Primary pulmonary hypertension (PPH)f an often fatal disease, is characterized by elevated pulmonary artery pressures in the absence of a secondary cause1. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm2. Diagnosis is often delayed because the initial symptoms of fatigue and dyspnea on exertion are nonspecific and definitive diagnosis requires invasive procedures. The average life expectancy after diagnosis is two to three years with death usually due to progressive right heart failure3. The aetiology of the disease is unknown. Although most cases appear to be sporadic, ∼6% of cases recorded in the NIH Primary Pulmonary Hypertension Registry are inherited in an autosomal dominant manner with reduced penetrance4–6. Following a genome-wide search using a set of highly polymorphic short tandem repeat (STR) markers and 19 affected individuals from six families, initial evidence for linkage was obtained with two chromosome 2q markers. We subsequently genotyped patients and all available family members for 19 additional markers spanning ∼40 centiMorgans (cM) on the long arm of chromosome 2. We obtained a maximum two-point lod score of 6.97 at θ=0 with the marker D2S389; multipoint linkage analysis yielded a maximum lod score of 7.86 with the marker D2S311. Haplotype analysis established a minimum candidate interval of ∼25 cM.
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Rubin, L.J. Primary pulmonary hypertension. Chest 104, 236–250 (1993).
Loyd, J.E. Atkinson, J.B. Pietra, G.G. Virmani, R. & Newman, J.H. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am. Rev. Respir. Dis. 138, 952–957 (1988).
D'Alonzo, G.E. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. 115, 343–349 (1991).
Rich, S. et al. Primary pulmonary hypertension. A national prospective study. Ann. Intern. Med. 107, 216–223 (1987).
Loyd, J.E. et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 152, 93–97 (1995).
Loyd, J.E. Primm, R.K. & Newman, J.H. Familial primary pulmonary hypertension: clinical patterns. Am. Rev. Respir. Dis. 129, 194–197 (1984).
O'Connell, J.R. & Weeks, D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).
Matise, T.C. Perlin, M. & Chakravarti, A. Automated construction of genetic linkage maps using an expert system (Multimap): a human genome linkage map. Nature Genet. 6, 384–390 (1994).
Terwilliger, J.D. & Ott, J. Handbook of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1994).
Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1991).
Dresdale, D.T. Schultz, M. & Michtom, R.J. Primary pulmonary hypertension: 1 Clinical and hemodynamic study. Am. J. Med. 11, 686–701 (1951).
Dresdale, D.T. Michtom, R.J. & Schultz, M. Recent studies in primary pulmonary hypertension including pharmacodynamic observartions on pulmonary vascular resistance. Bull. N.Y. Acad. Med. 30, 195–207 (1954).
Morse, J.H. Barst, R.J. & Fotino, M. Familial pulmonary hypertension: immunogenetic findings in four Caucasian kindreds. Am. Rev. Respir. Dis. 145, 787–792 (1992).
Girard, T.J. et al. Structure of the human lipoprotein-associated coagulation inhibitor gene. Intron/exon gene organization and localization of the gene to chromosome 2. J. Biol. Chem. 266, 5036–5041 (1991).
Fernandez-Ruiz, E. Pardo-Manuel de Villena, R. Rodriguez de Cordoba, S. & Sanchez-Madrid, F. Regional localization of the human vitronectin receptor alpha subunit gene(VNRA) to chromosome 2q31–q32. Cytogenet. Cell Genet. 62, 26–28 (1993).
Solomon, E. et al. Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family. Proc. Natl. Acad. Sci. USA 82, 3330–3334 (1985).
Emanuel, B.S. Cannizzaro, L.A. Seyer, J.M. & Myers, J.C. Human alpha 1(111) and alpha 2(V) procollagen genes are located on the long arm of chromosome 2. Proc. Natl. Acad. Sci. USA 82, 3385–3389 (1985).
Acampora, D. et al. The human HOX gene family. Nucl. Acids Res. 17, 10385–10402 (1989).
Willems, P.J. Dynamic mutations hit double figures. Nature Genet. 8, 213–215 (1994).
Morahan, G. Huang, D. Tait, B.D. Colman, P.G. & Harrison, L.C. Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus. Science 272, 1811–1813 (1996).
Schuler, G.D. et al. A gene map of the human genome. Science 274, 540–546 (1996).
Abenhaim, L. et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N. Engl. J. Med. 335, 609–616 (1996).
Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).
Sheffield, V.C. et al. A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps. Hum. Mol. Genet. 4, 1837–1844 (1995).
Murray, J.C. et al. A comprehensive human linkage map with centimorgan density. Science 265, 2049–2054 (1994).
Hudson, T.J. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).
Schaffer, A.A. Gupta, S.K. Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).
Cottingham, R.W. Jr. Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).
Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).
Boehnke, M. Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 48, 22–25 (1991).
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Nichols, W., Koller, D., Slovis, B. et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 15, 277–280 (1997). https://doi.org/10.1038/ng0397-277
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