Paternal Genetic History of the Basque Population of Spain

This study examines the genetic variation in Basque Y chromosome lineages using data on 12 Y-short tandem repeat (STR) loci in a sample of 158 males from four Basque provinces of Spain (Alava, Vizcaya, Guipuzcoa, and Navarre). As reported in previous studies, the Basques are characterized by high frequencies of haplogroup R1b (83%). AMOVA analysis demonstrates genetic homogeneity, with a small but significant amount of genetic structure between provinces (Y-short tandem repeat loci STRs: 1.71%, p 0.0369). Gene and haplotype diversity levels in the Basque population are on the low end of the European distribution (gene diversity: 0.4268; haplotype diversity: 0.9421). Post-Neolithic contribution to the paternal Basque gene pool was estimated by measuring the proportion of those haplogroups with a Time to Most Recent Common Ancestor (TMRCA) previously dated either prior (R1b, I2a2) or subsequent to (E1b1b, G2a, J2a) the Neolithic. Based on these estimates, the Basque provinces show varying degrees of post-Neolithic contribution in the paternal lineages (10.9% in the combined sample)

Autosomal short tandem repeat genetic variation of the Basques in Spain

Aim To examine population genetic structure and hypotheses of the origin of the modern Basque population in Spain using autosomal short tandem repeat (STR) data from individuals living in 27 mountain villages in the provinces of Alava, Vizcaya, Guipuzcoa, and Navarre, by comparing Basque autosomal STR variation with that of neighboring populations in Europe, as well as proposed ancestral populations in North Africa and the Caucasus. Methods Allele frequencies for 9 autosomal STR loci (D3S1358, D5S818, D7S820, D8S1179, D13S317, D18S51, D21S11, FGA, and vWA) and several population genetic parameters were determined for the 4 provinces in the Basque region of Spain (n = 377). Heterozygosity within the Basque population was measured using a locus-by-locus analysis of molecular variance. Relationships between the Basques and other populations were examined using a multidimensional scaling (MDS) plot of Shriver’s DSW distance matrix. Results Heterozygosity levels in the Basque provinces were on the low end of the European distribution (0.805-0.812). The MDS plot of genetic distances revealed that the Basques differed from both the Caucasian and North African populations with respect to autosomal STR variation. Conclusions Autosomal STR analysis does not support the hypotheses of a recent common ancestor between the Basques and populations either from the Caucasus or North Africa.Funding This work is supported in part by National Geographic Society Grant (Project 6935-00) to the University of Kansas Laboratory of Biological Anthropology

Self-Reported Barriers to Colorectal Cancer Screening in a Racially Diverse, Low-Income Study Population

Colorectal cancer (CRC) screening is underutilized, especially in low income, high minority populations. We examined the effect test-specific barriers have on colonoscopy and fecal immunochemical test (FIT) completion, what rationales are given for non-completion, and what “switch” patterns exist when participants are allowed to switch from one test to another. Low income adults who were not up-to-date with CRC screening guidelines were recruited from safety-net clinics and offered colonoscopy or FIT (n=418). Follow up telephone surveys assessed test-specific barriers. Test completion was determined from patient medical records. For subjects who desired colonoscopy at baseline, finding a time to come in and transportation applied more to non-completers than completers (p = 0.001 and p < 0.001, respectively). For participants who initially wanted FIT, keeping track of cards, never putting stool on cards, and not remembering to mail cards back applied more to non-completers than completers (p = 0.003, p = 0.006, and p < 0.001, respectively). The most common rationale given for not completing screening was a desire for the other screening modality: 7% of patients who initially preferred screening by FIT completed colonoscopy, while 8% of patients who initially preferred screening by colonoscopy completed FIT. We conclude that test-specific barriers apply more to subjects who did not complete CRC screening. As a common rationale for test non-completion is a desire to receive a different screening modality, our findings suggest screening rates could be increased by giving patients the opportunity to switch tests after an initial choice is made

Basal channels drive active surface hydrology and transverse ice shelf fracture

Ice shelves control sea-level rise through frictional resistance, which slows the seaward flow of grounded glacial ice. Evidence from around Antarctica indicates that ice shelves are thinning and weakening, primarily driven by warm ocean water entering into the shelf cavities. We have identified a mechanism for ice shelf destabilization where basal channels underneath the shelves cause ice thinning that drives fracture perpendicular to flow. These channels also result in ice surface deformation, which diverts supraglacial rivers into the transverse fractures. We report direct evidence that a major 2016 calving event at Nansen Ice Shelf in the Ross Sea was the result of fracture driven by such channelized thinning and demonstrate that similar basal channel–driven transverse fractures occur elsewhere in Greenland and Antarctica. In the event of increased basal and surface melt resulting from rising ocean and air temperatures, ice shelves will become increasingly vulnerable to these tandem effects of basal channel destabilization

Outcome of sustained virological responders with histologically advanced chronic hepatitis C

Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. Conclusion: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC. (H EPATOLOGY 2010;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78047/1/23744_ftp.pd

Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανβ3 testing in women with unexplained infertility

To evaluate endometrial leukemia inhibitor factor (LIF) expression as a marker of endometrial receptivity in women with unexplained infertility (UI)

Deletion of the Basement Membrane Heparan Sulfate Proteoglycan Type XVIII Collagen Causes Hypertriglyceridemia in Mice and Humans

Background: Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. Methods and Findings: We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. Conclusions: This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.National Institute of Health (NIH)[HL087228]National Institute of Health (NIH)[GM33063]National Institute of Health (NIH)[HL67255]CEPID/FAPESPCNPqUniversity of Colorado Denver Department of MedicineLeducq FoundationAmerican Heart Association[0735038N

Interaction of smoking and obesity susceptibility loci on adolescent BMI: The National Longitudinal Study of Adolescent to Adult Health

Background Adolescence is a sensitive period for weight gain and risky health behaviors, such as smoking. Genome-wide association studies (GWAS) have identified loci contributing to adult body mass index (BMI). Evidence suggests that many of these loci have a larger influence on adolescent BMI. However, few studies have examined interactions between smoking and obesity susceptibility loci on BMI. This study investigates the interaction of current smoking and established BMI SNPs on adolescent BMI. Using data from the National Longitudinal Study of Adolescent to Adult Health, a nationally-representative, prospective cohort of the US school-based population in grades 7 to 12 (12–20 years of age) in 1994–95 who have been followed into adulthood (Wave II 1996; ages 12–21, Wave III; ages 18–27), we assessed (in 2014) interactions of 40 BMI-related SNPs and smoking status with percent of the CDC/NCHS 2000 median BMI (%MBMI) in European Americans (n = 5075), African Americans (n = 1744) and Hispanic Americans (n = 1294). Results Two SNPs showed nominal significance for interaction (p < 0.05) between smoking and genotype with %MBMI in European Americans (EA) (rs2112347 (POC5): β = 1.98 (0.06, 3.90), p = 0.04 and near rs571312 (MC4R): β 2.15 (−0.03, 4.33) p = 0.05); and one SNP showed a significant interaction effect after stringent correction for multiple testing in Hispanic Americans (HA) (rs1514175 (TNNI3K): β 8.46 (4.32, 12.60), p = 5.9E-05). Stratifying by sex, these interactions suggest a stronger effect in female smokers. Conclusions Our study highlights potentially important sex differences in obesity risk by smoking status in adolescents, with those who may be most likely to initiate smoking (i.e., adolescent females), being at greatest risk for exacerbating genetic obesity susceptibility

Characterization of the contribution of shared environmental and genetic factors to metabolic syndrome methylation heritability and familial correlations

Abstract Background Transgenerational epigenetic inheritance has been posited as a possible contributor to the observed heritability of metabolic syndrome (MetS). Yet the extent to which estimates of epigenetic inheritance for DNA methylation sites are inflated by environmental and genetic covariance within families is still unclear. We applied current methods to quantify the environmental and genetic contributors to the observed heritability and familial correlations of four previously associated MetS methylation sites at three genes (CPT1A, SOCS3 and ABCG1) using real data made available through the GAW20. Results Our findings support the role of both shared environment and genetic variation in explaining the heritability of MetS and the four MetS cytosine-phosphate-guanine (CpG) sites, although the resulting heritability estimates were indistinguishable from one another. Familial correlations by type of relative pair generally followed our expectation based on relatedness, but in the case of sister and parent pairs we observed nonsignificant trends toward greater correlation than expected, as would be consistent with the role of shared environmental factors in the inflation of our estimated correlations. Conclusions Our work provides an interesting and flexible statistical framework for testing models of epigenetic inheritance in the context of human family studies. Future work should endeavor to replicate our findings and advance these methods to more robustly describe epigenetic inheritance patterns in human populations

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms