TNFA-863 polymorphism is associated with a reduced risk of chronic obstructive pulmonary disease: a replication study.

UNLABELLED: : BACKGROUND: TNF-α mediated inflammation is thought to play a key role in the respiratory and systemic features of Chronic Obstructive Pulmonary Disease. The aim of the present study was to replicate and extend recent findings in Taiwanese and Caucasian populations of associations between COPD susceptibility and variants of the TNFA gene in a Spanish cohort. METHODS: The 3 reported SNPs were complemented with nine tag single nucleotide polymorphisms (SNP) of the TNFA and LTA genes and genotyped in 724 individuals (202 COPD patients, 90 smokers without COPD and 432 healthy controls). Pulmonary function parameters and serum inflammatory markers were also measured in COPD patients. RESULTS: The TNFA rs1800630 (-863C/A) SNP was associated with a lower COPD susceptibility (ORadj = 0.50, 95% CI = 0.33-0.77, p = 0.001). The -863A allele was also associated with less severe forms of the disease (GOLD stages I and II) (ORadj = 0.303, 95%CI = 0.14-0.65, p = 0.014) and with lower scores of the BODE index (< 2) (ORadj = 0.40, 95%CI = 0.17-0.94, p = 0.037). Moreover, the -863A carrier genotype was associated with a better FEV1 percent predicted (p = 0.004) and a lower BODE index (p = 0.003) over a 2 yrs follow-up period. None of the TNFA or LTA gene variants correlated with the serum inflammatory markers in COPD patients (p > 0.05). CONCLUSIONS: We replicated the previously reported association between the TNFA -863 SNP and COPD. TNFA -863A allele may confer a protective effect to the susceptibility to the disease in the Spanish population.

A common haplotype of the LBP gene predisposes to severe sepsis.

OBJECTIVE: To investigate whether common variants across the LBP gene contribute to the development of severe sepsis. Sepsis is the leading cause of multiple system organ dysfunction and death in critically ill patients. The lipopolysaccharide-binding protein is an acute-phase protein that plays a dominant role in the genesis of sepsis by initiating signal transduction pathways leading to the activation of the inflammatory host response. DESIGN: Prospectively enrolled case-control study of adults with severe sepsis. SETTING: A network of intensive care units. PATIENTS: We enrolled 175 patients meeting international definition criteria for severe sepsis and 357 population-based controls for comparison. INTERVENTIONS: Genotyping of the LBP gene was performed and disease association was tested. Serum lipopolysaccharide-binding protein levels were measured in patients and related to genetic variants. MEASUREMENTS AND MAIN RESULTS: A haplotype window analysis revealed that a common 4-SNP risk haplotype from the 5'-flanking region of the LBP gene, comprising positions -1978 to -763 from the transcription start site, was strongly associated with susceptibility to severe sepsis. Risk haplotype homozygous carriers had an increased risk for severe sepsis (odds ratio = 2.21; 95% confidence interval = 1.39-3.51; unadjusted p < .001; adjusted p < .025). Mean serum lipopolysaccharide-binding protein levels from inclusion to 7th day were significantly higher in homozygous carriers patients (130.1 [102.9-164.5] and 98.9 [79.7-122.8] microg/mL, respectively) than in noncarriers (101.6 [87.9-117.5] and 58.7 [51.4-67.2] microg/mL, respectively) (p = .046). CONCLUSIONS: This study strongly supports the involvement of LBP gene variants in severe sepsis susceptibility and reinforces the merit of further exploration of the role of lipopolysaccharide-binding protein in sepsis.

Association of IL-6 gene polymorphisms and COPD in a Spanish population.

Interleukin-6 (IL-6) is a potential mediator of systemic effects of Chronic Obstructive Pulmonary Disease (COPD). In the present case-control study we investigated the association of promoter polymorphisms of this gene and COPD in a cohort of 191 patients, smokers without COPD (n=75) and a healthy control population (n=296). Besides spirometry, exercise capacity (6MWD, 6 min walking distance) and body mass index (BMI) were measured in COPD patients. Genotyping of the IL-6 polymorphisms at positions -174, -572 and -597 was performed. The -597G/A and -174G/C polymorphisms were not associated with the disease. However, the -572G/C polymorphism was significantly associated with COPD susceptibility under a dominant model of inheritance. The frequency of the genotypes containing the C allele was significantly lower in the COPD cases (9.9%) compared with the healthy control group (16.9%) and smokers (23.1%), (OR=0.46, p=0.032 and OR=0.28, p=0.012, respectively). The GCG (-597/-572/-174) haplotype was significantly associated with the disease (OR=0.37, p=0.022, COPD cases vs. healthy subjects and OR=0.17, p=0.011, COPD cases vs. smokers). Moreover, a borderline association was also found for the -572G allele and hypoxemia (PaO(2)<60 mmHg) (p=0.05). Our data suggest that the IL-6 -572C allele may confer a diminished risk of developing COPD.

Mitochondrial DNA variation in Jordanians and their genetic relationship to other Middle East populations.

BACKGROUND: The Levant is a crucial region in understanding human migrations between Africa and Eurasia. Although some mitochondrial DNA (mtDNA) studies have been carried out in this region, they have not included the Jordan area. This paper deals with the mtDNA composition of two Jordan populations. AIM: The main objectives of this article are: first, to report mtDNA sequences of an urban and an isolate sample from Jordan and, second, to compare them with each other and with other nearby populations. SUBJECTS AND METHODS: The analyses are based on HVSI and HVSII mtDNA sequences and diagnostic RFLPs to unequivocally classify into haplogroups 101 Amman and 44 Dead Sea unrelated individuals from Jordan. RESULTS: Statistical analysis revealed that, whereas the sample from Amman did not significantly differ from their Levantine neighbours, the Dead Sea sample clearly behaved as a genetic outlier in the region. Its outstanding Eurasian haplogroup U3 frequency (39%) and its south-Saharan Africa lineages (19%) are the highest in the Middle East. On the contrary, the lack ((preHV)1) or comparatively low frequency (J and T) of Neolithic lineages is also striking. Although strong drift by geographic isolation could explain the anomalous mtDNA pool of the Dead Sea sample, the fact that its mtDNA lineage composition mirrors, in geographic origin and haplogroup frequencies, its Y-chromosome pool, points to founder effect as the main cause. Ancestral M1 lineages detected in Jordan that have affinities with those recently found in Northwest but not East Africa question the African origin of the M1 haplogroup. CONCLUSION: Results are in agreement with an old human settlement in the Jordan region. However, in spite of the attested migratory spreads, genetically divergent populations, such as that of the Dead Sea, still exist in the area.

Angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome.

OBJECTIVE: The insertion/deletion (I/D) of a 289 base pair Alu repeat sequence polymorphism in the angiotensin-converting enzyme gene (ACE) has been shown to predict susceptibility and outcome in the acute respiratory distress syndrome (ARDS). We hypothesized that the I/D polymorphism also confers susceptibility to sepsis and is a predisposing factor for morbidity and mortality of patients with severe sepsis. DESIGN AND SETTING: Case-control study including 212 consecutive patients fulfilling criteria for severe sepsis admitted to a Spanish network of postsurgical and critical care units, and 364 population-based controls. Susceptibility to severe sepsis was evaluated as primary outcome; mortality in severe sepsis, susceptibility to sepsis-induced ARDS, and mortality in sepsis-induced ARDS were examined as secondary outcomes. An additive model of inheritance in which patients were classified into three genotype groups (II, ID, and DD) was used for association testing. MEASUREMENTS AND RESULTS: Genotype and allele frequencies of I/D were distributed similarly in all septic, ARDS, and non-ARDS patients and in population-based controls. ACE I/D polymorphism was not associated with severe sepsis susceptibility or mortality. The ACE I/D polymorphism was associated neither with sepsis-induced ARDS susceptibility (p=0.895) or mortality (p=0.950). These results remained nonsignificant when adjusted for other covariates using multiple logistic regression analysis or Kaplan-Meier estimates of 28-day survival. CONCLUSIONS: Our data do not support an association of the ACE gene I/D polymorphism with susceptibility or mortality in severe sepsis or with sepsis-induced ARDS in Spanish patients.

A CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis.

OBJECTIVE: Several studies have implicated the CXCL2 chemokine as a mediator in the development of sepsis. We hypothesized that a tandem repeat polymorphism (AC)n in the CXCL2 gene, previously associated with susceptibility to severe sepsis, contributes to morbidity and mortality in severe sepsis. DESIGN: Prospective, observational, genetic study of septic patients. SETTING: A network of Spanish postsurgical and critical care units. PATIENTS: A total of 183 critically ill patients fulfilling the International Sepsis Criteria for severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified into three groups according to the presence of compound 24 +/- 1 (AC) repeat genotypes: homozygote 24 +/- 1 carriers (HC group), heterozygote 24 +/- 1 carriers (HTC), and non 24 +/- 1 carriers (NC group). Mortality, development of acute respiratory distress syndrome, and number of failing organs were determined for each group. Overall mortality was 46.4%. HC patients had a lower mortality (39.9%) than HTC (52.2%) and NC (72.7%) patients (trend test p = .018). This difference remained significant when using a multiple logistic regression analysis (p = .035). The presence of population stratification was ruled out, since 20 independent genomic control markers demonstrated homogeneity among groups. An exploratory analysis of the effect of acute respiratory distress syndrome on mortality showed a relative risk of 2.60 in the HC group (p = .0004), while in the nonhomozygote carriers (NHC) group the relative risk was 3.34 (p = .0001). CONCLUSIONS: Our data suggest that a tandem repeat polymorphism (AC)n at position -665 in the CXCL2 gene may be an independent predictor of mortality for severe sepsis. Additional studies are needed to confirm these results.

Alu polymorphisms in Jerba Island population (Tunisia): comparative study in Arab and Berber groups.

Jerba Island represents an interesting area because four distinct ethnic groups have been cohabiting there until now: Arabs, Berbers, dark-skinned people of sub-Saharan origin and Jews. Religious and cultural differences seem to have constituted an obstacle to their intermixing. Our aim is to provide further information on the genetic structure of the Arab and Berber groups for whom previous data based on haploid markers confirmed their reproductive isolation. Five polymorphic Alu markers (HS 4.69, Sb 19.3, TPA-25, ACE and APO-A1) were analysed in a sample of 43 Arabs and 48 Berbers of Jerba. The genetic relationships among these groups and several populations from North Africa, sub-Saharan Africa and Europe were analysed using genetic distances based on allele frequencies. The results showed a homogeneous distribution of Alu insertions in the two geographically close groups, reflecting ancient relationships between them. This study also revealed that Arabs from Jerba present close genetic distances to other North African populations, whilst Berbers of Jerba occupy an intermediate position among Mediterranean populations.

Isolates in a corridor of migrations: a high-resolution analysis of Y-chromosome variation in Jordan.

A high-resolution, Y-chromosome analysis using 46 binary markers has been carried out in two Jordan populations, one from the metropolitan area of Amman and the other from the Dead Sea, an area geographically isolated. Comparisons with neighboring populations showed that whereas the sample from Amman did not significantly differ from their Levantine neighbors, the Dead Sea sample clearly behaved as a genetic outlier in the region. Its high R1*-M173 frequency (40%) has until now only been found in northern Cameroonian samples. This contrasts with the comparatively low presence of J representatives (9%), which is the modal clade in Middle Eastern populations, including Amman. The Dead Sea sample also showed a high presence of E3b3a-M34 lineages (31%), which is only comparable to that found in Ethiopians. Although ancient and recent ties with sub-Saharan and eastern Africans cannot be discarded, it seems that isolation, strong drift, and/or founder effects are responsible for the anomalous Y-chromosome pool of this population. These results demonstrate that, at a fine scale, the smooth, continental clines detected for several Y-chromosome markers are often disrupted by genetically divergent populations.

Description of a simple multiplex PCR-SSCP method for AB0 genotyping and its application to the peopling of the Canary Islands.

A simple and affordable multiplex polymerase chain reaction-single-strand conformation polymorphism method is proposed for the molecular study of AB0 polymorphisms. Application of this method to the peopling of the Canary Islands, analyzing a total of 2,200 chromosomes, detected that in addition to Berbers and Basques, the rare alleles 0210 and O303 are also present in the Iberian Peninsula and in the Canary Islands. Allele B101, with the highest frequency in Northwest (NW) Africa, shows a negative correlation (R = -0.822, p = 0.023) between geographic distances from this continent and insular frequencies, congruent with a main aborigine colonization from East to West still detectable today. Similar to previous autosomal studies, admixture estimations point to a major Iberian contribution (82 +/- 0.5%) to the Canary Islands, although, in some islands as La Gomera, the NW African component raised to 62 +/- 4.3%.

Mitochondrial DNA diversity in 17th-18th century remains from Tenerife (Canary Islands).

Mitochondrial DNA sequences and restriction fragment length polymorphisms were retrieved (with >80% efficiency) from a 17th-18th century sample of 213 teeth from Tenerife. The genetic composition of this population reveals an important ethnic heterogeneity. Although the majority of detected haplotypes are of European origin, the high frequency of sub-Saharan African haplotypes (15.63%), compared to that of the present-day population (6.6%), confirms the importance of the Canary Islands in the black slave trade of that epoch. The aboriginal substrate, inferred from the U6b1 haplotypes (8.59%), has also decreased due to European input. Finally, the presence of Amerindian lineages (1.5%) reveals that the Canary Islands have also received genetic flow from America.

Reduced genetic structure of the Iberian peninsula revealed by Y-chromosome analysis: implications for population demography.

Europe has been influenced by both intra- and intercontinental migrations. Since the Iberian peninsula was a refuge during the Last Glacial Maximum, demographic factors associated with contraction, isolation, subsequent expansion and gene flow episodes have contributed complexity to its population history. In this work, we analysed 26 Y-chromosome biallelic markers in 568 chromosomes from 11 different Iberian population groups and compared them to published data on the Basques and Catalans to gain insight into the paternal gene pool of these populations and find out to what extent major demographic processes account for their genetic structure. Our results reveal a reduced, although geographically correlated, Y-chromosomal interpopulation variance (1.2%), which points to a limited heterogeneity in the region. Coincidentally, spatial analysis of genetic distances points to a focal distribution of Y-chromosome haplogroups in this area. These results indicate that neither old or recent Levantine expansions nor North African contacts have influenced the current Iberian Y-chromosome diversity so that geographical patterns can be identified.

Bench-to-bedside review: understanding genetic predisposition to sepsis.

Sepsis is a complex syndrome that develops when the initial, appropriate host response to an infection becomes amplified, and is then dysregulated. Among other factors, the innate immune system is of central importance to the early containment of infection. Death from infection is strongly heritable in human populations. Hence, genetic variations that disrupt innate immune sensing of infectious organisms could explain the ability of the immune system to respond to infection, the diversity of the clinical presentation of sepsis, the response to current medical treatment, and the genetic predisposition to infection in each individual patient. Such genetic variations may identify patients at high risk for the development of sepsis and organ dysfunction during severe infections. Single base variations, known as single nucleotide polymorphisms (SNPs), are the most commonly used variants. There has been great interest in exploring SNP in those genes involved in the inflammatory cascade resulting from the systemic inflammatory response to micro organisms. The rationale for studying gene SNPs in critical illnesses seeks to identify potential markers of susceptibility, severity, and clinical outcome; seeks to identify potential markers for responders and non-responders in clinical trials, and seeks to identify targets for therapeutic intervention. In this review, we focus on the current state of association studies of those genes governing the powerful bacterial infection-induced inflammation and provide guidelines for future studies describing disease associations with genetic variations based on current recommendations. We envision a time in the near future when genotyping will be include in the standard evaluation of critically ill patients and will help to prioritize a therapeutic option.

Ancient mtDNA analysis and the origin of the Guanches.

The prehistoric colonisation of the Canary Islands by the Guanches (native Canarians) woke up great expectation about their origin, since the Europeans conquest of the Archipelago. Here, we report mitochondrial DNA analysis (HVRI sequences and RFLPs) of aborigine remains around 1000 years old. The sequences retrieved show that the Guanches possessed U6b1 lineages that are in the present day Canarian population, but not in Africans. In turn, U6b, the phylogenetically closest ancestor found in Africa, is not present in the Canary Islands. Comparisons with other populations relate the Guanches with the actual inhabitants of the Archipelago and with Moroccan Berbers. This shows that, despite the continuous changes suffered by the population (Spanish colonisation, slave trade), aboriginal mtDNA lineages constitute a considerable proportion of the Canarian gene pool. Although the Berbers are the most probable ancestors of the Guanches, it is deduced that important human movements have reshaped Northwest Africa after the migratory wave to the Canary Islands.

Mitochondrial DNA transit between West Asia and North Africa inferred from U6 phylogeography.

BACKGROUND: World-wide phylogeographic distribution of human complete mitochondrial DNA sequences suggested a West Asian origin for the autochthonous North African lineage U6. We report here a more detailed analysis of this lineage, unraveling successive expansions that affected not only Africa but neighboring regions such as the Near East, the Iberian Peninsula and the Canary Islands. RESULTS: Divergence times, geographic origin and expansions of the U6 mitochondrial DNA clade, have been deduced from the analysis of 14 complete U6 sequences, and 56 different haplotypes, characterized by hypervariable segment sequences and RFLPs. CONCLUSIONS: The most probable origin of the proto-U6 lineage was the Near East. Around 30,000 years ago it spread to North Africa where it represents a signature of regional continuity. Subgroup U6a reflects the first African expansion from the Maghrib returning to the east in Paleolithic times. Derivative clade U6a1 signals a posterior movement from East Africa back to the Maghrib and the Near East. This migration coincides with the probable Afroasiatic linguistic expansion. U6b and U6c clades, restricted to West Africa, had more localized expansions. U6b probably reached the Iberian Peninsula during the Capsian diffusion in North Africa. Two autochthonous derivatives of these clades (U6b1 and U6c1) indicate the arrival of North African settlers to the Canarian Archipelago in prehistoric times, most probably due to the Saharan desiccation. The absence of these Canarian lineages nowadays in Africa suggests important demographic movements in the western area of this Continent.

Mitochondrial DNA affinities at the Atlantic fringe of Europe.

Mitochondrial DNA analysis of Atlantic European samples has detected significant latitudinal clines for several clusters with Paleolithic (H) and Neolithic (J, U4, U5a1, and U5a1a) coalescence ages in Europe. These gradients may be explained as the result of Neolithic influence on a rather homogeneous Paleolithic background. There is also evidence that some Neolithic clusters reached this border by a continental route (J, J1, J1a, U5a1, and U5a1a), whereas others (J2) did so through the Mediterranean coast. An important gene flow from Africa was detected in the Atlantic Iberia. Specific sub-Saharan lineages appeared mainly restricted to southern Portugal, and could be attributed to historic Black slave trade in the area and to a probable Saharan Neolithic influence. In fact, U6 haplotypes of specific North African origin have only been detected in the Iberian peninsula northwards from central Portugal. Based on this peculiar distribution and the high diversity pi value (0.014 +/- 0.001) in this area compared to North Africa (0.006 +/- 0.001), we reject the proposal that only historic events such as the Moslem occupation are the main cause of this gene flow, and instead propose a pre-Neolithic origin for it.