A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Protein kinase C activation by 12-0-tetradecanoylphorbol 13-acetate in CG-4 line oligodendrocytes stimulates turnover of choline and ethanolamine phospholipids by phospholipase D and induces rapid process contraction.

Treatment of [3H]-choline- or [14C]-ethanolamine-labelled undifferentiated bipolar and differentiated multipolar CG-4 line oligodendrocytes with 12-0-tetradecanoylphorbol 13-acetate (TPA) to activate protein kinase C stimulated the release of choline or ethanolamine metabolites to the medium over controls. Ro31-8220, a PKC inhibitor, reduced TPA-stimulated release of choline- and ethanolamine-metabolites to basal levels. TPA treatment of both bipolar and multipolar cells caused rapid contraction of processes leaving rounded up cells: this effect was blocked by Ro31-8220. After 12-15 h exposure to TPA, bipolar undifferentiated CG-4 line cells extended short processes again and the cells became multipolar. Nocodozole, an agent which disrupts microtubules and caused CG-4 line cells to round up, caused increased choline or ethanolamine-metabolite release to the medium over basal levels suggesting that some release during TPA-treatment might occur due to process fragmentation. However, the transphosphatidylation reaction confirmed that phospholipase D was active in these cells. Exposure of bipolar undifferentiated CG-4 line cells to TPA resulted in down-regulatation of PKC-alpha and PKC-beta which could not be detected by Western blotting after a few hours; PKC-epsilon was down-regulated much more slowly but PKCs delta, zeta and iota were not influenced by 48 h exposure of cells to TPA. Formation of phosphatidylethanol in the transphosphatidylation reaction was markedly reduced in TPA down-regulated cells indicating a role for PKCs alpha and beta in phospholipase D activation in CG-4 line oligodendrocytes.

Association between use of spermicide-coated condoms and Escherichia coli urinary tract infection in young women.

Diaphragm/spermicide use increases the risk of urinary tract infection (UTI). To determine whether spermicide-coated condoms are also associated with an increased risk of UTI, the authors conducted a case-control study at a large health maintenance organization in Seattle, Washington. Cases were sexually active young women with acute UTI caused by Escherichia coli, identified from computerized laboratory files during 1990-1993. Age-matched controls were randomly selected from the enrollment files of the plan. Of 1,904 eligible women, 604 cases and 629 controls (65%) were interviewed. During the previous year, 40% of the cases and 31% of the controls had been exposed to any type of condom. The unadjusted odds ratio for UTI increased with frequency of condom exposure from 0.91 (95% confidence interval (CI) 0.65-1.28) for weekly or less during the previous month to 2.11 (95% CI 1.37-3.26) for more than once weekly. Exposure to spermicide-coated condoms conferred a higher risk of UTI, with odds ratios ranging from 1.09 (95% CI 0.58-2.05) for use weekly or less to 3.05 (95% CI 1.47-6.35) for use more than once weekly. In multivariate analyses, intercourse frequency (odds ratio (OR) = 1.14 per weekly episode), history of UTI (OR = 2.64), and frequency of spermicide-coated condom exposure (OR = 3.34 for more than once weekly and 5.65 for use more than twice weekly) were independent predictors of UTI. Spermicide-coated condoms were responsible for 42% of the UTIs among women who were exposed to these products.

PIP: A large population-based case-control study found that condoms coated with the spermicide nonoxynol-9 were responsible for 42% of urinary tract infections (UTIs) in women exposed to these products. 604 women 18-40 years old who presented to a health maintenance organization in Seattle, Washington, during 1990-93 with acute UTI caused By Escherichia coli served as cases; 629 age-matched controls were randomly selected from the health facility's files. In the preceding month, nonoxynol-coated condoms had been used by 35% of cases and 25% of controls. The unadjusted odds ratios for having an acute UTI among women who had used any type of condom in the previous month and previous year were 1.24 (95% confidence interval, 0.94-1.63) and 1.47 (1.16-1.85), respectively. The UTI risks for women who used the nonoxynol-9 coated condoms in the previous month and more than twice a week during the past year were 1.72 (1.08-2.75) and 2.39 (1.10-5.16), respectively. Independent predictors of UTI, identified through multivariate analyses, included intercourse frequency (odds ratio of 1.14 per weekly episode), past history of UTI (2.64), and frequency of coated condom exposure (3.34 for more than once weekly and 5.65 for use more than twice weekly). Among cases exposed to spermicide-coated condoms during the previous month, 41.9% of UTIs were due to coated condoms. The association confirmed in this study is supported by research indicating that nonoxynol-9 induces changes in the normal vaginal flora that facilitate colonization with coliform bacteria.