Genetic epidemiology of Genetic epidemiology of cystic fibrosis in cystic fibrosis in

Saguenay-Lac-St. Jean Saguenay-Lac-St. Jean (Quebec, Canada)(Quebec, Canada)

Daigneault J, Aubin G, Simard F, DeBraekeleer M

Clinical Genetics April 1991

Presented by Soodtida Tangpraphaphorn

IntroductionIntroduction

• Descriptive case-control genetic epidemiological study– Quantifies incidence, prevalence, carrier rates– Some EO associations, no causality established

• Makes etiological hypotheses, suggests associations and causal relationships for future study

• Study population shows elevated prevalence of CF compared to overall population at risk.

• Inbreeding slightly higher in CF group compared to controls due to remote consanguinity.

• Endogamy not higher in CF group than controls.

Clinical Cystic FibrosisClinical Cystic Fibrosis

• Genetic respiratory illness with pleiotropy– Most commonly affects populations of NW

European descent– Causes airway mucus to thicken, resulting in

chronic respiratory obstruction and infections– Impairs pancreatic exocrine function– Complications can decrease lifespan– Diagnosed by sweat test

Cellular Cystic FibrosisCellular Cystic Fibrosis

• Caused by mutation in CFTR gene– Most commonly F508

• Mutation results in defective protein product– Protein is a cell membrane ion channel

•Defective protein affects chloride anion transport in/out of cell

– Ion channel fails to export to cell membrane

– Ion channel is in cell membrane, but cannot function

Saguenay-Lac-St.JeanSaguenay-Lac-St.Jean

• 200km NE of Quebec City

• Inlet of St. Lawrence Seaway

• Very geographically remote

• Southernmost fjord in the world

SLSJ Epidemiological SLSJ Epidemiological MapMap

Study PopulationStudy Population

• Pop. 285,100 (1986); 98% French-speaking Catholics

• Isolation– Settled in 1840s, migrated from Charlevoix– Founder effects

• Mutation frequencies different from urban Canadian population

• Particularly interesting to geneticists– Elevated carrier rates and prevalence of many

different genetic disorders

Study PopulationStudy Population

• 127 CF cases in SLSJ– 125 patients from CF clinic at

Chicoutimi, 2 from Quebec City

• 3 groups population-based controls– Not described in this study

•Requires readers to refer to investigators’ other studies

MethodsMethods

• Study time-frame (1975-1988)• Extract demographic information

from database of CF cases in SLSJ• Migration histories from subjects

and their families• Calculate prevalence & incidence

from birth statistics and case data• Estimate carrier rate via Hardy-

Weinberg equation

ResultsResults

• Number of CF live births = 78• Total live births = 70351• CF incidence (#cases/#at risk) = 1 per

902– Incidence for all Canadian whites = 1 per 2500– Secular trends show stable annual IR

• Hardy-Weinberg carrier rate = 1 per 15• Stronger kinship and more inbreeding in

CF group

DiscussionDiscussion• SLSJ population not isolated for long

periods of time– High prevalence may be attributable to

mutations before migration from Charlevoix

– Migration of large founder group brought many alleles into population

• Different frequency of mutations• Good descriptive epidemiology

– Study stands alone well, better when taken in context

Prevention Prevention RecommendationsRecommendations

• Primary – increase genetic diversity by mating outside of population

• Secondary – screen locals for genetic mutations and offer genetic counseling with family planning, incl. PGD

• Tertiary – early detection in infants, more social-medical services, close medical supervision

ReferencesReferences1. Daigneault J, Aubin G, Simard F, DeBraekeleer M.

Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St. Jean (Quebec, Canada). Clinical Genetics. 1991;40:298-303.

2. Rozen R, DeBraekeleer M, Daigneault J, Ferreira-Rajabi L, Gerdes M, Lamoureaux L, Aubin G, Simard F, Fujiwara TM, Morgan K. Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis. American Journal of Medical Genetics. 1992;42:360-364.

3. DeBraekeleer M, Daigneault J. Spatial distribution of the DF508 mutation in cystic fibrosis. Human Biology. 1992;64:167-174.

4. Daigneault J, Aubin G, Simard F, DeBraekeleer M. Incidence of cystic fibrosis in Saguenay-Lac-St. Jean (Quebec, Canada). Human Biology. 1992;64:115-119.

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