Further information: Classification of Genetic Disorders (see p2551) from Cardiovascular Medicine, 3rd Edn*

In order to conduct a somewhat novel experiment, the investigators in a multicenter case-control study titled the Precocious Coronary Artery Disease (PROCARDIS) study [1] used a newly available chip designed to assay single-nucleotide polymorphisms (SNPs) to examine genetic associations in coronary artery disease (CAD) and to assess the associations of LPA gene variants with Lp(a) lipoprotein levels. From four European countries, 3145 patients with CAD and 3352 control subjects were recruited, and a novel gene chip that contained 48,742 SNPs in 2100 candidate genes was used to test the CAD patients and the control subjects. The chip identified three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13. The 6q26-27 region contained the LPA gene, and the investigators used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus for both the Lp(a) lipoprotein level and the risk of coronary disease. At least 36% of the total variation in the Lp(a) lipoprotein level was explained by two common variants at rs10455872 and rs3798220 that were independently associated with an increased risk of coronary disease: common variant rs10455872 at the LPA locus had odds ratio (OR) for coronary disease of 1.70 (95% CI, 1.49–1.95) and common variant rs3798220 had an OR of 1.92 (95% CI, 1.48–2.49). The two LPA variants had a linear-dose response with both the Lp(a) lipoprotein level and the risk of coronary disease. The investigators concluded that LP(a) lipoprotein has a causal role in coronary disease.

In an editorial accompanying the paper [2], the author acknowledged the conclusions reached by the investigators regarding the role of Lp(a) lipoprotein as a causal factor in coronary disease. However, he raised the issue of whether or not this knowledge has clinical relevance. He questioned the mechanism by which an increased level of Lp(a) lipoprotein led to an increased risk of coronary disease. He suggested that a therapeutic intervention that selectively lowered the Lp(a) lipoprotein level without other effects needed to be tested in a randomized clinical trial to gain a valid understanding of its role. He also expressed concerned that the study only included white subjects, specifically, white Europeans, and additional work would be needed to determine whether or not the variation in Lp(a) lipoprotein levels had a causal effect in other patient populations.

[1] Clarke R, Peden JF, Hopewell JC, et al. Genetic Variations Associated with Lp (a) Lipoprotein Level and Coronary Disease. N Engl J Med 2009;361:2518-28

[2] Kathiresan. Lp(a)Lipoprotein Redux – From Curious Molecule to Causal Risk Factor. N Engl J Med 2009;361:2573-2574

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Further information: Hypertrophic Cardiomyopathy (see p1261) and Muscular Dystrophies Affecting the Heart (see p2567) from Cardiovascular Medicine, 3rd Edn*

Over the past 25 years, infertility has become an increasing problem in the US as couples have delayed marriage and childbearing years. Among other efforts to solve infertility issues, sperm banks have been created to provide a woman a means to achieve pregnancy when her partner is infertile. The Food and Drug Administration (FDA) has in place an inspection process for the purpose of preventing the spread of infectious diseases, but at this time, there is no screening process to identify genetic diseases.

The authors of this paper [1] have provided a brief report of a case report that involved sperm donation and inherited heart diseases, in this case, hypertrophic cardiomyopathy (HCM). Because the donor’s contract with a sperm bank was for a 2-year period, and there were no restrictions as to the number of pregnancies permitted for the donor, 22 children were produced (13 families, including his own) and nine were positive for the HCM mutation. The donor in this report was healthy and had no prior knowledge of his underlying heart disease. The currently used standard testing procedure prior to sperm donation revealed no negative results, and the donor’s disease was not identified until after the disease was identified in his offspring. An important conclusion reached from this study stressed the significant value of a genetic screening requirement for sperm donors.

[1] Maron BJ, Lesser JR, Schiller NB. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. JAMA 2009;302:1681-4

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.