Chiara Scapoli

A genetic association study of dopamine metabolism‐related genes and chronic headache with drug abuse

To assess the role of dopamine metabolism‐related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono‐amino‐oxidase A (MAOA) and cathecol‐O‐methyl‐transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.

A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes

Abstract. We assessed the role of some dopamine metabolism genes in the genetic susceptibility to migraine. We performed an association study using three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine receptor gene (DRD4), a 40-bp tandem repeat in the dopamine transporter gene (DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase (DBH) gene. Allelic and genotypic frequencies for each polymorphism were assayed in two migraine populations (93 individuals with migraine with aura (MA) and 101 with migraine without aura (MO)) and were compared with those in a control group (117 individuals). No significant differences were found between control and migraine groups for DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene in the MO group was significantly different from those in both MA and control groups, with the shortest and longest alleles being less frequent in MO. Our data indicate that MO, but not MA, shows significant genetic association with DRD4.

Validation of reported genetic risk factors for periodontitis in a large-scale replication study.

AIM Many studies investigated the role of genetic variants in periodontitis, but few were established as risk factors. We aimed to validate the associations of recent candidate genes in aggressive periodontitis (AgP). MATERIAL AND METHODS We analysed 23 genes in 600 German AgP patients and 1441 controls on the Illumina custom genotyping array Immunochip. We tested a suggestive association in a Dutch and German/Austrian AgP case-control sample, and a German chronic periodontitis (CP) case-control sample using Sequenom iPlex assays. We additionally tested the common known risk variant rs1333048 of the gene ANRIL for its association in a Turkish and Italian population. RESULTS None of the analysed genes gave statistical evidence for association. Upon covariate adjustment for smoking and gender, in the pooled German-Austrian AgP sample, IL10 SNP rs6667202 was associated with p = 0.016, OR = 0.77 (95% CI = 0.6-0.95), and in the Dutch AgP sample, adjacent IL10 SNP rs61815643 was associated with p = 0.0009, OR = 2.31 (95% CI = 1.4-3.8). At rs61815643, binding of the transcription factor PPARG was predicted. ANRIL rs1333048 was associated in the Turkish sample (pallelic = 0.026, OR = 1.67 [95% CI = 1.11-2.60]). CONCLUSIONS Previous candidate genes carry no susceptibility factors for AgP. Association of IL-10 rs61815643 with AgP is suggested. ANRIL is associated with periodontitis across different populations.

Correlations between 15 polyclclic aromatic hydrocarbons (PAH) and the mutagenicity of the total PAH fraction in ambient air particles in La Spezia (Italy)

Airborne particulate matter has been monitored 4 times a month for 1 year (1988) in the city of La Spezia (Italy). The polycyclic aromatic hydrocarbon (PAH) fractions were extracted, purified and characterized for the content of 15 individual PAH. In general when concentrations of individual PAH were compared statistical correlation was obtained. Mutagenicity studies were performed by the use of the Ames plate test with the Salmonella strains TA98, TA100, TA98NR and TA98DNP6 with and without metabolic activation (S9 mix). The TA98 strain was by far the most responsive and the S9 mix was absolutely required as expected when PAH are assayed. Besides mutagenicity, toxicity was also considered and it proved to be correlated with mutagenicity in TA98, +S9. The TA98NR and TA98DNP6 strains showed no appreciable differences from the parental strain TA98 indicating the absence of significant amounts of direct-acting nitro derivatives in our PAH samples. Of the 15 PAH considered in this study the amounts of cyclopental[c,d]pyrene (CPP) correlated best with mutagenicity. The role of CPP in contributing to the indirect mutagenicity of urban air PAH samples is discussed.

Isonymy and the genetic structure of Switzerland. II. Isolation by distance

Isolation by distance in Switzerland was detected comparing the surname distributions between Cantons. The decay of isonymy with geographic distance between Cantons was consistent with Malecots exponential decay of kinship. Laskers distance was defined as the negative value of the logarithm of isonymy between localities, and it was found that it is linearly and significantly correlated with the log of geographic distance, both within and between languages. The peculiar geographic and linguistic structure of the Confederation, where mountain barriers exist at short distances separating different languages, might explain the rapid changes in surname similarity. It was predicted that the frequency of markers linked to the Y chromosome would show a similar association with distance in Switzerland.

Cytogenetic effects of benzimidazoles in mouse bone marrow

The cytogenetic effects of three benzimidazoles, i.e., benomyl, methyl thiophanate and methyl 2-benzimidazolecarbamate (MBC), were studied in mouse bone marrow cells by analyzing three genetic endpoints: micronuclei, structural chromosome aberrations plus or minus gaps, and aneugenic effects (hyperdiploidy or polyploidy). In general, the effects were small, but it was observed that benomyl and MBC significantly induced micronuclei as well as aneugenic effects, hyperdiploidy (no metaphases with more than one or two extra chromosomes, 2n + 1 or 2n + 2, were observed) and polyploidy (4n). The induction of chromosome gaps and breaks was less evident. Methyl thiophanate significantly induced micronuclei, but it was less effective than benomyl and MBC. Our results showed that micronuclei are a good indicator of aneugenic effects in mouse bone marrow cells. A curvilinear trend test has been devised to fit the curves originating from the time-dependent responses.

Elements of the surname structure of Austria

The isonymy structure of Austria was studied using the surname distributions in 1081002 private telephone users selected from about 4000000 registered in a 1996 commercial CD-ROM, which contains all Austrian users. The sample was distributed in 120 towns representing an approximately uniform distribution over the country. The number of different surnames found in the whole analysis was 140766. Laskers distance, the negative value of the logarithm of isonymy between localities, was found to be linearly and significantly correlated with the log of geographic distance, with r = 0.565 +/- 0.011. A dendrogram was built with the matrix of isonymy distance, using the Unweighted Pair-Group Method using Arithmetic averages, UPGMA. It separates the Austrian towns in five main clusters, one along the central portion of the country, another one which occupies the northern region of central Austria; then comes a third cluster at the north-eastern part, a fourth cluster in the western region, and finally a small cluster towards the border with Slovenia. Within each, small subclusters with specific geographic distributions could be delimited. The main clusters correspond fairly well to the classic regions of Austria. The results were compared with those obtained in similar analyses of Switzerland, Germany, Italy and Venezuela. From the present analysis, isolation by distance emerges clearly, and it is stronger than in Germany but smaller than that observed in Italy, Switzerland and Venezuela. The random component of inbreeding estimated from isonymy, at the level of resolution used here, indicates that the inbreeding level in Austria is rather uniform.

Isonymy and isolation by distance in the Netherlands.

The isonymy structure of the Netherlands was studied using the surname distribution of 2.4 million private telephone users selected from a 1996 commercial CD-ROM containing the names of 6.3 million users in the country. The users were distributed in 226 towns selected on a geographic basis to form an approximately regular grid throughout the Netherlands. Names of telephone users in each town were downloaded from the CD-ROM, with private users being selected for inclusion in the analysis. The shortest linear distance between several nearest neighboring towns was less than 2 km (e.g., Kampen and Ijsselmuiden, Krommen and Zaandijk, Hendrikdo and Papendrecht) and the longest distance was 326 km (Delfzijl and Oostburg ZL). The number of different surnames revealed by the analysis was 126,485. Laskers distance, the negative value of the logarithm of isonymy between localities, was found to be significantly correlated with linear geographic distance, with r = 0.47 ± 0.006. A dendrogram built using the matrix of isonymy distances, using the nearest neighbor-joining method, separates the Dutch towns into several clusters, most of them correlated with traditional Dutch regions. Comparisons with the results of previous analyses of the structure of other European countries are given. From the present analysis, isolation by distance emerges clearly, and it is relevant, although much weaker than in Switzerland, Austria, Italy, and Germany. The random component of inbreeding estimated from isonymy indicates a considerable degree of homogeneity in the Netherlands.

Isonymy structure of USA population

The isonymy structure of the 48 states of the continental United States of America was studied using the surname distributions of 18 million telephone users, distributed in 247 towns. The shortest linear distance between nearest neighbor towns included in the sample was 12.0 km. The largest distance was 4,577 km. The number of different surnames found in the whole analysis was 899,585. Laskers distance was found to be significantly but weakly correlated with the geographic distance, with r = 0.21 +/- 0.01. A dendrogram of the 48 states was built from the matrix of isonymy distances: it divides the US into several clusters, in general correlated with geography. A notable exception is California and New Jersey, which cluster together. Wisconsin is separated from all other states. An important cluster is formed by Texas, Colorado, New Mexico, Nevada, and Arizona, together with Illinois and Florida. It was observed that Hispanic surnames are among the most frequent in Illinois, as they are in New Jersey and California. No main distinction among the states clearly attributable to surnames of French origin was detected; however, New Hampshire, Vermont, and Maine which have a considerable number of these surnames belong to the same northeastern cluster. From the present analysis, the great mobility of the US population emerges clearly, and it seems relevant that the practical absence of isolation by distance is seen also considering only small towns. It appears that groups of different origin are well-mixed over the whole area of the United States. The values of isonymy indicate that the south-central area of the USA has the highest level of inbreeding. In fact, the heterogeneity in surname composition is greater in the coastal areas, particularly on the East Coast, than anywhere else in the USA.

Isonymy and the genetic structure of Sicily

The genetic structure of Sicily was analysed through the distribution of surnames of 758,793 users registered in the Italian Telephone Company, corresponding to 371 communes of the island. Estimates of the coefficient of consanguinity due to random isonymy, of Fishers a, an indicator of abundance of surnames, and of Karlin-McGregors v, an indicator of immigration rates, were obtained for each commune. Four different estimates of genetic distance between all possible pairs of communes within each province were also obtained, and their relationship with geographic distance was studied. The logarithmic transformation of Laskers coefficient of relationship showed correlations with the log of geographic distance which range between -0.78 and -0.40; the strongest, for the province of Catania, was attributed to the presence of Mount Etna, and the weakest, for Palermo, to the high population density of this province.