The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil.

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects.

AIMS/HYPOTHESIS: The development of insulin resistance may contribute to the occurrence and progression of the metabolic syndrome associated with obesity. Components contributing to the insulin pathway and its regulation are good candidates for the molecular study of metabolic syndrome pathogenesis. Protein tyrosine phosphatase 1B (PTP 1B) is an important negative regulator of insulin. We investigated whether PTP 1B SNPs are associated with obesity and obesity-related traits as well as global metabolic syndrome in morbidly obese subjects. METHODS: Untranslated and coding regions of the PTP 1B gene were screened in groups of non-diabetic and diabetic obese subjects and in non-obese subjects. Unrelated morbidly obese ( n=711) and non-obese ( n=427) French Caucasian subjects were genotyped for a case-control study. RESULTS: Six SNPs were identified: two rare variants were located in 5'UTR (-109 C>T and -69 C>T), two in the intronic regions (IVS3+38 G>T and IVS5+3666delT) and two have been described previously (P303P in exon 8 and P387L in exon 9). A case-control study showed an association between the frequent IVS5+3666delT SNP and obesity ( p=0.02). In the obese group, associations between PTP 1B SNPs and features of dyslipidaemia were found. P303P was associated with lower apolipoprotein A1 levels ( p=0.05) whereas P387L was associated with higher triglyceride ( p=0.0003), apolipoprotein B ( p=0.09) and lipoprotein a concentrations ( p=0.006). CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that the PTP 1B gene contributes to the polygenic basis of obesity. PTP 1B SNPs may interact with environmental factors to induce more severe phenotypes, e.g. atherogenic dyslipidaemia, in morbidly obese subjects.

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

A study of French centenarians: are ACE and APOE associated with longevity?

Association study is the method of choice to identify genes involved in complex processes that result from the interaction of environmental and genetic factors. However, because of biases that increase the risk of false positive reports, preliminary positive conclusions have to be reproduced on other populations to be validated as firm conclusions. In 1994, certain alleles of two genes, APOE (Apolipoprotein E) and ACE (angiotensin converting enzyme), were reported to be more frequent in French centenarians, suggesting an association with such a complex polyfactorial process as longevity. Enlargement of the French centenarian cohort allows a new assessment of this hypothesis on 563 centenarians. In contrast to APOE, the ACE association was not confirmed. Retrospective analysis of the initial study revealed discrepancies that may in part explain this observation. Risk of reporting false positive associations is discussed and recommendations to set up a rigorous experimental design are proposed.

The efficiency of genetic analysis of DNA from aged siblings to detect chromosomal regions implicated in longevity.

Studies of the frequencies of different alleles in young adults and aged individuals have implicated several genes, such as ApoE and ACE, in longevity. However such association studies can easily give rise to spurious results through unsuspected population subdivision, and an approach making use of genetic relationships among relatives is desirable. We have studied the effectiveness of non-parametric genetic analysis to detect different types of loci affecting longevity. The non-parametric method has high statistical power to detect infrequent recessive alleles that are required for, or significantly increase the probability of, survival to advanced age. Statistical power is reduced if a proportion of carriers of the alternative allele is allowed to survive. The method is least effective in detecting alleles that occur at low frequency in young individuals and that subsequently experience high mortality, as is the case for carriers of the epsilon4 allele of ApoE. Genotyping errors will also reduce the value of the NPL statistic in a linear fashion with the error rate and the number of loci genotyped. We have also used the method to analyse genotypes of seven highly polymorphic markers near the ApoE gene in a sample of 188 sibships of nonagenarians and centenarians (n=434) and their children (n=124), however no excess sharing of alleles was detected.