A common inversion under selection in Europeans.

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

A high-resolution recombination map of the human genome.

Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.

Costs and outcomes of abdominal, vaginal, laparoscopic and robotic hysterectomies.

BACKGROUND AND OBJECTIVES: To estimate the incidence of operative complications and compare operative cost and overall cost of different methods of benign hysterectomy including abdominal, vaginal, laparoscopic, and robotic techniques. METHODS: We performed a retrospective cohort analysis (Canadian Task Force classification II-2) of all patients who underwent a hysterectomy for benign reasons in 2009 at a single urban academic tertiary care center using the χ(2) test and Student t test. A multivariate regression analysis was also performed for predictors of costs. Cost data were gathered from the hospital's billing system; the remainder of data was extracted from patient's medical records. RESULTS: In 2009, 688 patients underwent a benign hysterectomy; 185 (26.9%) hysterectomies were abdominal, 135 (19.6%) vaginal, 352 (51.5%) laparoscopic, and 14 (2.0%) robotic. The rate of intraoperative complication was 1.7% for abdominal, 0.8% for vaginal, 0.3% for laparoscopic, and 0 for robotic. Mean total patient costs were $43,622 for abdominal, $31,934 for vaginal, $38,312 for laparoscopic, and $49,526 for robotic hysterectomies. Costs were significantly influenced by method of hysterectomy, operative time, and length of stay. CONCLUSION: Though complication rates did not vary significantly among minimally invasive methods of hysterectomy, patient costs were significantly influenced by the method of hysterectomy.

Prospective evaluation of quality of life in total versus supracervical laparoscopic hysterectomy.

STUDY OBJECTIVE: To evaluate and compare recovery times and quality of life (QOL) in patients undergoing a total laparoscopic hysterectomy (TLH) and laparoscopic supracervical hysterectomy (LSH). DESIGN: Patients underwent either a TLH or LSH. After surgery, patients maintained a daily log documenting pain, nausea, use of pain medications, and return to daily activities. They also completed a QOL questionnaire (SF-36) before and after surgery. DESIGN CLASSIFICATION: Prospective cohort study (Canadian Task Force Classification II-1). SETTING: University teaching hospital. PATIENTS: A total of 122 women undergoing laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: A total of 122 women underwent TLH (n = 71) or LSH (n = 51) for benign indications from February 2008 to January 2010. There was a significantly higher postoperative improvement of QOL scores in the LSH group in 6 of 10 questionnaire categories and summary scores, including physical functioning (p =.03), role physical (p =.002), and bodily pain (p =.03). There were no significant differences in use of pain medications, level of pain, level of nausea, or return to normal activities. CONCLUSION: LSH appears to provide greater improvement in short-term postoperative QOL compared with TLH. No significant differences were found in postoperative pain or return to daily activities.

The Feasibility of Societal Cost Equivalence between Robotic Hysterectomy and Alternate Hysterectomy Methods for Endometrial Cancer.

Objectives. We assess whether it is feasible for robotic hysterectomy for endometrial cancer to be less expensive to society than traditional laparoscopic hysterectomy or abdominal hysterectomy. Methods. We performed a retrospective cohort analysis of patient characteristics, operative times, complications, and hospital charges from all (n = 234) endometrial cancer patients who underwent hysterectomy in 2009 at our hospital. Per patient costs of each hysterectomy method were examined from the societal perspective. Sensitivity analysis and Monte Carlo simulation were performed using a cost-minimization model. Results. 40 (17.1%) of hysterectomies for endometrial cancer were robotic, 91 (38.9%), were abdominal, and 103 (44.0%) were laparoscopic. 96.3% of the variation in operative cost between patients was predicted by operative time (R = 0.963, P < 0.01). Mean operative time for robotic hysterectomy was significantly longer than other methods (P < 0.01). Abdominal hysterectomy was consistently the most expensive while the traditional laparoscopic approach was consistently least expensive. The threshold in operative time that makes robotic hysterectomy cost equivalent to the abdominal approach is within the range of our experience. Conclusion. It is feasible for robotic hysterectomy to be less expensive than abdominal hysterectomy, but unlikely for robotic hysterectomy to be less expensive than traditional laparoscopy.

A sequence variant on 17q21 is associated with age at onset and severity of asthma.

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Sequence variants in the RNF212 gene associate with genome-wide recombination rate.

The genome-wide recombination rate varies between individuals, but the mechanism controlling this variation in humans has remained elusive. A genome-wide search identified sequence variants in the 4p16.3 region correlated with recombination rate in both males and females. These variants are located in the RNF212 gene, a putative ortholog of the ZHP-3 gene that is essential for recombinations and chiasma formation in Caenorhabditis elegans. It is noteworthy that the haplotype formed by two single-nucleotide polymorphisms (SNPs) associated with the highest recombination rate in males is associated with a low recombination rate in females. Consequently, if the frequency of the haplotype changes, the average recombination rate will increase for one sex and decrease for the other, but the sex-averaged recombination rate of the population can stay relatively constant.

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for third-degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.