Gastroenterology
Volume 126, Issue 4 , Pages 1193-1195, April 2004

Functional gastrointestinal disease: has the genomic era arrived?☆

  • Eamonn M.M. Quigley

      Affiliations

    • Department of Medicine, National University of Ireland, Cork, Ireland
    • Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland
    • Corresponding Author InformationAddress requests for reprints to: Eamonn M. M. Quigley, M.D., F.R.C.P., F.A.C.P., F.A.C.G., F.R.C.P.I., Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland fax: (353) 21 490 1289

Article Outline

 

Functional gastrointestinal disorders (FGIDs) are common, disabling, poorly understood, and bereft of curative therapy. Within the broad canvas that is functional gastrointestinal disease are found all of those patients with a symptom or, more usually, symptoms apparently originating from the gut, yet in whom conventional endoscopic, radiologic, serologic, manometric, and pathologic studies fail to uncover any abnormality of diagnostic significance. For some time, clinicians have recognized a tendency for some of the more common of the many and varied functional symptoms to aggregate into 2 major “clusters” which, in turn, tend to focus on either the upper or lower gut. These 2 primary groupings of FGIDs are more commonly recognized as functional dyspepsia (FD) and irritable bowel syndrome (IBS), respectively. Though some have counselled against such an approach, insisting that unexplained symptoms should be recognized as such and no more,1 the syndromatic approach to FGIDs, supported, in part, by clinical studies and expert opinion, has held sway and has led to the recognition and acceptance of both FD and IBS as valid targets for investigative and therapeutic research.2 FGIDs have, in essence, become “respectable” and one can now admit openly to a clinical or research interest in FD or IBS without attracting condescending glances and even opprobrium from fellow academics, funding authorities and peer-reviewed journals, alike.

Even more tantalizing for the newly accepted “functionologists” have been recent descriptions of disrupted physiology, subtle pathologic abnormalities and even genetic predisposition in FGIDs; are these disorders functional after all? On the physiological front, both FD and IBS have been associated with abnormalities of motor function,3 visceral hypersensitivity,3 autonomic function,4 and cerebral perception. Reports of the precipitation of both of these functional disorders by infectious agents are now extant in the literature.5, 6, 7 Especially impressive is the association between IBS and prior bacterial gastroenteritis; the natural history, predisposing factors and functional and pathologic correlates of this particular relationship are now well documented.6, 7 Equally provocative are very recent reports, of firstly, inflammatory cell activation, in the colon, among unselected IBS patients, regardless of the nature of onset or symptom predominance,8 and, secondly, of epithelial and myenteric plexus inflammation, in the jejunum, in a group of patients with severe IBS9; taken together, these studies suggest an immunological basis for IBS.10 Our current knowledge of mucosal immunology and its interactions with the gut flora, as well as experimental models of immune-motor and immune-sensory interactions have, in turn, provided a conceptual framework within which one can construct direct links between a luminal trigger, a mucosal immune response and symptom-generating alterations in enteric myoneural function.11, 12, 13 As in all other hypotheses of infectious initiation of chronic unexplained disease, a genetic predisposition is assumed to lay the groundwork and thus explain why not all exposed develop the disorder under study. Evidence for such a predisposition, indeed, exists for some FGIDs14, 15, 16 and is now further supported by the study from Holtmann et al. reported in this issue of Gastroenterology.17 Taken to its limits, the infection/inflammation hypothesis would appear, therefore, and for the first time, to square the circle in IBS and FGIDs?

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Science, medicine, and life are never that simple 

The problems with FGIDs, and FD, in particular, begin with their very definition. Any disorder whose definition is based soley on the presence or absence of a common and nonspecific symptom is prey to many confounding variables. In the study by Holtmann et al. FGIDs were defined using the Bowel Disease Questionnaire and according to the Rome II criteria. Despite the widespread acceptance of these instruments in FGIDs and IBS, in particular, the integrity and reproducibility, over time, of the definition of FD, derived according this strategy, are not beyond question.18 Indeed, the problems associated with the issue of definition are evident within this very study; many of the subjects demonstrated significant overlap between FD and IBS (74% of FD subjects in study A had symptoms consistent with IBS!); how should such overlap patients be categorized? To which FGID do we ascribe an association if one is found? It is interesting that these authors focused on FD and found, indeed, more evidence for an association between the 825 CC genotype and FD when there is, to date, a more convincing basis for a genetic predisposition in IBS,14, 15, 16 a diagnosis which clinicians regard as more coherent and stable than FD.19 That the 825 CC association failed to hold for the IBS subpopulation in Holtmann’s study will strike many as counterintuitive but may have reflected a lack of power to perform such detailed subgroup analysis. However, it must also be stated that the association with the CC phenotype for this gene which encodes for the β 3 subunit of G-proteins held up in the 2 different study groups reported by Holtmann et al.17 The risk attributable to the CC genotype in FD must be low, however, as its prevalence in FD exceeded that of controls by < 20%. How significant is this finding, therefore?

Genetic polymorphisms are extremely common and may have no relevance to disease; the interpretation of studies of polymorphisms is therefore fraught with difficulties.20, 21, 22 In 1 recent assessment of 55 meta-analyses of genetic associations, only 9 replicated the proposed association; small studies appeared most to blame for unsubstantiated claims.20 This issue must be especially problematic for a polymorphism as frequent in the general population as that reported by Holtmann et al., here genuine heterogeneity could be prominent. Though Holtmann et al. did take steps to minimize its impact, population stratification can also, inadvertently, contribute to spurious associations in this context.21 They acknowledge the possible contributions of such confounding factors as comorbid psychopathology, a major determinant of disease expression in FGIDs; others such as age and prior drug therapy may have also contributed in some of their subjects. Statistical issues may also come in to play; some have questioned the appropriateness of a P value set at 0.05 in association studies.22 A cursory glimpse at the literature reveals, not surprisingly, given the biological function of the gene product, a host of proposed associations between polymorphisms in the G protein β subunit gene and such common diseases as hypertension, depression, and obesity. It is noteworthy, however, that findings are not universally consistent between studies in the same disorder.

If this genotype is associated with FD, what is it doing? Holtmann et al. speculate on potential roles in enteric myoneural activity, central perception, hypothlalmic-pituitary axis (HPA) function and the inflammatory response.17 However, the relative contributions of these and other factors to the pathophysiology of FD remains unclear; while various groups have identified impaired accommodation, delayed gastric emptying, visceral hypersensitivity,3 as well as autonomic and HPA dysfunction4 as pathogenetic mechanisms in FD, the prevalence of any one of these findings and their relationships to particular symptoms have varied significantly between studies. Furthermore, the contribution of Helicobacter pylori, the most widely promoted infectious trigger for FD, is, at best, highly controversial. At present, therefore, gene-product-function correlations are quite impossible in FD and it is nigh impossible to place this intriguing finding in a clinical context.

All would agree that FD is a heterogenous disorder; what remain to be defined are the contributors to this heterogeneity, be they environmental, pathological, or psychological. The study presented by Holtmann et al., suggests, at the very least, that genetic variation may be one such factor; whether the genotype described relates to one, as yet to be defined, subgroup of FD or to FD, in general, remains to be defined. Given the high prevalence of the CC genotype among control subjects and the relatively modest excess of the genotype in the FD subjects, the former would appear more plausible.

Concerns regarding definition, heterogeneity and methodology notwithstanding, this and other studies point FGID research in a new direction, which we are obliged, in the interest of our patients, to follow.

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References 

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☆ Supported by grants from Science Foundation Ireland.

PII: S0016-5085(04)00301-4

doi:10.1053/j.gastro.2004.02.028

Gastroenterology
Volume 126, Issue 4 , Pages 1193-1195, April 2004

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