Genome-wide association studies (GWAS) have identified several risk
variants for late-onset Alzheimer's disease (LOAD)1,2. These
common variants have replicable but small effects on LOAD risk and generally do
not have obvious functional effects. Low-frequency coding variants, not detected
by GWAS, are predicted to include functional variants with larger effects on
risk. To identify low frequency coding variants with large effects on LOAD risk,
we performed whole exome-sequencing (WES) in 14 large LOAD families and
follow-up analyses of the candidate variants in several large case-control
datasets. A rare variant in PLD3 (phospholipase-D family,
member 3, rs145999145; V232M) segregated with disease status in two independent
families and doubled risk for AD in seven independent case-control series (V232M
meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354
cases and controls of European-descent). Gene-based burden analyses in 4,387
cases and controls of European-descent and 302 African American cases and
controls, with complete sequence data for PLD3, indicate that
several variants in this gene increase risk for AD in both populations (EA: OR=
2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92;
p=1.40×10-3). PLD3 is highly expressed in
brain regions vulnerable to AD pathology, including hippocampus and cortex, and
is expressed at lower levels in neurons from AD brains compared to control
brains (p=8.10×10-10). Over-expression of PLD3 leads to a
significant decrease in intracellular APP and extracellular Aβ42 and
Aβ40, while knock-down of PLD3 leads to a significant increase in
extracellular Aβ42 and Aβ40. Together, our genetic and functional
data indicate that carriers of PLD3 coding variants have a
two-fold increased risk for LOAD and that PLD3 influences APP
processing. This study provides an example of how densely affected families may
be used to identify rare variants with large effects on risk for disease or
other complex traits.
TX 75083-3836, U.S.A., fax 01-972-952-9435.Abstract: Reverse circulation has always been viewed with some level of suspicion and reverse circulation with coiled tubing has often been avoided at all costs. Yet, results of over 1600 CT operations involving reverse circulating in Alaska's oil fields, with just a handful of failures, has proven reverse circulation to be a reliable procedure for a specific range of solids removal that is extremely effective in removing sand fill from wells with very large tubulars and in high deviations. Results from North Sea, Colombia, California and the US GoM are also included. This paper presents the basics of reverse circulation designed specifically for coiled tubing; including necessary surface equipment, BHA nozzle design, pump requirements, fluid rates, and procedures to reduce the potential for problems. The procedures and job overviews contained here were contributed during an ICOTA panel discussion on reverse circulating, held September 18, 2003, in Houston, TX.
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