Search

BACKGROUND: nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. MATERIALS AND METHODS: Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. RESULTS: Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. CONCLUSION: The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials. [ABSTRACT FROM AUTHOR]

The HLA-B*5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B*5701. The HCP5SNPwas present in all 98 HLA-B*5701-positive individuals and was absent in 999 of 1005 HLA-B*5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P<.0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available. [ABSTRACT FROM AUTHOR]

Besides its obvious intrinsic value, knowledge of population history, and of the demographic and evolutionary changes that accompany it, has proven fundamental to address applied research in human genetics. In this review we place current European genetic diversity in the context of the global human genome diversity and review the evidence supporting a recent African origin of the Europeans. We then discuss the results and the interpretation of genetic studies attempting to quantify the relative importance of various gene flow processes, both within Europe and from Asia into Europe, focusing especially on the initial, Paleolithic colonization of the continent, and on later, Paleolithic postglacial and Neolithic dispersals. Finally, we discuss how knowledge of the patterns of genetic diversity in Europe, and of their inferred generating processes, can be extremely useful in planning health care and in biomedical research. [ABSTRACT FROM AUTHOR]

Objectives: Female physicians in medicine are increasing, but disparities in female authorship exist. The aim of this study was to characterise factors associated with female first (FF) and female senior (SF) authorship in later phase systemic oncological clinical trials in biliary tract cancer (BTC) and identify any changes over time., Setting: Embase/Medline identified trial publications in BTC (2000-2020) were included. χ 2 tests and log regression were used (assessed factors associated with FF and SF authorship, including changes over time (STATA V.16))., Primary Outcome Measure: FF and SF authorship in later phase systemic oncological clinical trials in BTC., Secondary Outcome Measure: Any changes over time?, Results: Of 501 publications, 163 met inclusion criteria. The median percentage of female author representation in publications was 25%; there were no female authors in 13% of publications. Geographic location of the home institution of the first and senior authors was Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Overall, FF and SF author representation was 20% and 10%, respectively. The median position of the first female author was second in all the publication author lists. The phase of trial, journal-impact factor, industry funding or whether the study met its primary endpoint did not impact FF/SF author representation. More SF authors had home institutions in 'other' geographic locations (40% in 10 trials) (p=0.02) versus Asia (6%), Europe (8%) and USA (14%). There were no significant changes in FF/SF representation over time (p=0.61 and p=0.33 respectively)., Conclusions: FF and SF author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed., Competing Interests: Competing interests: The authors of this manuscript have the following competing interests; all outside of this submitted work: MGM has received research grant support from Servier, Ipsen, and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana, and Mylan. She has served on advisory boards for Incyte, Celgene, Ipsen, Sirtex, Baxalta and Astra Zeneca; all outside this submitted work. JB has received honoraria from Merck Serono, Roche, Sanofi, and Bayer; all outside this submitted work. LG has received research funding (to institution): Agios, Adaptimmune, Bayer, Merck, Macrogenics, Genentech, Novartis, Incyte, Loxo Oncology, Relay Therapeutics, QED, Taiho Oncology, Leap Therapeutics, Bristol Meyers Squibb, Nucana. Scientific Advisory Committee (to self): Agios Pharmaceuticals Inc, Alentis Therapeutics AG, H3Biomedicine, Incyte Corporation, QED Therapeutics, Sirtex Medical Ltd, Taiho Oncology Inc; Consulting (to self): Agios Pharmaceuticals Inc, Alentis Therapeutics, Genentech, Exelixis, Incyte Corporation, QED Therapeutics, Sirtex Medical Ltd, Taiho Oncology Inc; DSMC (to self): AstraZeneca; all outside this submitted work. ADW has received educational grant support from Roche, and honoraria from Bristol-Myers Squibb, Servier Suisse, Merck Sharp & Dohme, Bayer, EMD Serono, Lilly, Sanofi, Celgene, Astra Zeneca, AbbVie, Sanofi-Aventis Deutschland, SHIRE and Pfizer; all outside this submitted work. DG receives indirect research funding from Amgen, Celgene, and Pfizer and is on a data safety monitoring board for Sun Biopharma and has received honorarium from Astra Zeneca; all outside this submitted work. RS has received research funding from Merck, Exelis Pharmaceuticals, Pieris, Taiho, Rafael Pharmaceuticals and has served on advisory boards for Merck, Seattle Genetics, Exelis Pharmaceuticals, QED therapeutics, Debipharm, Agios, Clovis and Incyte; all outside this submitted work. MM receives research funding from Bayer and Lilly; all outside this submitted work. ML has received honoraria from Roche, Agios, Novartis, Astra-Zeneca; all outside of this submitted work. TB-S has received research funding (to institution): Agios, Arys, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS. Consulting (to institution): Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte and Merck. Consulting (to self): AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Astra Zeneca and Foundation Medicine. IDMC/DSMB (to self): Astra Zeneca, Exelixis, Lilly, PanCan and 1Globe; all outside this submitted work. RKK has received research funding (to institution): Adaptimmune, Agios, Astra Zeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Merck, Novartis, Partner Therapeutics, QED, Taiho. Consulting (to institution): Agios, Astra Zeneca, BMS. IDMC/DSMB (to self): GNE/Roche. Scientific Advisory Board (to self): GNE/Roche, Gilead, Exact Sciences, Ipsen; all outside this submitted work. JF has received research funding (to institution): Ono Pharmaceutical, MSD, Sumitomo Dainippon, J-Pharma, Yakult Honsha, AstraZeneca, Daiichi Sankyo, Eisai, Bayer, Pfizer, NanoCarrier, Kyowa Hakko Kirin, Taiho Pharmaceutical, Chugai Pharma, Sanofi, Takeda, Mochida Pharmaceutical, Astellas Pharma, Eli Lilly Japan, and honoraria from Eisai, Bayer Yakuhin, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Yakult Honsha, Teijin pharma, Shionogi, EA pharma, Eli Lilly Japan, Takeda, Chugai Pharma, Mochida Pharmaceutical, Nihon Servier, Sanofi, Fujifilm Toyama Chemical, Nobel pharma, Pfizer, Sawai Pharmaceutical, Daiichi Sankyo, Sumitomo Dainippon, Merck Bio, Nippon Kayaku, MSD, Shire, Kyowa Hakko Kirin; all outside this submitted work. LR had received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks; all outside this submitted work. CM received grants from ONO Pharmaceutical, grants and personal fees from Yakult Honsha, grants from Eisai, grants and personal fees from MSD K.K., grants and personal fees from J-Pharma, grants and personal fees from AstraZeneca, grants from Merck biopharma, personal fees from Teijin Pharma, grants and personal fees from Taiho Pharmaceutical, personal fees from Novartis, personal fees from Abbvie; all outside this submitted work. AL has received travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath. Speaker honoraria from Merck, Pfizer, Ipsen, and Incyte. Advisory honoraria from EISAI, Nutricia Ipsen, QED, and Roche. Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen; all outside this submitted work. RH has served on advisory boards for Roche, BMS, Eisai, Celgene, Beigene, Ipsen, BTG. He has received speaker fees from Eisai, Ipsen, Mylan, PrimeOncology and has received travel and educational support from Bayer, BMS and Roche; all outside this submitted work. JK has received research funding (to institution) from AstraZeneca, Merck, Roche, Ipsen. Advisory board (to self) received from Pfizer, Merck, Celgene, AstraZeneca, Roche, EISAI, Lilly, BMS; all outside this submitted work. JV has had a consulting or advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited, Ipsen, Novartis, Nucana; and received Travel Grants from Celgene and Nucana; all outside this submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection., Methods: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided., Results: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients., Conclusions: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Background: Ethnic minority is associated with higher cancer incidence and poorer survival than is being in the majority group. We did a systematic review and meta-analysis to assess whether psychological morbidity and health-related quality of life (HRQoL) were affected by minority status., Methods: We searched Medline, AMED, PsycINFO, Embase, CENTRAL, CINAHL, PubMed, Sociological Abstracts, and Web of Science for English-language articles published between Jan 1, 1995, and October, 2009. Articles were eligible if they reported original data on anxiety, depression, distress (for psychological morbidity), or HRQoL in minority and majority cancer patients or survivors. Minority status was defined as being an immigrant or having an ethnic, linguistic, or religious background different to the majority of the population in the country where the research was done. We excluded African Americans and indigenous groups. Eligible articles were rated for quality of reporting, external validity, internal validity, sample size, and power. Each quality criterion was rated independently by two reviewers until inter-rater reliability was achieved. In a meta-analysis we compared mean scores adjusted for socioeconomic status and other sociodemographic and clinical variables, where available. Effect sizes greater than 0·5 and 95% CI that included 0·5 or -0·5 were deemed clinically important, with negative values indicating worse outcomes in minority patients. We assessed publication bias by estimating the number of potential unpublished studies and the number of non-signficant studies with p=0·05 required to produce a non-significant overall result., Findings: We identified 21 eligible articles that included 18 datasets collected in the USA and one in each of Canada, Romania, and the UK. Ethnic minority groups were Hispanic, Asian or Pacific Islander, or Hungarian (one dataset). Overall, we found minority versus majority groups to have significantly worse distress (mean difference -0·37, 95% CI -0·46 to -0·28; p<0·0001), depression (-0·23, -0·36 to -0·11; p=0·0003), and overall HRQoL (-0·33, -0·58 to -0·07; p=0·013). Further analyses found disparities to be specific to Hispanic patients in the USA, in whom poorer outcomes were consistent with potentially clinically important differences for distress (effect size -0·37, 95% CI -0·54 to -0·20; p<0·0001), social HRQoL (-0·45, -0·87 to -0·03; p=0·035), and overall HRQoL (-0·49, -0·78 to -0.20; p=0·0008). Results were significantly heterogeneous for overall HRQoL and all domains. Tests for interaction, for adjusted versus unadjusted and comparisons of high-quality, medium-quality, and low-quality articles, were generally non-significant, which suggests no bias. We found no evidence of any substantive publication bias., Interpretation: Hispanic cancer patients in the USA, but not other ethnic minority groups, report significantly worse distress, depression, social HRQoL, and overall HRQoL than do majority patients, of which all but depression might be clinically important. Heterogeneous results might, however, have limited the interpretation. Data for other minority groups and for anxiety are scarce. More studies are needed from outside the USA. Future reports should more clearly describe their minority group samples and analyses should control for clinical and sociodemographic variables known to predict outcomes. Understanding of why outcomes are poor in US Hispanic patients is needed to inform the targeting of interventions., Funding: Prince of Wales Hospital, Sydney, Australia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: To assess the quality of life in curatively treated patients with rectal cancer in a prospectively collected cohort., Methods: Patients with stage I-III rectal cancer who were treated curatively in a single institution were accrued prospectively. Quality of life was assessed by use of the European Organization for Research and Treatment of Cancer questionnaire module for all cancer patients (QLQ-C30) and for colorectal cancer patients (QLQ-CR29). Quality of life among different treatment modalities and between stoma and nonstoma patients was evaluated in all patients., Results: A total of 154 patients were assessed. The median time of completion for the questionnaires was 10 months after all the treatments. For patients with different treatment modalities, faecal incontinence and diarrhea were significantly higher in radiation group (p = 0.002 and p = 0.001, respectively), and no difference in male or female sexual function was found between radiation group and non-radiation group. For stoma and nonstoma patients, the QLQ-CR29 module found the symptoms of Defaecation and Embarrassment with Bowel Movement were more prominent in stoma patients, while no difference was detected in scales QLQ-C30 module., Conclusions: Our study provided additional information in evaluating QoL of Chinese rectal cancer patients with currently widely used QoL questionnaires. As a supplement to the QLQ-C30, EORTC QLQ-CR29 is a useful questionnaire in evaluating curatively treated patients with rectal cancer. Bowel dysfunction (diarrhea and faecal incontinence) was still the major problem compromising QoL in patients with either pre- or postoperative chemoradiotherapy.

Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction., Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background., Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4))., Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory., (Copyright 2008 Wiley-Liss, Inc.)

Previous Y chromosome studies have shown that the Cohanim, a paternally inherited Jewish priestly caste, predominantly share a recent common ancestry irrespective of the geographically defined post-Diaspora community to which they belong, a finding consistent with common Jewish origins in the Near East. In contrast, the Levites, another paternally inherited Jewish caste, display evidence for multiple recent origins, with Ashkenazi Levites having a high frequency of a distinctive, non-Near Eastern haplogroup. Here, we show that the Ashkenazi Levite microsatellite haplotypes within this haplogroup are extremely tightly clustered, with an inferred common ancestor within the past 2,000 years. Comparisons with other Jewish and non-Jewish groups suggest that a founding event, probably involving one or very few European men occurring at a time close to the initial formation and settlement of the Ashkenazi community, is the most likely explanation for the presence of this distinctive haplogroup found today in >50% of Ashkenazi Levites.

Background: Effective gene mapping based on genetic association data will require detailed knowledge of patterns of linkage disequilibrium (LD) in human populations. It has been recently suggested that linkage disequilibrium in humans may be organized in a block-like structure, with islands of high LD separated by regions of rapid breakdown of LD due to recombination hotspots. The experimental data to date, however, are limited, and fundamental questions remain about the implications of recombination rate heterogeneity. Here, we use computer simulations to evaluate how such heterogeneity influences patterns of LD, and we develop formal criteria to assess whether the patterns are functionally block like in the context of association mapping., Results: Our analyses suggest that, even in models of extreme recombination rate heterogeneity, some human populations will have a functionally block-like structure to the pattern of LD, but others will not, depending on their precise demographic histories. In fact, for many models, we find that, following an LD-generating event, populations may move through discrete phases that can be functionally described as pre-block, block, and post-block. An analysis of observed and expected patterns of LD surrounding hotspots within the MHC Class II region confirms these theoretical expectations., Conclusions: Even if highly punctuated patterns of recombination are the rule, patterns of LD are still likely to show differences among populations and among genomic regions that are of practical importance in the design of genetic association studies. The notion that the average extent of LD is a useful concept for the design of association studies must be abandoned in light of the experimental and theoretical evidence.