Is There an Association Between GNβ3–C825T Genotype and Lower Functional Gastrointestinal Disorders?
2006; Elsevier BV; Volume: 130; Issue: 7 Linguagem: Inglês
10.1053/j.gastro.2006.03.017
ISSN1528-0012
AutoresViola Andresen, Michael Camilleri, H. Jae Kim, Debra Stephens, Paula J. Carlson, Nicholas J. Talley, Yuri A. Saito, Raúl Urrutia, Alan R. Zinsmeister,
Tópico(s)Gastroesophageal reflux and treatments
ResumoBackground & Aims: GNβ3 influences G-protein translation of a majority of ligand-receptor activations. It has been reported that functional dyspepsia (FD) is associated with homozygous genotypes of the C825T polymorphism in the GNβ3 gene. It is unknown whether the GNβ3 genotype is associated with lower functional gastrointestinal disorders (FGID). We aimed to compare the prevalence of the different GNβ3–C825T genotypes in patients with lower FGID and healthy controls and to test the associations of these genetic variations with subgroups of irritable bowel syndrome (IBS), functional abdominal pain (FAP), lower FGID–FD overlap, and high somatic symptom scores. Methods: GNβ3–C825T polymorphism was analyzed in DNA from blood samples of 233 patients with lower FGID and 152 healthy controls. A validated bowel questionnaire characterized the FGID phenotype: 82 with IBS constipation, 94 with IBS diarrhea, 38 with IBS alternating bowel function, and 19 with FAP. There were 159 patients with lower FGID and overlap FD using Rome II criteria. Regression analyses assessed associations of the GNβ3 genotypes with lower FGID as a group, and subgroups of FGID and somatic symptom scores. Results: GNβ3–C825T genotype distributions were similar between healthy controls (50.7% CC, 40.8% TC) and patients with lower FGID (8.6% TT, 51.5% CC, 40.8% TC, and 7.7% TT). There were no significant associations of GNβ3–C825T polymorphism with lower FGID overall or with the separate symptom subgroups including IBS, FAP, lower FGID–FD overlap, or high somatic symptom scores.Conclusions: In contrast to the reported association with FD, GNβ3–C825T polymorphism is not associated significantly with lower FGID, with different IBS or FAP phenotypes, or lower FGID–FD overlap. Background & Aims: GNβ3 influences G-protein translation of a majority of ligand-receptor activations. It has been reported that functional dyspepsia (FD) is associated with homozygous genotypes of the C825T polymorphism in the GNβ3 gene. It is unknown whether the GNβ3 genotype is associated with lower functional gastrointestinal disorders (FGID). We aimed to compare the prevalence of the different GNβ3–C825T genotypes in patients with lower FGID and healthy controls and to test the associations of these genetic variations with subgroups of irritable bowel syndrome (IBS), functional abdominal pain (FAP), lower FGID–FD overlap, and high somatic symptom scores. Methods: GNβ3–C825T polymorphism was analyzed in DNA from blood samples of 233 patients with lower FGID and 152 healthy controls. A validated bowel questionnaire characterized the FGID phenotype: 82 with IBS constipation, 94 with IBS diarrhea, 38 with IBS alternating bowel function, and 19 with FAP. There were 159 patients with lower FGID and overlap FD using Rome II criteria. Regression analyses assessed associations of the GNβ3 genotypes with lower FGID as a group, and subgroups of FGID and somatic symptom scores. Results: GNβ3–C825T genotype distributions were similar between healthy controls (50.7% CC, 40.8% TC) and patients with lower FGID (8.6% TT, 51.5% CC, 40.8% TC, and 7.7% TT). There were no significant associations of GNβ3–C825T polymorphism with lower FGID overall or with the separate symptom subgroups including IBS, FAP, lower FGID–FD overlap, or high somatic symptom scores. Conclusions: In contrast to the reported association with FD, GNβ3–C825T polymorphism is not associated significantly with lower FGID, with different IBS or FAP phenotypes, or lower FGID–FD overlap. In most communities in Western countries, there is a high prevalence of lower functional gastrointestinal disorders (FGID) such as irritable bowel syndrome (IBS) and functional abdominal pain (FAP).1Drossman D.A. Li Z. Andruzzi E. Temple R.D. Talley N.J. Thompson W.G. Whitehead W.E. Janssens J. Funch-Jensen P. Corazziari E. et al.U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact.Dig Dis Sci. 1993; 38: 1569-1580Crossref PubMed Scopus (1877) Google Scholar These disorders are associated with several pathophysiologic abnormalities including abnormal gastrointestinal motor function, visceral hypersensitivity, psychosocial changes (eg, depression, anxiety, or abuse), autonomic dysfunction, and inflammation.2Drossman D.A. Camilleri M. Mayer E.A. Whitehead W.E. AGA technical review on irritable bowel syndrome.Gastroenterology. 2002; 123: 2108-2131Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar Approximately 80% of all known membrane receptors that are linked to intracellular effector systems are coupled to heterotrimeric G proteins. G proteins are expressed in all cells of the human body and play a pivotal role in the signal translation from the cell surface (eg, ligand-receptor interaction) to subsequent cellular responses. Thus, qualitative or quantitative changes in G proteins could result in disease by blocking or enhancing intracellular signal transduction. G proteins are composed of 3 different α, β, and γ subunit isoforms; the βγ subunits form a functional monomer. On receptor activation, the α and βγ subunits dissociate from their respective receptor and, in turn, modulate a large variety of intracellular effector systems. The β subunit protein Gβ3 belongs to a superfamily of propeller proteins that are composed of 7 tryptophan–aspartate repeat domains (each consisting of repeats of tryptophan–aspartate residues). These domains are involved in the interaction between the G-protein β and γ subunits and in the effect of the βγ dimer.3Sondek J. Bohm A. Lambright D.G. Hamm H.E. Sigler P.B. Crystal structure of a G-protein beta gamma dimer at 2.1A resolution.Nature. 1996; 379: 369-374Crossref PubMed Scopus (705) Google Scholar The Gβ3 protein is encoded by the GNβ3 gene. In the GNβ3 gene, there is a common C825T single nucleotide polymorphism (SNP) with an exchange from cytosine to thymidine, which gives rise to 3 possible genotypes (ie, CC, TC, and TT). The C825T polymorphism is located on exon 10, and the 825T allele (TC or TT genotype) is associated with alternative splicing of the gene in exon 9 and the formation of a truncated splice variant Gβ3s, a protein product with 41 amino acids less than in the Gβ3 wild-type protein.4Baumgart D. Naber C. Haude M. Oldenburg O. Erbel R. Heusch G. Siffert W. G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation.Circ Res. 1999; 85: 965-969Crossref PubMed Scopus (129) Google Scholar, 5Rosskopf D. Manthey I. Habich C. Kielbik M. Eisenhardt A. Nikula C. Urban M. Kohnen S. Graf E. Ravens U. Siffert W. Identification and characterization of G beta 3s2, a novel splice variant of the G-protein beta 3 subunit.Biochem J. 2003; 371: 223-232Crossref PubMed Scopus (42) Google Scholar This corresponds to the lack of the equivalent of one entire tryptophan–aspartate repeat domain.6Siffert W. Rosskopf D. Siffert G. Busch S. Moritz A. Erbel R. Sharma A.M. Ritz E. Wichmann H.E. Jakobs K.H. Horsthemke B. Association of a human G-protein beta3 subunit variant with hypertension.Nat Genet. 1998; 18: 45-48Crossref PubMed Scopus (732) Google Scholar The Gβ3s protein variant is associated with enhanced G-protein activation7Rosskopf D. Koch K. Habich C. Geerdes J. Ludwig A. Wilhelms S. Jakobs K.H. Siffert W. Interaction of Gbeta3s, a splice variant of the G-protein Gbeta3, with Ggamma- and Galpha-proteins.Cell Signal. 2003; 15: 479-488Crossref PubMed Scopus (45) Google Scholar and the 825T allele corresponding to the formation of Gβ3s has been associated with cardiovascular, affective, and metabolic disorders.6Siffert W. Rosskopf D. Siffert G. Busch S. Moritz A. Erbel R. Sharma A.M. Ritz E. Wichmann H.E. Jakobs K.H. Horsthemke B. Association of a human G-protein beta3 subunit variant with hypertension.Nat Genet. 1998; 18: 45-48Crossref PubMed Scopus (732) Google Scholar, 8Ruiz-Velasco V. Ikeda S.R. A splice variant of the G protein beta 3-subunit implicated in disease states does not modulate ion channels.Physiol Genomics. 2003; 13: 85-95PubMed Google Scholar, 9Avissar S. Schreiber G. Ziskind-Somerfeld Research Award. The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders.Biol Psychiatry. 1992; 31: 435-459Abstract Full Text PDF PubMed Scopus (107) Google Scholar, 10Siffert W. Cardiovascular pharmacogenetics on the way toward individually tailored drug therapy.Kidney Int Suppl. 2003; 84: S168-S171Crossref PubMed Scopus (14) Google Scholar The homozygous C allele (CC genotype) results predominantly in the synthesis of the Gβ3 wild-type protein and only minute amounts of the β3 splice variant. The homozygous CC genotype is associated with diminished G-protein activity, decreased signal transduction responses,4Baumgart D. Naber C. Haude M. Oldenburg O. Erbel R. Heusch G. Siffert W. G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation.Circ Res. 1999; 85: 965-969Crossref PubMed Scopus (129) Google Scholar and was shown to be associated with unexplained or community dyspepsia.11Holtmann G. Siffert W. Haag S. Mueller N. Langkafel M. Senf W. Zotz R. Talley N.J. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia.Gastroenterology. 2004; 126: 971-979Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 12Camilleri C.E. Carlson P.J. Camilleri M. Castillo E.J. Locke 3rd, C.R. Geno D.M. Stephens D. Zinsmeister A.R. Urrutia R. A study of candidate genotypes associated with dyspepsia in a U.S. community.Am J Gastroenterol. 2006; 101: 581-592Crossref PubMed Scopus (96) Google Scholar Interestingly, a subgroup of 20 patients with dyspepsia, who also had IBS symptoms, also showed a trend to a significant association with the CC genotype.11Holtmann G. Siffert W. Haag S. Mueller N. Langkafel M. Senf W. Zotz R. Talley N.J. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia.Gastroenterology. 2004; 126: 971-979Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Holtmann et al13Holtmann G. Liebregts T. Siffert W. Molecular basis of functional gastrointestinal disorders.Best Pract Res Clin Gastroenterol. 2004; 18: 633-640Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar proposed that genetic factors interact with environmental factors in the etiology of FGID. In this model, it is biologically plausible for either the 825C or T allele to be associated with the development of lower FGID, which may correspond to different physiologic effects of either enhanced or decreased G-protein activity (eg, resulting in either rapid or slow gastrointestinal transit). Thus, the aims of this study were to compare the prevalence of the different genotypes of the GNβ3 C825T polymorphism in patients with lower FGID and healthy controls. Furthermore, because genetic associations have been shown for IBS subtypes,14Kim H.J. Camilleri M. Carlson P.J. Cremonini F. Ferber I. Stephens D. McKinzie S. Zinsmeister A.R. Urrutia R. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders.Gut. 2004; 53: 829-837Crossref PubMed Scopus (158) Google Scholar and because the GNβ3–C825T genotype has been associated with functional dyspepsia (FD)11Holtmann G. Siffert W. Haag S. Mueller N. Langkafel M. Senf W. Zotz R. Talley N.J. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia.Gastroenterology. 2004; 126: 971-979Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 12Camilleri C.E. Carlson P.J. Camilleri M. Castillo E.J. Locke 3rd, C.R. Geno D.M. Stephens D. Zinsmeister A.R. Urrutia R. A study of candidate genotypes associated with dyspepsia in a U.S. community.Am J Gastroenterol. 2006; 101: 581-592Crossref PubMed Scopus (96) Google Scholar and affective disorders,15Lee H.J. Cha J.H. Ham B.J. Han C.S. Kim Y.K. Lee S.H. Ryu S.H. Kang R.H. Choi M.J. Lee M.S. Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders.Pharmacogenomics J. 2004; 4: 29-33Crossref PubMed Scopus (109) Google Scholar we also aimed to test associations of these genetic variations with subgroups of lower FGID, lower FGID–FD overlap, and high somatic symptom scores (SoSCs). IBS participants (ages, 18–75 y) were selected from an administrative database of 752 patients with IBS who had been evaluated previously at the Mayo Clinic and were residing within a 150-mile radius of Rochester, Minnesota. All were invited to participate by mailed invitation. The 233 patients who agreed to participate completed a questionnaire and agreed to provide a peripheral blood sample for DNA analysis. All IBS patients had been evaluated previously by a staff gastroenterologist and undergone clinically indicated tests including a colonoscopy with mucosal biopsy examinations as indicated and clinical tests for rectal evacuation disorders. All IBS patients had to fulfill Rome II criteria16Thompson W.G. Longstreth G.F. Drossman D.A. Heaton K.W. Irvine E.J. Muller-Lissner S.A. Functional bowel disorders and functional abdominal pain.Gut. 1999; 45: II43-II47Crossref PubMed Scopus (2008) Google Scholar by their questionnaire responses. A total of 152 healthy volunteers (ages, 18–75 y) were recruited by public advertisement in Rochester, Minnesota. All participants signed informed consent for the study, which was approved by the Mayo Foundation Institutional Review Board. The majority of participants in the study came from a cohort evaluated for a genetic association between candidate adrenergic and serotonergic genotypes and lower FGID.14Kim H.J. Camilleri M. Carlson P.J. Cremonini F. Ferber I. Stephens D. McKinzie S. Zinsmeister A.R. Urrutia R. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders.Gut. 2004; 53: 829-837Crossref PubMed Scopus (158) Google Scholar All participants completed a validated bowel disease questionnaire17Talley N.J. Phillips S.F. Wiltgen C.M. Zinsmeister A.R. Melton 3rd, L.J. Assessment of functional gastrointestinal disease the bowel disease questionnaire.Mayo Clin Proc. 1990; 65: 1456-1479Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar including questions that corresponded to Rome II criteria16Thompson W.G. Longstreth G.F. Drossman D.A. Heaton K.W. Irvine E.J. Muller-Lissner S.A. Functional bowel disorders and functional abdominal pain.Gut. 1999; 45: II43-II47Crossref PubMed Scopus (2008) Google Scholar and a somatic symptom checklist. The latter questionnaire has been used in the literature to identify people with a propensity to report somatic symptoms.18Castillo E.J. Camilleri M. Locke G.R. Burton D.D. Stephens D.A. Geno D.M. Zinsmeister A.R. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia.Clin Gastroenterol Hepatol. 2004; 2: 985-996Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar The symptoms surveyed were as follows: headache, backache, wheezing, trouble breathing, difficulty sleeping, fatigue (tiredness), depression (feeling sad or blue), general stiffness, palpitations, joint pains, eye pain associated with reading, dizziness, weakness, nervousness (or shakiness), hot or cold spells, and high blood pressure. Data on the SoSCs were available for more than 90% of all participants. The SoSC was summarized as a mean of the frequency and severity scores over the 16 items each participant recorded on a scale of 0–4. Participants were classified as having a high somatic score when their mean score across the 16 domains was higher than .75, which was the 90th percentile of mean scores for the healthy participants in this study. We and others have used these 2 questionnaires extensively in epidemiologic studies (eg, in people with FGID).18Castillo E.J. Camilleri M. Locke G.R. Burton D.D. Stephens D.A. Geno D.M. Zinsmeister A.R. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia.Clin Gastroenterol Hepatol. 2004; 2: 985-996Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 19Kalantar J.S. Locke 3rd, G.R. Zinsmeister A.R. Beighley C.M. Talley N.J. Familial aggregation of irritable bowel syndrome a prospective study.Gut. 2003; 52: 1703-1707Crossref PubMed Scopus (130) Google Scholar All patients were symptomatic with their functional bowel disorder at the time of the questionnaire assessment and were categorized in disease phenotypes using the validated bowel disease questionnaire17Talley N.J. Phillips S.F. Wiltgen C.M. Zinsmeister A.R. Melton 3rd, L.J. Assessment of functional gastrointestinal disease the bowel disease questionnaire.Mayo Clin Proc. 1990; 65: 1456-1479Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar in accordance with Rome II criteria. There is evidence of a significant likelihood of category transitions between constipation-predominant IBS (IBS-C) and functional constipation, and similar transitions in the categories of diarrhea-predominant IBS (IBS-D) and functional diarrhea.20Locke G.R.I. Fett S.L. Zinsmeister A.R. Transition probabilities between functional gastrointestinal disorders in the community.Gastroenterology. 2001; 120: A52Abstract Full Text PDF Google Scholar Hence, patients whose symptoms at the time of the questionnaire suggested IBS-C and functional constipation were grouped into 1 group (designated IBS-C), or those with IBS-D and functional diarrhea into a second group (designated IBS-D). Other independent categories were IBS with alternating bowel habits (IBS-A) and FAP. The bowel disease questionnaire also was used to determine the co-existence of dyspepsia, using 2 different definitions for dyspepsia. Definition 1 (DI) was based on the Rome II definition of dyspepsia and used the following criteria: frequent upper-abdominal pain or frequent early satiety within the past year. Definition 2 (DII) also included frequent early satiety but was stricter in requiring that the upper-abdominal pain be associated either with frequent nausea (at least once a week) or occurred after meals. The latter definition was added given the observation that approximately 60% of dyspeptic people in a community study experienced meal-related symptoms.18Castillo E.J. Camilleri M. Locke G.R. Burton D.D. Stephens D.A. Geno D.M. Zinsmeister A.R. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia.Clin Gastroenterol Hepatol. 2004; 2: 985-996Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Venous blood drawn from a forearm vein was stored as de-identified samples. Genomic DNA was isolated from whole blood in 385 participants by the alkaline lysis method using the QIAamp DNA Blood Maxi Kit (Qiagen Inc., Valencia, CA). GNβ3 genotypes were determined by methods described in the literature.6Siffert W. Rosskopf D. Siffert G. Busch S. Moritz A. Erbel R. Sharma A.M. Ritz E. Wichmann H.E. Jakobs K.H. Horsthemke B. Association of a human G-protein beta3 subunit variant with hypertension.Nat Genet. 1998; 18: 45-48Crossref PubMed Scopus (732) Google Scholar Real-time polymerase chain reaction using TaqMan chemistries (Applied Biosystems, Foster City, CA) was used to determine alleles present in each sample. Real-time polymerase chain reactions were performed in an Applied Biosystems 7500 machine (Applied Biosystems). TaqMan primer-probe assays for GNβ3 SNPs C825T (rs6489738) were purchased from Applied Biosystems. Each reaction volume was 25 μL and consisted of 13.75 μL of a master mix containing 12.5 μL 2× TaqMan Universal reaction mix (Applied Biosystems), 1.25 μL of a 20× primer-probe assay mix (Applied Biosystems), and 11.25 μL (20 ng) genomic DNA. Amplification conditions consisted of 10 minutes at 95°C followed by 40 cycles at 92°C for 15 seconds and 60°C for 60 seconds. Fluorescence intensity was measured before and after amplification and then analyzed using automated software (SDS 2.1; Applied Biosystems) to determine the genotype of each sample. Genotypes were confirmed or assessed selectively by direct sequencing as previously described.12Camilleri C.E. Carlson P.J. Camilleri M. Castillo E.J. Locke 3rd, C.R. Geno D.M. Stephens D. Zinsmeister A.R. Urrutia R. A study of candidate genotypes associated with dyspepsia in a U.S. community.Am J Gastroenterol. 2006; 101: 581-592Crossref PubMed Scopus (96) Google Scholar Statistical analyses assessed the associations of the 3 different genotypes (CC, TC, and TT) and of CC vs combined TC and TT with lower FGID. The latter analysis was of specific interest because the CC genotype relative to non-CC (or combined TC and TT) has been associated with an increased risk for unexplained dyspepsia and dyspepsia in a community-based sample.11Holtmann G. Siffert W. Haag S. Mueller N. Langkafel M. Senf W. Zotz R. Talley N.J. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia.Gastroenterology. 2004; 126: 971-979Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 12Camilleri C.E. Carlson P.J. Camilleri M. Castillo E.J. Locke 3rd, C.R. Geno D.M. Stephens D. Zinsmeister A.R. Urrutia R. A study of candidate genotypes associated with dyspepsia in a U.S. community.Am J Gastroenterol. 2006; 101: 581-592Crossref PubMed Scopus (96) Google Scholar A χ2 test was used to assess the deviation of the observed genotype frequencies for the controls participating in the study from that expected based on the Hardy–Weinberg equilibrium principle (HWE).21Hedrick P.H. Genetics of populations. Jones and Bartlett Publishers, Boston2005Google Scholar The univariate association between the GNβ3 genotypes and symptom groups (overall FGID group and, separately, different symptom phenotype subgroups including the lower FGID–FD overlap group vs the control group) were assessed using a χ2 test or Fisher exact test as appropriate. Logistic regression models were used to estimate the odds ratios for specific phenotypes of IBS in participants with different GNβ3 genotypes relative to the wild type. Specifically, the odds ratios (and the 95% confidence intervals) for a specific phenotype were computed from the estimated logistic regression model coefficients (and their standard errors) examining the CC genotype relative to the combined TC and TT genotypes. Race and sex were included as covariates in each of the logistic regression models. The association of the somatic symptom checklist score with the genotype subgroup was assessed using a linear regression model with genotype (coded as dummy regression variables with TC subtype as the reference level) as the primary predictor variable, adjusting for age and sex. The statistical software used for all analyses was SAS (SAS Institute Inc., Cary, NC). After the study was completed, we estimated the effect size detectable with 80% power to identify significant associations given the number of participants in different subgroups included in this study. The symptom phenotypes of patients with lower FGID, for whom DNA was available for analysis, were as follows: 82 IBS-C, 94 IBS-D, 38 IBS-A, and 19 FAP. There were 159 patients with lower FGID–FD overlap according to DI and 143 patients with lower FGID–FD overlap according to DII. With both FD definitions, there were patients in all 4 lower FGID phenotypes who had evidence of overlap with FD. Thus, almost all patients with IBS-A and FAP and about 50 patients in each of the IBS-D and IBS-C groups had FD. In 14 patients with lower FGID, the FD status could not be assessed because of incomplete questionnaire data. The demographics of patients in the different lower FGID subgroups are shown in Table 1. Female participants predominated in the patient (85%) and control (74%) groups; 92% of controls and 98% of patients were Caucasians; there were 5% Asian and 3% Hispanic healthy participants. Other racial groups constituted less than 1% in the 2 groups.Table 1Patient Characteristics and Mean SoSCs in 233 Patients With Lower FGID and 152 Healthy ControlsControlsAll lower FGIDIBS-CIBS-DIBS-AFAPN15223382943819Age, mean (range)42 (18–81)50 (18–82)52 (23–82)49 (19–77)47 (18–69)47 (26–78)Sex, n (% female)112 (74)197 (85)76 (93)77 (82)30 (79)14 (74)SoSC,aThe SoSC was not available for all participants. mean (±SD).35 (.36).9 (.59).90 (.57).89 (.58).92 (.65).88 (.62)[N][134][215][79][80][38][18]Caucasians, n (%)139 (92)228 (98)79 (96)93 (99)37 (97)19 (100)Hispanics, n (%)4 (3)1 (.4)1 (1.2)0 (0)0 (0)0 (0)African Americans, n (%)1 (.7)0 (0)0 (0)0 (0)0 (0)0 (0)Asians, n (%)7 (5)2 (.9)1 (1.2)1 (1.1)0 (0)0 (0)Other, n (%)1 (.7)2 (.9)1 (1.2)0 (0)1 (2.6)0 (0)a The SoSC was not available for all participants. Open table in a new tab FGID subgroups were associated significantly with high SoSCs; patients in the different symptom subgroups had higher scores than the healthy controls (P < .01). The observed genotype frequencies of the GNβ3 polymorphism in the control participants are shown in Table 2. The genotype frequencies in the control group were in accordance with the HWE.Table 2Distribution of the GNβ3–C825T Genotypes in 233 Patients With Lower FGID and 152 Healthy Controls Across Overall Groups and SubtypesGNβ3–C825T genotypeControls (N = 152)All lower FGID (N = 233)IBS-C (N = 82)IBS-D (N = 94)IBS-A (N = 38)FAP (N = 19)CC, %50.751.551.257.539.547.4TC, %40.840.83935.157.942.1TT, %8.67.79.87.42.610.5NOTE. Values are column percentages. χ2 analysis for controls and FGID subgroups: P = .51. Open table in a new tab NOTE. Values are column percentages. χ2 analysis for controls and FGID subgroups: P = .51. The observed genotype frequencies of the GNβ3 polymorphism in patients with lower FGID and subgroups are shown in Table 2. The proportions of GNβ3 C825T genotypes in patients with lower FGID or subgroups were not significantly different from controls. When the analysis used 6 FGID phenotypes by separating IBS-C from functional constipation and IBS-D from functional diarrhea, there were no significant associations with the GNβ3–C825T genotype (data not shown). Table 3 summarizes the distribution of controls and of lower FGID subgroups within the 3 GNβ3 genotypes (CC, TC, and TT). No association between GNβ3 genotype and phenotype (overall lower FGID vs controls, or phenotypic subgroups vs controls) was detected (P > .05, Table 3).Table 3The Distribution of Controls and Different IBS Symptom Phenotypes in Categories of the GNβ3–C825T GenotypeIBS phenotype in each genotypeCC (N = 197)TC (N = 157)TT (N = 31)Controls39.139.541.9IBS-C21.320.425.8IBS-D27.421.022.6IBS-A7.614.03.2FAP4.65.16.5SoSC (mean ± SD).65 (.52).72 (.62).76 (.63)NOTE. Values are column percentages, except as noted. Open table in a new tab NOTE. Values are column percentages, except as noted. Table 4, Table 5 summarize the distribution of the 3 different GNβ3 genotypes in controls and patients with lower FGID–FD overlap, presented separately for the overall lower FGID group (Table 4), or for the different lower FGID subgroups (Table 5). The proportions of GNβ3 C825T genotypes were not significantly different in controls and in patients with lower FGID without or with FD overlap (Table 4, Fisher exact test: P = .18 for DI and P = .29 for DII). Similarly, the GNβ3–C825T genotype was not associated significantly with any lower FGID subgroup with or without overlapping FD when compared with controls (Table 5, data are presented only for DI).Table 4Distribution of the GNβ3–C825T Genotypes in Patients With Overall Lower FGID With (+D) and Without (−D) Overlap FD by Two Different Dyspepsia DefinitionsGNβ3–C825T genotypeUsing DI Controls (N = 152)Any FGIDUsing DII Controls (N = 152)Any FGID−DI (N = 60)+DI (N = 159)−DII (N = 76)+DII (N = 143)CC, %50.758.349.750.756.649.6TC, %40.830.045.340.832.945.4TT, %8.611.75.08.610.54.9P = .18aTest for association of genotype with phenotype (including controls) and dyspepsia status using the Fisher exact test; P values are unadjusted for multiple comparisons.P = .29aTest for association of genotype with phenotype (including controls) and dyspepsia status using the Fisher exact test; P values are unadjusted for multiple comparisons.NOTE. A total of 14 IBS-D participants could not be classified as to dyspepsia status.DI, Rome II; DII, early satiety or frequent abdominal pain in relation to meal or frequent abdominal pain with frequent nausea.a Test for association of genotype with phenotype (including controls) and dyspepsia status using the Fisher exact test; P values are unadjusted for multiple comparisons. Open table in a new tab Table 5Distribution of the GNβ3–C825T Genotypes in Patients With Lower FGID Subgroups With (+D) and Without (−D) Overlap FD by DIGNβ3–C825T genotypeControls (N = 152)FGID IBS-CFGID IBS-DFGID IBS-AFGID FAP−DI (N = 32)+DI (N = 50)−DI (N = 28)+DI (N = 52)−DI (N = 0)+DI (N = 38)−DI (N = 0)+DI (N = 19)CC, %50.762.544.053.663.5039.5047.4TC, %40.821.950.039.332.7057.9042.1TT, %8.515.66.07.13.802.6010.5P = .11aTest for association of genotype with phenotype (including controls) and dyspepsia status using the Fisher exact test; P values are unadjusted for multiple comparisons.P = .59aTest for association of genotype with phenotype (including controls) and dyspepsia status using the Fisher exact test; P values are unadjusted for multiple comparisons.P = .16aTest for association of genotype with phenotype (including controls) and
Referência(s)