Association of 5-hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene polymorphisms with asthma

Background and objective: The neurotransmitter, 5‐hydroxytryptamine, acts as an immunomodulator by stimulating the release of inflammatory cytokines and regulating the function of dendritic cells and monocytes. The 5‐hydroxytryptamine receptor 4 (HTR4) gene is located in a region previously linked to an increased risk of asthma and atopy. The aim of this study was to investigate the association between HTR4 and asthma. Methods: Thirty‐two single nucleotide polymorphisms (SNP) in HTR4 were investigated by direct sequencing of 24 DNA samples from unrelated Korean subjects. Results: The 32 genetic variants comprised 22 intronic SNP, two SNP in the 3′‐untranslated region (exon 7) and eight SNP in the 3′‐downstream region. Logistic regression analysis showed that two intronic polymorphisms were significantly associated with the risk of asthma. Two minor HTR4 alleles, +142828G > A and +122769G > A, occurred at significantly higher frequencies in the asthmatic group than in the healthy control group (49.59% vs 42.29%, P = 0.003, and 47.99% vs 40.35%, P = 0.008, respectively), and these differences remained significant after correction for multiple testing (P = 0.05, dominant mode of inheritance; and P = 0.03, dominant mode, respectively). Haplotype analysis revealed three haplotype blocks. The frequency of haplotype 1 in block 2 was significantly higher in asthmatics (P = 0.003, dominant mode), whereas the frequency of haplotype 4 in block 3 was significantly lower in asthmatics (P = 0.0009, dominant mode). Conclusions: SNP and haplotypes of the HTR4 gene were associated with the asthma phenotype and genetic variation of HTR4 may affect susceptibility to the development of asthma.     

Robin Goodfellow (42-5)

Three years since Robin began his column, his enthusiasm andiconoclasm know no bounds. He only wishes he had paid more attentionto anatomy as a boy (‘Mr Robin’, said the Dean ofhis medical school as Robin asked if that was all after an astonishingshort 2nd MB viva, ‘You know, and I know, that there islittle to be gained except pain from prolonging this interview’).But rheumatology lends itself to anatomical studies and alongcome Fairbank and Corlett to show how interesting tennis elbowscan be, anatomically speaking (J Hand Surg 2003;27B:405–9). It is the extensor digitorum communis that is exciting. Do youdo Maudsley's test? Does it confirm     

Robin Goodfellow (43-5)

Whenever Robin despairs that no misprints have fallen in hislap for the next column, four come along at once. The LondonCollege of Physicians is advertising a lecture (in October)entitled ‘Beyond Harvey Crushing: enzymes and the redefinitionof corticosteroid hormone action’. Methinks someone wasthinking of crush injury to inflict such a cushing indictmenton medical history—but then again, one of Robin’scolleagues, invoking the principles of Semmelweiss to persuadehis trainees to wash their hands between patients, was asked‘Who’s Semmelweiss?’ And the dear Sunday Times has been doing its bit for disease.In an admirable article about designing homes for disabilityit quoted a sufferer from hip dysphasia, which     

Molecular stability and function of hemoglobins Hasharon (alpha(2)47 (CD5)Asp----His beta 2) and Hasharon (alpha(2)47 (CD5)Asp----His delta 2)

The molecular stability and function of hemoglobin (Hb) Hasharon (alpha 2 H beta 2) and Hb Hasharon2 (alpha 2 H delta 2) were studied and compared to Hbs A, A2 and S. Hb Hasharon and Hb Hasharon2 had slightly lower P50 values than Hb A and Hb A2 but had normal responses to organic phosphates. The molecular stability of Hb Hasharon and Hb Hasharon2 (as measured by mechanical shaking and heat denaturation at 60 degrees C) were less than Hb A and Hb A2 but greater than Hb S in the oxy- and carbonmonoxy-forms. In the met-form, however, Hb Hasharon and Hb Hasharon2 were less stable than hemoglobins S, A and A2. The oxy-form of Hb Hasharon forms methemoglobin at a faster rate than Hb A and Hb S. The mechanical and heat stabilities and the rate of methemoglobin formation of oxy-Hb Hasharon were studied in the presence of sulfisoxazole. This drug increased the rate of methemoglobin formation, thus causing a further decrease in the stability of Hb Hasharon. The relationship between these laboratory findings and previously observed clinical findings associated with Hb Hasharon are discussed.     

5''-O-Monophosphoryladenylyl(2'' goes to 5'')adenylyl(2'' goes to 5'')adenosine is an antagonist of the action of 5''-O-triphosphoryladenylyl-(2'' goes to 5'')adenylyl(2'' goes to 5'')adenosine and double-stranded RNA.

5'-O-Monophosphoryladenylyl(2' goes to 5')adenylyl-(2' goes to 5')adenosine [(2' goes to 5')(pA)3] antagonizes the protein synthesis inhibitory effects of 5'-O-triphosphoryladenylyl-(2' goes to 5')adenylyl(2' goes to 5')adenosine by preventing activation of the (2' goes to 5')oligo(a)-activated ribonuclease which degrades mRNA. The oligoribonucleotide (2' goes to 5')(pA)3 also antagonizes the translational inhibitory capacity of poly(I).poly(C) in extracts of interferon-treated L cells, suggesting that (2' goes to 5')oligo(A) is the primary mediator of the protein synthesis inhibitory effects of poly(I).poly(C) in this cell-free system.     

Mutational analysis of insertion sequence 50 (IS50) and transposon 5 (Tn5) ends.

Insertion sequence 50 (IS50) transposition utilizes a 19-base-pair "outside" end and a 19-base-pair "inside" end in inverted orientation relative to each other, whereas transposon 5 (Tn5) transposition utilizes two inverted outside ends. The frequency of transposition events that involve an inside end is regulated 1000-fold by the host dam methylase system. The end sequence requirements for transposition and its regulation by dam methylase were analyzed in Escherichia coli by generating random single base pair mutations in either an IS50 inside end or outside end placed in inverted orientation with respect to an unmutagenized outside end. The mutations were then isolated, assayed for transposition phenotype, and sequenced. Mutations were isolated at 15 of the 19 sites in the outside end. All of these mutations except those at position 4 decreased transposition. Mutations at position 4 (which is the only nonidentical base pair in a region of homology between the outside and inside ends) had no effect on transposition. Mutations were isolated at 11 of the 19 sites in the inside end. All of these mutations, including one at position 4, decreased transposition in dam- cells. Mutations at position 10 (within a dam recognition sequence) and 2 (not within a dam recognition sequence) reduced the magnitude of dam regulation. A mutation within a dam recognition sequence adjacent to the required 19 base pairs of the inside end did not reduce the magnitude of dam regulation.     

5'-Terminal m-7G(5')ppp(5')G-m-p in vivo: identification in reovirus genome RNA.

Methylated reovirus mRNA was synthesized in vitro in the presence of S-adenosyl-L-[methyl-3H]-methionine. Viral genome double-stranded RNA that was uniformly labeled with 32-P was isolated from purified virions. The RNAs were mixed and their 5'-terminal structures compared by electrophoretic and chromatographic analyses after enzymatic digestion. Both the mRNA and the corresponding strand in the genome RNA contain m-7G(5')ppp(5')G-m-pCp, indicating that infected cells synthesize viral RNA with blocked, methylated 5' termini.