Human Genetics of Abdominal  Aortic Aneurysms

Helena Kuivaniemi, M.D., Ph.D.
Center for Molecular Medicine and Genetics,
and Department of Surgery
Wayne State University School of Medicine

The idea that abdominal aortic aneurysms (AAAs) even when they were not part of rare genetic diseases such as the Ehlers-Danlos syndrome or the Marfan syndrome could be a genetic disease was first conceived about 30 years ago (see Kuivaniemi 2004; Kuivaniemi & Shibamura, in press). Systematic studies to identify heritability patterns were initiated by Drs. Tilson (Tilson & Seashore 1984) and Norrgård (Norrgård et al. 1984) about 20 years ago.  Familial aggregation of AAAs is now widely recognized (see Kuivaniemi & Shibamura, in press) and two formal statistical analyses using segregation studies (Majumder et al. 1991; Verloes et al. 1995) suggested the presence of a major gene effect. 

Susceptibility genes, however, have not yet been identified. Our approach to find susceptibility genes has been to collect families with AAAs and to perform DNA linkage analyses to identify regions on the human chromosomes which are linked to AAAs and could, therefore, harbor susceptibility genes for AAAs. Families for the study were recruited through various vascular surgery centers in the USA, Finland, Belgium, Canada, the Netherlands, Sweden and the United Kingdom, as well as through our patient recruitment web site (Salkowski et al. 2001; http://www.genetics.wayne.edu/ags).

We identified 233 families that had at least two individuals diagnosed with AAAs (Kuivaniemi et al. 2003). There were 653 patients with a confirmed diagnosis of AAA in these families and an average of 2.8 cases per family. The majority of the families were small, with only two affected individuals; some were quite large, however, and we found six families with six, three with seven and one with eight affected individuals. The majority of the probands (82%) and affected relatives (77%) were males and the most common relationship to the proband was that of brother. When evaluating mode of inheritance, 167 (72%) families were consistent with autosomal recessive inheritance, whereas 58 (25%) families were consistent with autosomal dominant inheritance and in eight families the familial aggregation could be explained by autosomal dominant inheritance with incomplete penetrance.  In the 66 families where AAAs appeared to be inherited in a dominant manner, 141 transmissions of the disease from one generation to another were identified. 

We asked two questions about these apparently dominant transmissions: 1) Was there any difference in the frequency with which AAAs were inherited from a mother or a father? 2) Did both daughters and sons inherit AAAs from their parents? Altogether 46% of the 141 transmissions were from father to son, 11% were from father to daughter, 32% from mother to son and 11% from mother to daughter. This preliminary analysis suggested that it was more likely that a son than a daughter inherited an AAA from her parents.
For our genetic studies, blood samples from altogether 235 affected relative pairs (ARPs) and their unaffected relatives, if available, were collected for DNA isolation and the DNA used for genotyping using highly variable microsatellite markers (Shibamura et al. 2004).  We included covarites in the statistical analyses to allow for genetic heterogeneity. Such statistical approaches have been successful in dissecting the genetic components in other complex diseases such as prostate cancer, Alzheimer’s disease and systemic lupus erythematosus (see Shibamura et al. 2004). We carried out the study in two phases to reduce the amount of genotyping. In the first phase, 75 ARPs from 36 families were used for a whole genome scan with approximately 400 microsatellite markers and five chromosomal regions exceeded our set threshold logarithm of odds (lod) score of 0.8. One region had a lod score of 4.4 with covariate analyses and was studied further with 160 additional ARPs from 83 families. The results remained significant with a lod score of 4 in this larger sample. In combined analyses with a total of 119 families, the results were significant with sex, number of affected first-degree relatives, and their interaction as covariates. This best, most parsimonious model was the same in both cohorts as well as the combined sample (Shibamura et al. 2004) and suggested that females and AAA families with more affected individuals are more likely to have this genetic risk factor. The chromosomal region under study contains many plausible candidate genes whose protein products are important in the physiology of arteries. 

The future research will include more detailed studies of these positional candidate genes in the pathogenesis of AAAs. The success to identify the genetic risk factors for AAAs and their contribution to the pathogenesis of AAAs will require multidisciplinary approaches (Wassef et al. 2001).

Acknowledgements

The study was supported in part by a grant from NHLBI (HL064310), a grant from the NCHGR (HG01577), and a grant from the NCRR (RR03655). Some of the results were obtained using S.A.G.E., which is also supported by RR03655. We thank Dr. J. Weber and the NHLBI Mammalian Genotyping Service at the Marshfield Medical Research Foundation, Marshfield, WI, for performing the whole genome scan. I gratefully acknowledge the dedicated collaboration of many vascular surgeons, molecular biologists and geneticists who are shown as coauthors in the original publications listed in the reference section.

References

Kuivaniemi H. Editorial: Are there genes for aneurysms in the blueprint of the human genome? Ann Vasc Surg 18: 2004 (in press)

Kuivaniemi H, Shibamura H. Candidate genes for abdominal aortic aneurysms. In: Diseases of the Aorta. D. Liotta and M. del Rio, eds. (in press).