Alberto Piazza

Y chromosome sequence variation and the history of human populations

Binary polymorphisms associated with the non-recombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of our species that has persisted to the present, permitting inference of human evolution, population affinity and demographic history. We used denaturing high-performance liquid chromatography (DHPLC; ref. 2) to identify 160 of the 166 bi-allelic and 1 tri-allelic site that formed a parsimonious genealogy of 116 haplotypes, several of which display distinct population affinities based on the analysis of 1062 globally representative individuals. A minority of contemporary East Africans and Khoisan represent the descendants of the most ancestral patrilineages of anatomically modern humans that left Africa between 35,000 and 89,000 years ago.

DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study

Individuals differ widely in their ability to repair DNA damage, and DNA‐repair deficiency may be involved in modulating cancer risk. In a case‐control study of 124 bladder‐cancer patients and 85 hospital controls (urological and non‐urological), 3 DNA polymorphisms localized in 3 genes of different repair pathways (XRCC1‐Arg399Gln, exon 10; XRCC3‐Thr241Met, exon 7; XPD‐Lys751Gln, exon 23) have been analyzed. Results were correlated with DNA damage measured as 32P‐post‐labeling bulky DNA adducts in white blood cells from peripheral blood. Genotyping was performed by PCR‐RFLP analysis, and allele frequencies in cases/controls were as follows: XRCC1‐399Gln = 0.34/0.39, XRCC3‐241Met = 0.48/0.35 and XPD‐751Gln = 0.42/0.42. Odds ratios (ORs) were significantly greater than 1 only for the XRCC3 (exon 7) variant, and they were consistent across the 2 control groups. XPD and XRCC1 appear to have no impact on the risk of bladder cancer. Indeed, the effect of XRCC3 was more evident in non‐smokers [OR = 4.8, 95% confidence interval (CI) 1.1–21.2]. XRCC3 apparently interacted with the N‐acetyltransferase type 2 (NAT‐2) genotype. The effect of XRCC3 was limited to the NAT‐2 slow genotype (OR = 3.4, 95% CI 1.5–7.9), suggesting that XRCC3 might be involved in a common repair pathway of bulky DNA adducts. In addition, the risk of having DNA adduct levels above the median was higher in NAT‐2 slow acetylators, homozygotes for the XRCC3‐241Met variant allele (OR = 14.6, 95% CI 1.5–138). However, any discussion of interactions should be considered preliminary because of the small numbers involved. Our results suggest that bladder‐cancer risk can be genetically modulated by XRCC3, which may repair DNA cross‐link lesions produced by aromatic amines and other environmental chemicals.

Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme A Major Risk Factor and a Marker of Risk for Coronary Stent Restenosis

BACKGROUND Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study. METHODS AND RESULTS One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (+/-SEM) were 40.8+/-3.5 and 20.7+/-1.0 U/L, respectively (P<.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (r=.352 and -.387, respectively P<.001). Twenty-one of 62 patients (33.9%) with D/D genotype, 13 of 80 (16.3%) with I/D genotype, and 1 of 34 (2.9%) with I/I genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele D. CONCLUSIONS In a selected cohort of patients, both the D/D genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted.

Human genomic diversity in Europe: a summary of recent research and prospects for the future.

Gene frequencies in Europe are intermediate with respect to those of other continents. A phylogenetic tree reconstructed from 95 gene frequencies tested on 26 European samples shows some deviant populations (Lapps, Sardinians, Greeks, Yugoslavs, Basques, Icelanders and Finns) and other weakly structured populations. This behavior may have a simple interpretation: Europeans have not evolved according to a tree of descent probably because of the major role played by migrations in prehistorical and historical times. The leading component of the European genetic landscape is a gradient that originates in the Middle East and is directed to the northwest. According to the hypothesis by Ammerman and Cavalli-Sforza this gradient was generated by a migration of Neolithic farmers from Anatolia followed by continuous, partial admixture of the expanding farmers with local hunter-gatherers. Other leading components of the gene frequencies in Europe show correlations with possible movements of Uralic-speaking people and pastoral nomads from a region north of the Caucasus and Black Sea, which according to Gimbutas is the area of origin of Indo-European speakers. This analysis is based on classical pre-DNA genetic markers. The prospect of future research using DNA polymorphisms is discussed in the context of the Human Genome Project.

No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age

Background—We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results—This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A &bgr;-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: OR, 0.9; CI, 0.8 to 1.2), fibrinolysis (G185T factor XIII: OR, 1.2; CI, 0.9 to 1.6; and 4G/5G plasminogen activator inhibitor type 1: OR, 0.9; CI, 0.7 to 1.2), or homocysteine metabolism (C677T methylenetetrahydrofolate reductase: OR, 0.9; CI, 0.8 to 1.1) were associated with an increased or decreased risk of myocardial infarction. Conclusions—This study provides no evidence supporting an association between 9 polymorphisms of genes encoding proteins involved in hemostasis and the occurrence of premature myocardial infarction or protection against it.

A genetic history of Italy

Statistical techniques for displaying the geographical distribution of many genes in few synthetic images have been used to represent the various patterns of gene frequencies in Europe and in the world (Menozzi et al. 1978; Piazza et al. 1981a). It has also been shown that such synthetic displays are particularly useful in detecting clines of genetic differentiation associated with movements of populations like those accompanying the Neolithic expansion of farmers from the Near East or, in more recent times, the putative diffusion of Indo‐European‐speaking populations (Ammerman & Cavalli‐Sforza, 1984; Gimbutas, 1973).

Polymorphisms/Haplotypes in DNA Repair Genes and Smoking: A Bladder Cancer Case-Control Study

Bladder cancer is associated with tobacco smoking and occupational exposure. The repair of DNA damage has a key role in protecting the genome from the insults of cancer-causing agents. We analyzed 13 polymorphisms in seven DNA repair genes belonging to different repair pathways [X-ray repair cross-complementing group 1 (XRCC1): 26304C>T, 26651A>G, 28152A>G; xeroderma pigmentosum-D (XPD): 23591A>G, 35931A>C; excision repair complementing defective in Chinese hamster, group 1 (ERCC1): 19007C>T; XRCC3: 4541T>C, 17893A>G, 18067C>T; proliferating cell nuclear antigen (PCNA): 6084G>C; ERCC4: 30028C>T, 30147A>G; and XRCC2-31479A>G] in 317 incident bladder cancer patients and 317 controls. After adjustment for age and smoking, the PCNA-6084C variant was significantly associated with an increased risk of bladder cancer [CC + CG versus GG, odds ratio (OR), 1.61; 95% confidence interval (95% CI), 1.00-2.61], as well as the XRCC1-26651G variant (GG+AG versus AA: OR, 1.73; 95% CI, 1.17-2.56). After stratifying by smoking habits, an elevated risk for carriers of the XRCC3-18067T allele was detected both in current (TT versus CC: OR, 2.65; 95% CI, 1.21-5.80; CT versus CC: OR, 1.96; 95% CI, 1.09-3.52) and never smokers (TT versus CC: OR, 4.34; 95% CI, 1.14-16.46; CT versus CC: OR, 2.02; 95% CI, 0.72-5.66), whereas an opposite and slightly weaker effect was associated to the XRCC3-17893G allele in current smokers (GG versus AA: OR, 0.30; 95%CI, 0.11-0.82; AG versus AA: OR, 0.73; 95% CI, 0.42-1.27). XRCC3,XRCC1, ERCC4, and XPD-ERCC1 haplotype frequencies were estimated by the maximum likelihood method. The XRCC3-TAT haplotype was associated with an enhanced risk in the current smokers group (OR, 1.62; 95% CI, 1.15-2.29), whereas a reduction of the risk in the overall sample was observed in the presence of the XRCC3-TAC (OR, 0.69; 95% CI, 0.50-0.97). A significant protective effect of the XPD-ERCC1-ACC haplotype was observed among never smokers (OR, 0.16; 95% CI, 0.03-0.81). Our results suggest that polymorphisms and/or haplotypes in XRCC3, XRCC1, and PCNA genes and spanning XPD-ERCC1 region may modulate bladder cancer risk and that some of these effects may preferentially affect current smokers.

Mitochondrial DNA Variation of Modern Tuscans Supports the Near Eastern Origin of Etruscans

The origin of the Etruscan people has been a source of major controversy for the past 2,500 years, and several hypotheses have been proposed to explain their language and sophisticated culture, including an Aegean/Anatolian origin. To address this issue, we analyzed the mitochondrial DNA (mtDNA) of 322 subjects from three well-defined areas of Tuscany and compared their sequence variation with that of 55 western Eurasian populations. Interpopulation comparisons reveal that the modern population of Murlo, a small town of Etruscan origin, is characterized by an unusually high frequency (17.5%) of Near Eastern mtDNA haplogroups. Each of these haplogroups is represented by different haplotypes, thus dismissing the possibility that the genetic allocation of the Murlo people is due to drift. Other Tuscan populations do not show the same striking feature; however, overall, ~5% of mtDNA haplotypes in Tuscany are shared exclusively between Tuscans and Near Easterners and occupy terminal positions in the phylogeny. These findings support a direct and rather recent genetic input from the Near East--a scenario in agreement with the Lydian origin of Etruscans. Such a genetic contribution has been extensively diluted by admixture, but it appears that there are still locations in Tuscany, such as Murlo, where traces of its arrival are easily detectable.

Genetic analysis of Sardinia: I. Data on 12 polymorphisms in 21 linguistic domains

(1) The microgeographic structure of Sardinia, well documented from a historical and linguistic point of view, further supported by archaeological evidence, can also be dissected at the genetic level: gene frequencies show heterogeneities which are statistically significant.

Genetic and population structure of four Sardinian villages

1. Data on microgeographic population structure on four neighbouring villages of Sardinia island (Italy) are presented and discussed.