanians), Finnic (Finns and Saamis) and Germanic (Swedes). The Ala frequency in an Asiatic population (Chinese) was significantly lower than in most European populations. This polymorphism may affect the mitochondrial targeting rate of MnSOD which may result in mitochondrial damage with implication in various late-onset neurological diseases.

alpha1-antitrypsin (PI) alleles as markers of Westeuropean influence in the Baltic Sea region.

The distribution of alpha1-antitrypsin (PI) alleles was studied in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. The frequency of the PI Z allele, a typically Northwesteuropean marker gene, showed a highly significant regional variation in the Baltic Sea region. The highest frequency (4.5%) was found in the western part of Latvia (Courland). The PI S allele, another marker of Westeuropean influence, also showed an increased frequency in the Courland population. These results indicate that among the populations east of the Baltic Sea the Curonian population has the most pronounced Westeuropean influence. Archaeological data have shown that from the 7th century and for several hundreds of years Courland received immigrations from mainland Sweden and the island of Gotland. We speculate that the increased frequencies of the PI Z alleles and S alleles in Courland may have been caused by these migrations.

Transferrin variants as markers of migrations and admixture between populations in the Baltic Sea region.

Transferrin (TF) types were examined by isoelectric focusing in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. A highly significant heterogeneity between populations was found with respect to TF*C subtypes as well as the rare TF variants B2, B0-1 and DCHI. With the exception for Estonia, increased frequencies of the TF*C3 allele were observed east of the Baltic Sea. The island of Gotland in the middle of the Baltic Sea also showed a high TF*C3 frequency indicating an eastern influence. The TF*DCHI allele, a marker of eastern (Finno-Ugric) influence, was found in Finland and Estonia and on the island of Gotland, but not in mainland Sweden and in the Baltic peoples (Latvians and Lithuanians). These results indicate the presence of a Finno-Ugric, most likely Estonian or Livonian, genetic influence in the Gotland population.

The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe.

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co-receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delta ccr5 allele was investigated in 18 European populations. A North to South gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%). Highly polymorphic microsatellites (IRI3.1, D3S4579 and IRI3.2, D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant. A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3.1 and IRI3.2 microsatellites: >95% of the Delta ccr5 chromosomes carried the IRI3.1-0 allele, while 88% carried the IRI3.2-0 allele. These alleles were found respectively in only 2 or 1.5% of the chromosomes carrying a wild-type CCR5 gene. From these data, it was inferred that most, if not all Delta ccr5 alleles originate from a single mutation event, and that this mutation event probably took place a few thousand years ago in Northeastern Europe. The high frequency of the Delta ccr5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with homo- or heterozygous carriers of the Delta ccr5 allele.

Effect of p53 alleles on placental weight.

The relationship between three p53 polymorphisms (BstUI and MspI RFLPs in exon 4 and intron 6, respectively, and a 16-bp duplication in intron 3) in placental tissue and placental weight was examined in an attempt to elucidate the effect of p53 alleles on non-malignant growth. Placental tissue is expressing the fetal genotype. Using the quantitative trait loci approach, allelic frequencies of the three p53 polymorphisms and ten alleles at other loci (ABO, PLAP, GC and ACP1) were compared for the high (> or = 700 g) and low (< 400 g) tails (+/- 1.4 SD) of the placental weight distribution in a Swedish sample of newborns. Significant associations were found in the three p53 polymorphisms examined but not for the other loci, suggesting that non-malignant cell growth may be influenced by polymorphic p53 variants. High placental weight was associated with increased frequencies of the 16-bp duplication (A2 allele), the codon 72 BstUI A1 (pro) allele and the MspI A1 allele. These three alleles were in strong linkage disequilibria, and high placental weight was therefore associated with the 2-1-1 haplotype. The fact that the strongest associations were found with intronic markers suggests linkage disequilibrium with growth-promoting sites at the p53 molecule as the most likely mechanism, although a direct functional involvement of the codon 72 pro/arg substitution in normal cell growth cannot be excluded.

Association between the p21 codon 31 A1 (arg) allele and lung cancer.

In previous investigations p53 polymorphisms and haplotypes have been found to be associated with different types of cancer. In this paper the codon 31 polymorphism of the p53-inducible protein p21 was studied in 144 Swedish lung cancer patients and two different control groups: 95 patients with chronic obstructive pulmonary disease (COPD) and 761 healthy controls. An increased frequency of the p21 codon 31 A1 (arg) allele was found in lung cancer patients, especially in comparison with COPD patients (p = 0.004). There was a significantly increased frequency among lung cancer patients of individuals carrying the arg allele both in comparison with COPD controls (OR = 5.2, 95% CI 1.5-18.1) and healthy controls (OR = 1.7, 95% CI = 1.0-2.9). The results of this and previous studies indicate that allelic variants of both p53 and its effector protein p21 may have an influence on lung cancer.

p53 polymorphisms and haplotypes in breast cancer.

Three polymorphisms in the human tumor suppressor gene p53 (BstUI and MspI RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotype combinations were studied in patients with breast cancer and controls. A significant increase in the codon 72 BstUI A1 (pro) allele frequency (P = 0.016) and of individuals carrying the pro allele (pro/pro and pro/arg) (OR, 1.47; P = 0.01 4; 95 % CI, 1.08-2.00) was observed in breast cancer. This increase was most pronounced in highly differentiated breast cancer. Significant associations were found only in BstUI and haplotypes containing this polymorphism, which indicates that the codon 72 pro allele may be functionally involved in low malignancy breast cancer. The distributions of genotypic combinations in breast cancer patients and controls were significantly different (P = 0.005). Two BstUI-16 bp-MspI combinations were significantly overrepresented; 2-1, 1-1, 2-2 (OR, 1.61; 95% CI, 1.13-2.30) and 1-1, 2-1, 2-1 (OR, 2.94; 95% CI, 1.37-6.27).

The codon 31 polymorphism of the p53-inducible gene p21 shows distinct differences between major ethnic groups.

The codon 31 polymorphism of the p53-inducible protein p21 was studied with respect to allele frequency variations between some major ethnic groups. The frequency of the Al (Arg) allele showed highly significant variations ranging from 4% in Caucasians (Swedes) to 50% in Chinese. Compared to Caucasians, a relatively high frequency was found in African Blacks (29%) and Indians (16%). Furthermore, Finns and Mordvinians also had higher frequencies (9-10%) than west Europeans (French and Swedes), consistent with an Asiatic Mongoloid influence known to exist in Finno-Ugrian tribes. The geographic allele frequency patterns of p53 and its effector protein p21 were quite different. The p21 A1 mutations in African, Asiatic and European populations were identical at the DNA level. The geographical distribution of the A1 allele suggests an independent origin in Africa and Asia. The very pronounced ethnic differentiation of tumour suppressor genes and the fact that tumour suppressor genes may be teratogenes suggest that these polymorphisms are maintained by natural selection, probably operating in the intrauterine period.

p53 polymorphisms and haplotypes in nasopharyngeal cancer.

Three p53 DNA polymorphisms (BstUI and MspI RFLPs in exon 4 and intron 6, respectively, and a 16-bp duplication in intron 3) and their haplotype combinations were studied in 73 patients (61 males and 12 females) with nasopharyngeal cancer and 105 healthy controls from the Guizhou province in southern China. Increased frequencies of the 16-bp A2 allele (p = 0.005), MspI A1 allele (p = 0.021) and the BstUI A1 (Pro) allele (p = 0.072) were found among the patients, with more pronounced differences in male patients (p = 0.003, 0.014 and 0.052, respectively). Haplotype frequencies and linkage disequilibria differed from those in Caucasians. The differences between controls and patients, especially male patients, increased when the analysis was based on haplotypes. The lowest risk for nasopharyngeal cancer was associated with the haplotype 16-bp A1, BstUI A2, MspI A2 (1-2-2). A somewhat higher risk was observed in the 1-1-2 haplotype (replacing the Arg with a Pro allele). The highest risk was, however, found in the rare combinations including the 16-bp A2 and MspI A1 alleles with an odds ratio of 4.9 [95% confidence interval (CI) = 1.8-13.2] in all patients and 5.4 (95% CI = 2.0-14.8) in male patients. The haplotype associations found in this study differ from those found in previous cancer association studies in Caucasians. This together with the fact that the intronic markers conferred the highest risk figures suggest that the mechanism behind the observed associations is linkage disequilibrium and not direct functional involvement of the codon 72 alleles.

p53 polymorphisms and haplotypes show distinct differences between major ethnic groups.

Three different p53 DNA polymorphisms (a 16-bp duplication in intron 3 and BstUI and MspI RFLPs in exon 4 and intron 6, respectively) and haplotype combinations were studied in some major ethnic groups: Caucasians (Swedes), Chinese, Dravidian Indians and African Blacks. Significant ethnic differences in single polymorphisms were found between all groups except for African Blacks-Dravidian Indians, who differed only in their MspI7-16-bp duplication haplotype distribution. Since previous results have shown that p53 alleles are correlated with latitude (degree of insolation), the similarity between these two groups, who are genetically quite distinct, may be due to ecological adaptation to similar climatic conditions. All other major ethnic groups differed significantly from each other with respect to their haplotype distributions; thus, p53 alleles and haplotypes should be very useful as anthropological markers. Asiatic Mongoloid groups appear to be characterized by very low frequencies of the 16-bp duplication and the MspI A1 allele. These mutations have probably been introduced by migration to east Asia from either Europe or Africa, where the highest frequencies were found. The results of this study indicate that p53, besides its role as a tumor suppressor, shows distinct ethnic heterogeneity and may be involved in ecological (climatic) adaptation.

P53 polymorphisms and haplotypes in lung cancer.

An association between the BstU I 1-1 (Pro-Pro) genotype of the p53 codon 72 polymorphism and lung cancer has previously been reported by Kawajiri et al. A reanalysis of the data by Kawajiri et al. revealed no significant difference between patients and controls with respect to allele frequencies, and the increased frequency of BstU I 1-1 homozygotes was mostly ascribable to a deviation from the Hardy-Weinberg equilibrium. In an attempt to replicate the results by Kawajiri et al. we have studied three p53 polymorphisms (BstU I and Msp I RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotypes in Swedish lung cancer patients and controls. The results concerning the codon 72 polymorphism were largely negative. Thus there was no significant association between lung cancer and the BstU I 1-1 type, and only a marginal difference (P = 0.044) with respect to the BstU I allele frequency when lung cancer patients were compared with patients with chronic obstructive pulmonary disease (COPD). However, when the analysis was based on haplotype frequencies larger differences appeared and it was found that only BstU I 1 (pro) alleles linked to 16 bp 1 alleles were associated with lung cancer. Pro alleles linked to the 16 bp duplication appeared instead to confer some protection against cancer. Thus the codon 72 alleles need not be functionally involved in lung cancer, but may rather be markers in linkage disequilibrium with other cancer susceptibility sites on p53.

P53 germ line haplotypes associated with increased risk for colorectal cancer.

Three p53 DNA polymorphisms (BstU I and Msp I restriction fragment length polymorphisms (RFLPs) in exon 4 and intron 6 respectively, and a 16 bp duplication in intron 3) and their haplotype combinations were studied in patients with colorectal cancer and compared with patients with ulcerative colitis and healthy controls. There were only minor differences between patients with ulcerative colitis and controls, the only significant difference was observed in the distribution of BstU I-Msp I haplotypes. When single polymorphisms were studied, a significantly lower frequency of the 16 bp duplication was found in patients with colorectal cancer. The protective effect of the 16 bp duplication was more pronounced in haplotype combinations with the BstU I A1 and Msp I A1 alleles, whereas these alleles in combination with the 16 bp A1 allele (no duplication) were associated with an increased risk for colorectal cancer. The genotypic combination BstU I 2-1, 16 bp 1-I, Msp I 2-1 was found in 8.4% of cases among patients with colorectal cancer and 0.5% of cases in the controls (odds ratio = 18.8). The extended haplotype responsible for the high cancer risk of this genotype appears to be BstU I A1-16 bp A1-Msp I A1. The results of this study indicate that the haplotype approach to the identification of p53 germ line alleles associated with increased susceptibility to cancer is far more powerful than the analysis of single polymorphisms, since the capacity to identify germ line alleles predisposing to cancer should increase with the number of polymorphic sites included in the analysis.

p53 polymorphisms and haplotypes in different ethnic groups.

Three different p53 polymorphisms (a codon 72 BstUI RFLP, a 16-bp duplication in intron 3 and an MspI RFLP in intron 6) and haplotype combinations were studied in three northern European populations, viz. Finns, Swedes and Swedish Saamis. Significant ethnic differences were found in the codon 72 and 16-bp polymorphisms. The three polymorphisms were in strong linkage disequilibria, all of which were highly significant (p < 1 x 10(-18)), and ethnic differences with respect to linkage disequilibria were observed. Estimates of the frequencies of extended haplotypes showed that the most common ('wild-type') haplotype in the three populations was 2-1-2, viz, the codon 72 Arg allele linked to absence of the 16-bp duplication and presence of the MspI site. There were two additional common haplotypes, 1-1-2 and 1-2-1, and five rare haplotypes with a combined frequency of about 0.03. The present results indicate that extended haplotypes would be more informative in studies of population differences and associations between p53 germline mutations and cancer.

Placental alkaline phosphatase types and transplacental IgG transport.

Recently, results have been presented which suggest that placental alkaline phosphatase (PLAP) is an IgG receptor, and that the transplacental transport of IgG from mother to fetus is dependent on the fetal PLAP genotype. In order to confirm the relationship between the PLAP types and transplacental IgG transport, we studied fetal (cord serum) IgG levels in relation to PLAP types, quantitative variations in PLAP activity, maternal IgG levels and gestation length. Fetal IgG levels and the fetal/maternal IgG ratio showed no significant correlation with PLAP types and PLAP activity. Thus differences between PLAP types with respect to transplacental IgG transport are unlikely to play a selective role in the maintenance of the PLAP polymorphism. In accordance with results from previous studies, significant correlations were found with maternal IgG levels and gestation length. Perusal of the literature suggests that PLAP is mainly an IgG1 receptor.

Is p53 polymorphism maintained by natural selection?

We present here a new interesting feature of the human tumor suppressor gene p53: a very pronounced ethnic and clinal variation of polymorphic codon 72 alleles. The frequency of the A1 (Pro) allele showed a north-south cline from 17% in Swedish Saamis to 63% in African Blacks (Nigerians), and there was a significant (p < 0.001) correlation (r = 0.95) between the A2 frequency and latitude. In the Finnish and Swedish populations no significant differences were found with respect to the genotype and allele distributions in spontaneously aborted fetuses and liveborn children, which makes differential intrauterine selection unlikely. However, the ethnic and clinal variations suggest that the codon 72 polymorphism is balanced and maintained by natural selection.