Hum Hered 1991;41:168-173
© 1991 S. Karger AG. Basel 0001-5652/91/0413-0168 S 2.75/0
Founder Effect in Familial Hyperchylomicronemia among French Canadians of Quebec Marc De Braekeleer ' , Carole Diortnea . Claude Gagnéb. Pierre Julien b , Daniel Brunb, M.R. Ven Murthyc , Paul-J.Lupienh *SOREP, Université du Québec à Chicoutimi, Qué.: b Centre de Recherches sur les Maladies Lipidiques et Département de Médecine, Centre Hospitalier de l'Université Laval, Ste-Foy, Qué.; 1 Département de Biochimie, Faculté de Médecine, Université Laval, Ste-Foy, Qué., Canada
Key Words. French Canadian • Hyperchylomicronemia • Lipoprotein lipase deficiency • Founder effect • Genetic epidemiology • Population genetics
Introduction Familial hyperchylomicronemia [pri mary lipoprotein lipase (LPL) activity de ficiency, type 1 hyperlipoproteinemia] is a rare autosomal recessive disorder charac terized by massive accumulation of chylomicra in the plasma of fasting patients [1]. Elevated concentrations of triglycerides are due to defective plasma LPL activity, the enzyme responsible for the hydrolysis of the triglycerides of chylomicra and
very-low-density lipoproteins. Brunzell et al. [2] identified a number of LPL-deficient variants including absence of LPL enzyme and activity, presence of an inac tive and structurally modified LPL en zyme, presence of plasma LPL enzyme with defective binding to endothelium [3], selective tissue lipase deficiency [4], pres ence of an inherited plasma LPL inhibitor [5] and lack of LPL activity due to apopro tein CI1 deficiency [6], In the French Ca nadian population of Quebec, a defect in
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Abstract. Familial hyperchlyomicronemia has reached a high prevalence in the French Canadian population of eastern Quebec. The birth places of 58 carriers iden tified through the birth of one affected child clustered in three regions. The genealogies of these 58 individuals showed that no founder was common to all of them. Three sets of founders were found, one for each region, with little overlapping between two regions. These results strongly suggest that more than one mutation, introduced by the French migrants in the 17th century, are segregating in the French Canadian population. Perche, a region situated between Paris and Normandy, appeared to be the most likely putative center of diffusion of at least one mutation in the lipoprotein lipase gene segre gating in the modern-day French Canadian population of Quebec.
the LPL enzyme and not in its activator, the apoprotein CI I, was shown to be re sponsible for the observed hyperchylo micronemia [7]. The prevalence of familial hyperchy lomicronemia in the general population was estimated at 1 case per million [1], However, we recently identified 56 cases of familial hyperchylomicronemia in east ern Quebec and described the related clini cal manifestations such as abdominal pains, pancreatitis, lipemia retinalis, erup tive xanthomas, hepatomegaly and sple nomegaly [7]. The incidence in this Quebec population was shown to be 30 times higher than previously published [7], We hypothesized that a unique mutant gene spread in the French Canadian popula tion due to a founder effect. We now report a genealogical study based on 43 cases of familial hyperchy lomicronemia distributed in 29 families found in this Quebec population. Detailed genealogical studies led us to conclude that the LPL deficiency was introduced by at least three founders and suggest that more than one gene defect may underlie the familial hyperchylomicronemia disor der observed in this population. Materials and Methods The genealogical studies were carried out in 43 hyperchylomicronemic patients from 29 different French Canadian families living in the province of Quebec. These patients were evaluated and are being regularly followed at the Lipid Research Center of the ‘Centre Hospitalier de l'Université Laval', De tailed clinical data related to this population were previously published [7, 8). Blood samples were ob tained after a 12-hour fasting period for lipid and li poprotein analyses and showed the presence of chylomicra with a mean plasma triglyceride level well
169
above 10 mmol/l. The diagnosis of familial hyper chylomicronemia was confirmed after determination of plasma LPL activity measured 10 and 20 min be fore and after intravenous injection of 60 lU/kg of heparin as previously described [9], All 29 families were contacted and asked to fill a questionnaire regarding their date and place of birth, the date and place of birth of their parents and grandparents as well as the dale and place of marri age of their parents and grandparents. The genealogies of the 29 probands were recon structed using various sources. For those who were born in the Saguenay-Lac-Si-Jean (SLSJ) region, the genealogies were reconstructed using the computer ized population register maintained at SOREP [10, 11). This stage allowed occasional reconstructions as far as the middle of the 19th century. The genealogi cal reconstruction was then pursued manually, using several marriage repositories of Quebec [see, for ex ample, ref. 12—14). Other sources included the "Fi chier Loiselle’ which contains more than 410,000 marriage records from various parishes in Quebec and the ‘Fichier Jette' which contains more than 140,000 marriage records from the origins of Quebec in the 17th century to 1825. Genealogical dictionaries were also consulted; these are the ‘Dictionnaire généalogique des familles du Québec’, which con tains all civic records of all individuals having lived in Quebec from the origins of the French colony to 1730 [15], and the ‘Dictionnaire généalogique des fa milles canadiennes', which includes civic records of individuals who lived in Quebec from the origins to 1800 [16], The genealogies of the probands not living in the SLSJ region were reconstructed manually us ing the same sources. The genealogies were recon structed to an average depth of 17 generations, allow ing recognition of the founders of the French Cana dian population in Europe, mainly in France, in the 17th century. When necessary, the concerned par ishes were contacted by phone to obtain further in formation regarding particular marriages. The genealogies were then recorded in a compu terized genealogical database (BELGE developed at SOREP). Each record contains a set of three num bers (ego, father, mother), the sex of the individual, his date and place of marriage, and his status (e.g. af fected, carrier). The genealogies were analyzed using MEDIC4-BELGE (software developed at SOREP), which calculates inbreeding and kinship coefficients.
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Founder Effect in Hyperchylomicronemia in Quebec
170
De Braekeleer/Dionne/Gagné/Julien/Brun/Ven Murthy/Lupien
and PED-BELGE (also developed at SOREP), which, based on an algorithm determining the closest relationship between individuals at each generation, identifies the most likely founders in a set of families with a given disorder [11, 17J. The most likely paths of descent of the gene were determined using PEDDESC (developed at SOREP) and the pedigrees drawn using PEDIGREE/DRAW developed at the Southwest Foundation for Biomedical Research in San Antonio, Tex., USA [18].
Results Figure 1 shows the spatial distribution of the birthplaces of the 58 heterozygote parents. Most of the carriers were born in northeastern Quebec (SLSJ and Charle voix). Five carriers were born in three dif ferent municipalities located within a ra
dius of 20 km in Beauce whereas an other set of 5 carriers was born in the TroisRivières region (Mauricie). No single founder was found to be common to all carriers. A group of 11 founders, born in the 17th century, was shown to be common to all carriers born in SLSJ, Charlevoix, the Quebec City area and Portneuf (fig. I). One founder was born in Switzerland and, of the remaining 10, 8 were born in Perche, a small region of France situated between Paris and Nor mandy. A set of 109 founders common to the 5 carriers born in Beauce was found. It in cluded all founders common to the carri ers born in northeast Quebec. The remain ing founders mainly originated from
Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
Fig. 1. Geographic distribution of the birthplaces of the 58 obligate carriers of an LPL gene deficiency in the province of Quebec.
171
Founder Effect in Hyperchylomicronemia in Quebec
□
i
□
□
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□
Xi o à 6=0 à
□
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9 °— = Discussion
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BHyperchylomicronemia is a very rare autosomal recessive disorder which has a high prevalence in eastern Quebec and, more particularly, in Charlevoix and SLSJ Fig. 2. Genealogical reconstruction of the 5 obli [7], It was postulated that a founder effect gate carriers of an LPL gene deficiency born in the might explain the presence of this disorder Beauce region showing a common ancestor couple at in French Canadians [7]. Therefore, a ge the 6th generation. nealogical reconstruction was attempted to test this hypothesis. However, genealogical reconstruction has its limits. Cases of adoption and non paternity should be considered; depend ing upon the sources, it was occasionally possible to identify such cases. As an ex ample, it was not unusual for the priest in tion is usually limited by its lack of com the 17th or 18th century to indicate on the pleteness. Indeed, although all available baptism record whether the child was legi sources have been consulted, a few marri age records could not be found. There are timate or not. An additional limit of the genealogical several explanations including the inac reconstruction is the reliability of the cessibility of the marriage records of a par sources. The familial links were usually ticular parish, the destruction of the origi identiFied through several sources and, nal record or a change in the surname, whenever any differences were found, the which was common practice in Quebec in priest or his secretary was asked by phone the 17th and 18th centuries. Therefore, to read the original marriage record kept when interpreting the results we have to keep in mind that the gene may have been in the parish. transmitted through a missing genealogi Finally, the genealogical reconstruc-
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Perche and Normandy whereas 2 founders were of Acadian origin. A couple who got married in 1767 in St-François de Beauce was also found to be common to all 5 car riers born in Beauce (Fig. 2). Nineteen founders were found to be common to all 3 carriers born in the TroisRivières region as well as I carrier born in the Bois-Francs region (Fig. 1). Five foun ders originated from Perche and 3 from Saintonge, another region of France.
De Braekeleer/Dionne/Gagné/Julien/Brun/Ven Murthy/Lupien
cal link. However, with the exception of France. Among those from France, for ex the maternal side of a patient whose ge ample, 13.2% came from Normandy, nealogy could not be reconstructed be 13.0% from Paris and Ile de France, 8.9% yond the 4th generation, and was not in from Poitou, 8.0% from Aunis, 4.8% from cluded in the analysis, only a few marri Saintonge and 2.6% from Perche [19-21]. ages were not found, all of them beyond Among the 139 founders (II for northeast the 6th generation. Quebec +109 for Beauce +19 for TroisOur results strongly suggest that more Rivières) of hyperchylomicronemia, 21 than one mutation is present in the French (15.1%) came from Normandy, 9 (6.5%) Canadian population. Although it cannot from Paris, 6 (4.3%) from Poitou, 8 (5.8%) be excluded that only one mutation segre from Aunis and Saintonge each, and 34 gates in this population, it seems that at (24.5%) from Perche. Although it remains least one mutation is segregating in the to be seen if such a distribution is not the population of northeastern Quebec and consequence of differential fertility, these that a different mutation is present in the results suggest that Perche was a putative Trois-Rivieres population. Since the set of center of diffusion in the 17the century for founders common to all the carriers born at least one mutation in the LPL gene in in Beauce included all founders common the French Canadian population. A simi to the carriers from northeast Quebec, the lar conclusion was already reached for mutation(s) present in Beauce could be one mutation of phenylketonuria (PK.U) identical to the one(s) found in northeast segregating in the present French Cana Quebec. dian population of Quebec [De Braekeleer Our results also suggest that the muta et al., submitted]. It must be noted that 15 tions present in the French Canadian pop of the 17 founders of the PKU mutation ulation were introduced in the province of originating from Perche were also Quebec by French immigrants in the 17th amongst the founders of hyperchylomic century. Indeed, from the origins of the ronemia. French colony to 1763, year of the take Molecular studies are underway in an over by the English, some 25,000 individu attempt to identify the mutation(s) in the als came to Quebec. However, a large LPL gene which is (are) segregating in the number of them did not settle in the col French Canadian population. They ony and it is estimated that only 8,500 per should give us clues to the accuracy of the sons, including 1,600 women, settled conclusions drawn from the genealogical permanently and founded the French Ca reconstruction. nadian population [19-21]. Because of its relative cultural and linguistic isolation, it Acknowledgements is believed that the present French Cana dian population is mostly derived from This work was supported by research grants from that founding nucleus [21, 22], Studies on the ‘Fondation de l'Université du Québec à Chicou the places of origin in Europe of the foun timi’. the Quebec Heart Foundation and Parke-Davis ders of the French Canadian population Canada. J.J. is a career scientist of the ‘Fonds de la also showed that only 4.1% were not from Recherche en Santé du Québec’.
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Founder Effect in Hyperchylomicronemia in Quebec
1 Brunzell JD: Familial lipoprotein lipase defi ciency and other causes of the chylomicronemia syndrome: in Scriver CR, Beaudet LA. Sly WS, Valle (eds): The Metabolic Basis of Inherited Dis ease. New York, McGraw-Hill, 1989. pp 11651180. 2 Brunzell JD, Chait A. Nikkila EA. Ehnholm JK, Steiner G: Heterogeneity of primary lipoprotein lipase deficiency. Metabolism 1980;29:624-629. 3 Brunzell JD. Auwerx JH. Babirak SP, Fujimoto WY. Hayden MR: Classification of lipoprotein lipase deficiency based on enzyme protein defect. 8th Int Symp on Atherosclerosis, Rome, Oct 1988. 4 Brunzell JD, Iverius PH, Scheibel MS, Fujimoto WY, Hayden MR, McLeod R. Frölich J: Primary lipoprotein lipase deficiency; in Angel A, Frolich J (eds): Lipoprotein Deficiency Syndromes. New York. Plenum. 1986, pp 227-239. 5 Brunzell JD, Miller NE. Alaupovic P, St-Hilaire RJ. Wang CS. Sarson DL, Bloom SR, Lewis B: Familial hyperchylomicronemia due to a circu lating inhibitor of lipoprotein lipase activity. J Lipid Res 1983:24:12-19. 6 Breckenridge WC, Little A, Steiner G, Chow A, Poapot M: Hypertriglyceridemia associated with deficiency of apolipoprotein C-ll. N Engl J Med 1978:298:1265-1273. 7 Gagné C. Brun LD, Julien P, Moorjani S, Lupien PJ: Primary lipoprotein-lipase activity deficiency: clinical investigation of a French Canadian pop ulation. Can Med Assoc J 1989;40:405-411. 8 Gagné C, Brun LD, Moorjani S, Lupien PJ: Hyperchylomicronémie familiale: Étude de l'activité lipolytique dans une famille. Union Med Can 1977:106:333-338. 9 Brun LD, Gagné C, Julien P, Tremblay A. Moor jani S, Bouchard C, Lupien PJ: Familial lipopro tein lipase activity deficiency: Study of total body fatness and subcutaneous fat tissue distribution. Metabolism 1989:38:1005-1009. 10 Bouchard G, Roy R, Casgrain B: Reconstruction automatique des familles: Le système SOREP. Chicoutimi, SOREP, 1985.
11 De Braekeleer M, Larochelle J: Genetic epidem iology of hereditary tyrosinemia in SaguenayLac-St-Jean and in Quebec. Am J Hum Genet 1990:47:302-307. 12 Ponthriand B: Mariages du comté de Portneuf (1679-1950). Sillery, 1978. 13 Talbot E-G: Recueil de généalogies des com tés de Beauce-Dorchester-Frontenac 1625-1946. Beauceville. Collège du Sacré-Coeur, 1948. 14 Roberge C: Répertoire des mariages de la pa roisse St-Sauveur de Québec (1867-1971). Qué bec, Société de généalogie de Québec, 1976. 15 Jetté R: Dictionnaire généalogique des familles du Québec. Montréal, Presses de l'Université de Montréal. 1983. 16 Tanguay C: Dictionnaire généalogique des fa milles canadiennes. Québec, Eusèbc Sénécal, 1871. 17 Mathieu J, De Braekeleer M, Prévost C: Gene alogical reconstruction of myotonie dystrophy in the Saguenay-Lac-St-Jean area (Quebec, Ca nada). Neurology 1990:40:839-842. 18 Mamelka PM, Dyke B. MacCluerJW: Pedigree/ Draw. San Antonio, Southwest Foundation for Biomédical Research, 1987. 19 Harris RC, Matthews G: Historical atlas of Ca nada. 1. From the beginning to 1800. Toronto, University of Toronto Press, 1987. 20 Boleca M: Les migrations au Canada sous le ré gime français (1608-1760). Cah Québ Démogr 1984;13:23-40. 21 Charbonneau H, Desjardins B, Guillcmette A, Landry Y. Légaré J. Nault F: Naissance d'une population: Les Français établis au Canada au XVI le siècle. Paris. INED, 1987. 22 De Braekeleer M: Homogénéité génétique des Canadiens français du Québec: Mythe ou réalité? Cah Québ Démogr, in press.
Dr. Marc De Braekeleer SOREP Université du Québec à Chicoutimi 555 Boulevard de l'université Chicoutimi, Qué. G7H 2BI (Canada) Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
References
173
© 1991 S. Karger AG. Basel 0001-5652/91/0413-0168 S 2.75/0
Founder Effect in Familial Hyperchylomicronemia among French Canadians of Quebec Marc De Braekeleer ' , Carole Diortnea . Claude Gagnéb. Pierre Julien b , Daniel Brunb, M.R. Ven Murthyc , Paul-J.Lupienh *SOREP, Université du Québec à Chicoutimi, Qué.: b Centre de Recherches sur les Maladies Lipidiques et Département de Médecine, Centre Hospitalier de l'Université Laval, Ste-Foy, Qué.; 1 Département de Biochimie, Faculté de Médecine, Université Laval, Ste-Foy, Qué., Canada
Key Words. French Canadian • Hyperchylomicronemia • Lipoprotein lipase deficiency • Founder effect • Genetic epidemiology • Population genetics
Introduction Familial hyperchylomicronemia [pri mary lipoprotein lipase (LPL) activity de ficiency, type 1 hyperlipoproteinemia] is a rare autosomal recessive disorder charac terized by massive accumulation of chylomicra in the plasma of fasting patients [1]. Elevated concentrations of triglycerides are due to defective plasma LPL activity, the enzyme responsible for the hydrolysis of the triglycerides of chylomicra and
very-low-density lipoproteins. Brunzell et al. [2] identified a number of LPL-deficient variants including absence of LPL enzyme and activity, presence of an inac tive and structurally modified LPL en zyme, presence of plasma LPL enzyme with defective binding to endothelium [3], selective tissue lipase deficiency [4], pres ence of an inherited plasma LPL inhibitor [5] and lack of LPL activity due to apopro tein CI1 deficiency [6], In the French Ca nadian population of Quebec, a defect in
Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
Abstract. Familial hyperchlyomicronemia has reached a high prevalence in the French Canadian population of eastern Quebec. The birth places of 58 carriers iden tified through the birth of one affected child clustered in three regions. The genealogies of these 58 individuals showed that no founder was common to all of them. Three sets of founders were found, one for each region, with little overlapping between two regions. These results strongly suggest that more than one mutation, introduced by the French migrants in the 17th century, are segregating in the French Canadian population. Perche, a region situated between Paris and Normandy, appeared to be the most likely putative center of diffusion of at least one mutation in the lipoprotein lipase gene segre gating in the modern-day French Canadian population of Quebec.
the LPL enzyme and not in its activator, the apoprotein CI I, was shown to be re sponsible for the observed hyperchylo micronemia [7]. The prevalence of familial hyperchy lomicronemia in the general population was estimated at 1 case per million [1], However, we recently identified 56 cases of familial hyperchylomicronemia in east ern Quebec and described the related clini cal manifestations such as abdominal pains, pancreatitis, lipemia retinalis, erup tive xanthomas, hepatomegaly and sple nomegaly [7]. The incidence in this Quebec population was shown to be 30 times higher than previously published [7], We hypothesized that a unique mutant gene spread in the French Canadian popula tion due to a founder effect. We now report a genealogical study based on 43 cases of familial hyperchy lomicronemia distributed in 29 families found in this Quebec population. Detailed genealogical studies led us to conclude that the LPL deficiency was introduced by at least three founders and suggest that more than one gene defect may underlie the familial hyperchylomicronemia disor der observed in this population. Materials and Methods The genealogical studies were carried out in 43 hyperchylomicronemic patients from 29 different French Canadian families living in the province of Quebec. These patients were evaluated and are being regularly followed at the Lipid Research Center of the ‘Centre Hospitalier de l'Université Laval', De tailed clinical data related to this population were previously published [7, 8). Blood samples were ob tained after a 12-hour fasting period for lipid and li poprotein analyses and showed the presence of chylomicra with a mean plasma triglyceride level well
169
above 10 mmol/l. The diagnosis of familial hyper chylomicronemia was confirmed after determination of plasma LPL activity measured 10 and 20 min be fore and after intravenous injection of 60 lU/kg of heparin as previously described [9], All 29 families were contacted and asked to fill a questionnaire regarding their date and place of birth, the date and place of birth of their parents and grandparents as well as the dale and place of marri age of their parents and grandparents. The genealogies of the 29 probands were recon structed using various sources. For those who were born in the Saguenay-Lac-Si-Jean (SLSJ) region, the genealogies were reconstructed using the computer ized population register maintained at SOREP [10, 11). This stage allowed occasional reconstructions as far as the middle of the 19th century. The genealogi cal reconstruction was then pursued manually, using several marriage repositories of Quebec [see, for ex ample, ref. 12—14). Other sources included the "Fi chier Loiselle’ which contains more than 410,000 marriage records from various parishes in Quebec and the ‘Fichier Jette' which contains more than 140,000 marriage records from the origins of Quebec in the 17th century to 1825. Genealogical dictionaries were also consulted; these are the ‘Dictionnaire généalogique des familles du Québec’, which con tains all civic records of all individuals having lived in Quebec from the origins of the French colony to 1730 [15], and the ‘Dictionnaire généalogique des fa milles canadiennes', which includes civic records of individuals who lived in Quebec from the origins to 1800 [16], The genealogies of the probands not living in the SLSJ region were reconstructed manually us ing the same sources. The genealogies were recon structed to an average depth of 17 generations, allow ing recognition of the founders of the French Cana dian population in Europe, mainly in France, in the 17th century. When necessary, the concerned par ishes were contacted by phone to obtain further in formation regarding particular marriages. The genealogies were then recorded in a compu terized genealogical database (BELGE developed at SOREP). Each record contains a set of three num bers (ego, father, mother), the sex of the individual, his date and place of marriage, and his status (e.g. af fected, carrier). The genealogies were analyzed using MEDIC4-BELGE (software developed at SOREP), which calculates inbreeding and kinship coefficients.
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170
De Braekeleer/Dionne/Gagné/Julien/Brun/Ven Murthy/Lupien
and PED-BELGE (also developed at SOREP), which, based on an algorithm determining the closest relationship between individuals at each generation, identifies the most likely founders in a set of families with a given disorder [11, 17J. The most likely paths of descent of the gene were determined using PEDDESC (developed at SOREP) and the pedigrees drawn using PEDIGREE/DRAW developed at the Southwest Foundation for Biomedical Research in San Antonio, Tex., USA [18].
Results Figure 1 shows the spatial distribution of the birthplaces of the 58 heterozygote parents. Most of the carriers were born in northeastern Quebec (SLSJ and Charle voix). Five carriers were born in three dif ferent municipalities located within a ra
dius of 20 km in Beauce whereas an other set of 5 carriers was born in the TroisRivières region (Mauricie). No single founder was found to be common to all carriers. A group of 11 founders, born in the 17th century, was shown to be common to all carriers born in SLSJ, Charlevoix, the Quebec City area and Portneuf (fig. I). One founder was born in Switzerland and, of the remaining 10, 8 were born in Perche, a small region of France situated between Paris and Nor mandy. A set of 109 founders common to the 5 carriers born in Beauce was found. It in cluded all founders common to the carri ers born in northeast Quebec. The remain ing founders mainly originated from
Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
Fig. 1. Geographic distribution of the birthplaces of the 58 obligate carriers of an LPL gene deficiency in the province of Quebec.
171
Founder Effect in Hyperchylomicronemia in Quebec
□
i
□
□
~à
□
Xi o à 6=0 à
□
ô 0
d—
9 °— = Discussion
Q
0
« > = T = C
f= o
6 ô =t)
BHyperchylomicronemia is a very rare autosomal recessive disorder which has a high prevalence in eastern Quebec and, more particularly, in Charlevoix and SLSJ Fig. 2. Genealogical reconstruction of the 5 obli [7], It was postulated that a founder effect gate carriers of an LPL gene deficiency born in the might explain the presence of this disorder Beauce region showing a common ancestor couple at in French Canadians [7]. Therefore, a ge the 6th generation. nealogical reconstruction was attempted to test this hypothesis. However, genealogical reconstruction has its limits. Cases of adoption and non paternity should be considered; depend ing upon the sources, it was occasionally possible to identify such cases. As an ex ample, it was not unusual for the priest in tion is usually limited by its lack of com the 17th or 18th century to indicate on the pleteness. Indeed, although all available baptism record whether the child was legi sources have been consulted, a few marri age records could not be found. There are timate or not. An additional limit of the genealogical several explanations including the inac reconstruction is the reliability of the cessibility of the marriage records of a par sources. The familial links were usually ticular parish, the destruction of the origi identiFied through several sources and, nal record or a change in the surname, whenever any differences were found, the which was common practice in Quebec in priest or his secretary was asked by phone the 17th and 18th centuries. Therefore, to read the original marriage record kept when interpreting the results we have to keep in mind that the gene may have been in the parish. transmitted through a missing genealogi Finally, the genealogical reconstruc-
Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
Perche and Normandy whereas 2 founders were of Acadian origin. A couple who got married in 1767 in St-François de Beauce was also found to be common to all 5 car riers born in Beauce (Fig. 2). Nineteen founders were found to be common to all 3 carriers born in the TroisRivières region as well as I carrier born in the Bois-Francs region (Fig. 1). Five foun ders originated from Perche and 3 from Saintonge, another region of France.
De Braekeleer/Dionne/Gagné/Julien/Brun/Ven Murthy/Lupien
cal link. However, with the exception of France. Among those from France, for ex the maternal side of a patient whose ge ample, 13.2% came from Normandy, nealogy could not be reconstructed be 13.0% from Paris and Ile de France, 8.9% yond the 4th generation, and was not in from Poitou, 8.0% from Aunis, 4.8% from cluded in the analysis, only a few marri Saintonge and 2.6% from Perche [19-21]. ages were not found, all of them beyond Among the 139 founders (II for northeast the 6th generation. Quebec +109 for Beauce +19 for TroisOur results strongly suggest that more Rivières) of hyperchylomicronemia, 21 than one mutation is present in the French (15.1%) came from Normandy, 9 (6.5%) Canadian population. Although it cannot from Paris, 6 (4.3%) from Poitou, 8 (5.8%) be excluded that only one mutation segre from Aunis and Saintonge each, and 34 gates in this population, it seems that at (24.5%) from Perche. Although it remains least one mutation is segregating in the to be seen if such a distribution is not the population of northeastern Quebec and consequence of differential fertility, these that a different mutation is present in the results suggest that Perche was a putative Trois-Rivieres population. Since the set of center of diffusion in the 17the century for founders common to all the carriers born at least one mutation in the LPL gene in in Beauce included all founders common the French Canadian population. A simi to the carriers from northeast Quebec, the lar conclusion was already reached for mutation(s) present in Beauce could be one mutation of phenylketonuria (PK.U) identical to the one(s) found in northeast segregating in the present French Cana Quebec. dian population of Quebec [De Braekeleer Our results also suggest that the muta et al., submitted]. It must be noted that 15 tions present in the French Canadian pop of the 17 founders of the PKU mutation ulation were introduced in the province of originating from Perche were also Quebec by French immigrants in the 17th amongst the founders of hyperchylomic century. Indeed, from the origins of the ronemia. French colony to 1763, year of the take Molecular studies are underway in an over by the English, some 25,000 individu attempt to identify the mutation(s) in the als came to Quebec. However, a large LPL gene which is (are) segregating in the number of them did not settle in the col French Canadian population. They ony and it is estimated that only 8,500 per should give us clues to the accuracy of the sons, including 1,600 women, settled conclusions drawn from the genealogical permanently and founded the French Ca reconstruction. nadian population [19-21]. Because of its relative cultural and linguistic isolation, it Acknowledgements is believed that the present French Cana dian population is mostly derived from This work was supported by research grants from that founding nucleus [21, 22], Studies on the ‘Fondation de l'Université du Québec à Chicou the places of origin in Europe of the foun timi’. the Quebec Heart Foundation and Parke-Davis ders of the French Canadian population Canada. J.J. is a career scientist of the ‘Fonds de la also showed that only 4.1% were not from Recherche en Santé du Québec’.
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1 Brunzell JD: Familial lipoprotein lipase defi ciency and other causes of the chylomicronemia syndrome: in Scriver CR, Beaudet LA. Sly WS, Valle (eds): The Metabolic Basis of Inherited Dis ease. New York, McGraw-Hill, 1989. pp 11651180. 2 Brunzell JD, Chait A. Nikkila EA. Ehnholm JK, Steiner G: Heterogeneity of primary lipoprotein lipase deficiency. Metabolism 1980;29:624-629. 3 Brunzell JD. Auwerx JH. Babirak SP, Fujimoto WY. Hayden MR: Classification of lipoprotein lipase deficiency based on enzyme protein defect. 8th Int Symp on Atherosclerosis, Rome, Oct 1988. 4 Brunzell JD, Iverius PH, Scheibel MS, Fujimoto WY, Hayden MR, McLeod R. Frölich J: Primary lipoprotein lipase deficiency; in Angel A, Frolich J (eds): Lipoprotein Deficiency Syndromes. New York. Plenum. 1986, pp 227-239. 5 Brunzell JD, Miller NE. Alaupovic P, St-Hilaire RJ. Wang CS. Sarson DL, Bloom SR, Lewis B: Familial hyperchylomicronemia due to a circu lating inhibitor of lipoprotein lipase activity. J Lipid Res 1983:24:12-19. 6 Breckenridge WC, Little A, Steiner G, Chow A, Poapot M: Hypertriglyceridemia associated with deficiency of apolipoprotein C-ll. N Engl J Med 1978:298:1265-1273. 7 Gagné C. Brun LD, Julien P, Moorjani S, Lupien PJ: Primary lipoprotein-lipase activity deficiency: clinical investigation of a French Canadian pop ulation. Can Med Assoc J 1989;40:405-411. 8 Gagné C, Brun LD, Moorjani S, Lupien PJ: Hyperchylomicronémie familiale: Étude de l'activité lipolytique dans une famille. Union Med Can 1977:106:333-338. 9 Brun LD, Gagné C, Julien P, Tremblay A. Moor jani S, Bouchard C, Lupien PJ: Familial lipopro tein lipase activity deficiency: Study of total body fatness and subcutaneous fat tissue distribution. Metabolism 1989:38:1005-1009. 10 Bouchard G, Roy R, Casgrain B: Reconstruction automatique des familles: Le système SOREP. Chicoutimi, SOREP, 1985.
11 De Braekeleer M, Larochelle J: Genetic epidem iology of hereditary tyrosinemia in SaguenayLac-St-Jean and in Quebec. Am J Hum Genet 1990:47:302-307. 12 Ponthriand B: Mariages du comté de Portneuf (1679-1950). Sillery, 1978. 13 Talbot E-G: Recueil de généalogies des com tés de Beauce-Dorchester-Frontenac 1625-1946. Beauceville. Collège du Sacré-Coeur, 1948. 14 Roberge C: Répertoire des mariages de la pa roisse St-Sauveur de Québec (1867-1971). Qué bec, Société de généalogie de Québec, 1976. 15 Jetté R: Dictionnaire généalogique des familles du Québec. Montréal, Presses de l'Université de Montréal. 1983. 16 Tanguay C: Dictionnaire généalogique des fa milles canadiennes. Québec, Eusèbc Sénécal, 1871. 17 Mathieu J, De Braekeleer M, Prévost C: Gene alogical reconstruction of myotonie dystrophy in the Saguenay-Lac-St-Jean area (Quebec, Ca nada). Neurology 1990:40:839-842. 18 Mamelka PM, Dyke B. MacCluerJW: Pedigree/ Draw. San Antonio, Southwest Foundation for Biomédical Research, 1987. 19 Harris RC, Matthews G: Historical atlas of Ca nada. 1. From the beginning to 1800. Toronto, University of Toronto Press, 1987. 20 Boleca M: Les migrations au Canada sous le ré gime français (1608-1760). Cah Québ Démogr 1984;13:23-40. 21 Charbonneau H, Desjardins B, Guillcmette A, Landry Y. Légaré J. Nault F: Naissance d'une population: Les Français établis au Canada au XVI le siècle. Paris. INED, 1987. 22 De Braekeleer M: Homogénéité génétique des Canadiens français du Québec: Mythe ou réalité? Cah Québ Démogr, in press.
Dr. Marc De Braekeleer SOREP Université du Québec à Chicoutimi 555 Boulevard de l'université Chicoutimi, Qué. G7H 2BI (Canada) Downloaded by: University of Leeds 129.11.21.2 - 9/24/2018 12:07:50 PM
References
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