Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.

Evidence of a founder effect for the protein C gene 3363 inserted C mutation in thrombophilic pedigrees of French origin.

We have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was present in four unrelated French patients and in four French Canadian families with type I protein C deficiency as well as in a large Vermont protein C deficient kindred of French Canadian origin. The present study was designed to investigate the likelihood of the existence of a founder effect for this mutation in protein C deficient individuals of French origin living in France, Quebec and Vermont. In order to demonstrate a possible founder effect for the 3363 InsC mutation, we have previously constructed a high-resolution genetic map to locate several highly polymorphic markers close to the protein C locus. Thereafter, the markers D2S347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygotes from France (n = 7), Quebec (n = 36) or Vermont (n = 74). The allelic frequency distribution of these five markers was also determined in fifty control French Canadian subjects and thirty-two unaffected members of the Vermont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Quebec and Vermont carry a common haplotype at the protein C locus. Moreover, in order to study the evolutionary history of the 3363 InsC mutation, we traced back the ascending genealogy of one proband in each of the families with this mutation. These results showed that the 3363 InsC mutation was most probably introduced in North America by a couple of French settlers who established themselves in 1669 on Isle d'Orleans located near Quebec City. All heterozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a unique opportunity to evaluate the role of the protein C system in thrombophilia due to the high degree of linkage disequilibrium at the protein C gene, which in essence holds that variable more constant than in a more heterogeneous population.

Type I protein C deficiency in French Canadians: evidence of a founder effect and association of specific protein C gene mutations with plasma protein C levels.

Protein C (PROC) deficiency is one of the most common autosomal codominant diseases. Although more than 150 germline mutations in the PROC gene have been described around the world, the spectrum of mutations among French Canadians is unknown. We have identified one frameshift (3363 ins C) and two missense mutations (R178Q and T298M) in 7 French Canadian families with type I PROC deficiency. In order to demonstrate a possible founder effect for the 3363 ins C mutation, we have constructed a high-resolution genetic map to locate several highly polymorphic markers close to PROC locus. We have then genotyped five markers in 36 heterozygotes for the 3363 ins C mutation. Our data suggest that these patients carry a common haplotype at the PROC locus. Immunologic plasma PROC levels of heterozygotes and genetically normal relatives were also correlated with the nature of the mutation in the coding sequence and with the genotype of three polymorphisms in the PROC promoter. We found that the mean immunologic plasma PROC levels were lower in heterozygotes for the frameshift mutation 3363 ins C compared to heterozygotes for one of the two missense mutations R178Q and T298M (0.46 vs 0.61; P = 0.0004). Moreover, this difference cannot be explained by the genetic variation of the three polymorphisms in the PROC promoter which accounts for only 10.4% of the variation of immunologic PROC levels in non-deficient subjects. These results suggest that the nature of the mutation in the coding sequence of PROC gene may modulate immunologic plasma PROC levels.