Letter to the Editor

Evaluation of a Familial Predisposition toRecurrent Urinary Tract Infections in Women

To the Editor:

Many adult women and female children are highlysusceptible to urinary tract infection (UTI) without anidentifiable anatomic abnormality [Engel, et al., 1980].Theories to explain this predisposition have focused ondiminished bladder defense mechanisms [Hopkins, etal., 1993; Hopkins and Uehling, 1995] and introitalcolonization with uropathogenic bacteria [Raz andStamm, 1993]. Despite the clinical observation thatUTIs tend to be more common in mothers, sisters, anddaughters of patients being seen for recurrent infec-tions, there has been insufficient and equivocal infor-mation in the literature regarding inheritance patternswithin families. Asymptomatic bacteriuria among Af-rican-American school girls has been reported to be lessthan among caucasion school girls; however, the au-thors found no difference in UTI history within familiesexcept for apparent clusters of cases in some families[Kunin, 1964]. Fennell reported that 14% of sisters hadhad UTIs [Fennell, et al., 1977]. Stansfeld et al. [1966]reported lack of a familial association for UTIs in 350hospitalized children, but many of these children hadstructural abnormalities. The objective of the presentstudy was to obtain better documentation of the famil-ial incidence of UTIs as preliminary evidence sugges-tive of a possible genetic basis for UTI susceptibility.

With Institutional Review Board approval, 41women with recurrent UTIs participated in the studyby filling out a questionnaire on their own infectionhistory and that of their mother, sisters, and daughterswhere applicable. Women entering were between 18and 70 years old (median age of 47 years), had 3 ormore UTIs during the past year, and normal results ofa clinical evaluation usually consisting of renal ultra-sonography and cystoscopy. Patient responses in thequestionnaire did not specify a time frame associatedwith the number of infections, and among those indi-cating more than 5 infections, the numbers ranged

from 6 to 30 infections. Data from the questionnaireswere used to determine the incidence of UTIs in femalerelatives and to construct pedigrees.

The incidence of UTIs in mothers, daughters, andsisters was approximately 50% or greater (Table I) and,thus, appeared to be high relative to the population atlarge. Even if we assumed an incidence of 20% for UTIsin adult women, this value would be well outside the95% confidence intervals obtained for each immediatefemale relative, indicating that UTIs are more preva-lent in female relatives of women with recurrent UTIs.The pedigrees in Figure 1 appear to further substanti-ate the clinical impression of a familial predispositionto UTIs within kindreds; however, the number of fami-lies studied is too small to allow definitive conclusionsto be drawn about mechanisms of inheritance. Wewould expect penetrance to be incomplete given thevariability of exposure to the infectious agents, otheraspects of host defenses, and the infecting organismsthemselves. Nevertheless, the vertical transmission ob-served in pedigrees A-D and F-H suggests that in thosefamilies it is possible that predisposition is a dominanttrait determined by a single gene. Limitation to singlesibships in pedigrees E and I could be interpreted asevidence of a recessively inherited single gene determi-nant, but we do not have sufficient documentation ofthe absence of affected individuals in these families todraw that conclusion. Genetic heterogeneity would notbe surprising given the multiplicity of causal factorsinvolved. Polygenic and multilocus determinants arecertainly possible as well.

Genetic predisposition to recurrent UTIs has beenpreviously investigated in both patient populations andanimal models. We have studied major histocompat-ibility complex and red blood cell antigen phenotypefrequencies of UTI-susceptible women and found nostatistically significant differences from a control popu-lation [Hopkins et al., 1998b]. In contrast, genetically

Contract grant sponsor: NIH; Contract grant number:DK44378; Contract grant number: DK30808.

*Correspondence to: Dr. Walter J. Hopkins, Department of Sur-gery, University of Wisconsin Medical School, 600 Highland Ave.,Madison, WI 53792. E-mail: hopkins@surgery.wisc.edu

Received 10 December 1997; Accepted 24 November 1998

TABLE I. Incidence of Urinary Tract Infections in the FemaleRelatives of Index Cases

Relationshipto patient

% with UTIs(95% C. I.)

Mother 65.5 (48–83)Daughter 60.7 (43–79)Sister 48.6 (32–65)

American Journal of Medical Genetics 83:422–424 (1999)

© 1999 Wiley-Liss, Inc.

distinct inbred strains of mice differ in their ability toresolve an induced Escherichia coli UTI [Hopkins, etal., 1998a]. It has also been shown that Western blotpatterns of antibodies to specific E. coli antigens candifferentiate patients susceptible to recurrent UTIfrom unaffected women [Hopkins et al., 1995]. Takentogether, these findings suggest that there may be animmunogenetic basis for the heightened susceptibilityof some women.

In light of broadening developments in the under-standing of the genetic bases of common diseases, andthe observations described in this report, further re-search efforts are warranted to verify a familial predis-position to UTIs in some kindreds. The eventual iden-tification of genetic or biological markers closely asso-ciated with a predisposition to UTIs would presumablylead to more appropriate and effective clinical evalua-tion as well as novel approaches to prophylaxis andtreatment.

REFERENCES

Engel G, Schaeffer AJ, Grayhack JT, Wendel EF. 1980. The role of excre-tory urography and cystoscopy in the evaluation and management ofwomen with recurrent urinary tract infection. J Urol 123:190–191.

Fennell RS, Wilson SG, Garin EH, Pryor ND, Sorgen CD, Walker R, Rich-ard GA. 1977. Bacteriuria in families of girls with recurrent bacteri-uria. Clin Pediatr 16:1132–1135.

Hopkins WJ, Gendron-Fitzpatrick A, Balish W, Uehling DT. 1998a. Timecourse and host responses to Escherichia coli urinary tract infection ingenetically distinct mouse strains. Infect Immun 66:2787–2802.

Hopkins WJ, Heisey DM, Lorentzen DF, Uehling DT. 1998b. A compara-tive study of major histocompatibility and red blood cell antigen phe-notypes as risk factors for recurrent urinary tract infections in women.J Infect Dis 177:1296–1301.

Hopkins WJ, James LJ, Balish E, Uehling DT. 1993. Congenital immuno-deficiencies in mice increase susceptibility to urinary tract infection. JUrol 149:922–925.

Hopkins WJ, Uehling DT.. 1995. Resolution time of Escherichia coli cystitisis correlated with levels of preinfection antibody to the infecting Esch-erichia coli strain. Urology 45:42–46.

Fig. 1. Pedigrees demonstrating possible familial predisposition to UTIs. Full-shaded symbols indicate more than five UTIs in an adult and more thantwo UTIs in a prepubescent child. Half-shaded symbols indicate 3–5 UTIs in an adult or when a person was reported to have had an unspecified numberof UTIs. Pedigrees A–I represent 9 unrelated kindreds. Infection history was not given for individual I-1 in pedigree I.

Letter to the Editor 423

Hopkins WJ, Xing Y, Dahmer LA, Balish E, Uehling DT. 1995. Westernblot analysis of anti-Escherichia coli serum immunoglobulins inwomen susceptible to recurrent urinary tract infections. J Infect Dis175:1612.

Kunin CM, Deutscher R, Paquin A. 1964. Urinary tract infection in schoolchildren: An epidemiologic, clinical and laboratory study. Medicine 43:91–130.

Raz R, Stamm WE. 1993. A controlled trial of intravaginal estriol in post-menopausal women with recurrent urinary tract infections. N Engl JMed 329:753–756.

Stansfeld, JM. 1966. Clinical observations relating to incidence andaetiology of urinary-tract infections in children. Brit Med J 1:631–635.

Walter J. Hopkins*David T. UehlingDepartment of SurgeryUniversity of Wisconsin Medical SchoolMadison, Wisconsin

David S. WargowskiDepartment of PediatricsUniversity of Wisconsin Medical SchoolMadison, Wisconsin

424 Hopkins et al.