No abstract

The new genetic information, in particular the greatly increased density of markers in the chromosomal maps, may permit analysis of the importance of genes in the development of disease exclusively from molecular epidemiological studies. Motivated by our previous results on the same region in relation to basal cell carcinoma we have investigated the occurrence of post-menopausal breast cancer in relation to a number of single nucleotide polymorphisms in the chromosomal region 19q13.2-3. A case-control study including 425 human cases and a similar number of controls was nested in a population-based prospective investigation encompassing 24 697 Danish post-menopausal women (aged 50-64 at inclusion) living in Copenhagen or Aarhus. We combined three markers located together in or near the gene RAI into a high-risk haplotype. Compared with all other haplotypes, those who were homozygous had a rate ratio of 1.64 (95% CI 1.17-2.29, P < or = 0.004) for development of breast cancer. When we further focused on those persons with post-menopausal breast cancer before age 55 the rate ratio increased to 9.5 (95% CI 2.21-40.79, P < or = 0.003). The likely explanation for our results is a common recessive genetic variant located in or near the gene RAI, which, when homozygous, conveys an increased risk of breast cancer. Presumably it is identical to the genetic variant previously observed in the same region that increases the risk of basal cell carcinoma before age 50.

BackgroundPrevious results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibrium mapping. The study groups included 434 postmenopausal breast cancer cases and an identical number of individually matched controls.Methods and ResultsStudying one marker at a time, we found a region spanning the gene RAI (alias PPP1R13L or iASPP) and the 5' portion of XPD to be associated with this cancer. The region corresponds to a haplotype block, in which there seems to be very limited recombination in the Danish population. Studying combinations of markers, we found that two to four neighboring markers gave the most consistent and strongest result. The haplotypes with strongest association with cancers were located in the gene RAI and just 3' to the gene. Coinciding peaks were seen in the region of RAI in groups of women of different age.In a follow-up to these results we sequenced 10 cases and 10 controls in a 44 kb region spanning the peaks of association. This revealed 106 polymorphisms, many of which were not in the public databases. We tested an additional 44 of these for association with disease and found a new tandem repeat marker, called RAI-3'd1, located downstream of the transcribed region of RAI, which was more strongly associated with breast cancer than any other marker we have tested (RR = 2.44 (1.41–4.23, p = 0.0008, all cases; RR = 6.29 (1.49–26.6), p = 0.01, cases up to 55 years of age).ConclusionWe expect the marker RAI-3'd1 to be (part of) the cause for the association of the chromosome 19q13.3 region's association with cancer.

BackgroundMutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%.MethodsThe coding sequence of DNAI1 was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families.ResultsThree previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in DNAI1 (54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort.ConclusionsThe worldwide involvement of DNAI1 mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.