1. ¹Department of Internal Medicine, Green Town Clinic Center, Saitama, Japan
2. ²Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
3. ³Department of Internal Medicine, Saitama Medical College, Saitama, Japan
4. ⁴Medicinal Safety Research Laboratories, Sankyo Co. Ltd., Shizuoka, Japan
5. ⁵Department of Internal Medicine, Sanno Hospital, Tokyo, Japan.

Correspondence: Dr. Yoichi Ohno, Department of Internal Medicine, Green Town Clinic Center, 2-23-3 Midoricho, Yashio City, Saitama, 340-0808, Japan E-mail: yo1-ohno@cb3.so-net.ne.jp

^*This work was supported by a research grant from the National Dairy Promotion and Research Association, and by TEPCO Hospital Funds.

Received 28 October 2004; Revised 2 December 2004; Accepted 22 December 2004.

Abstract

Background Increased intracellular calcium ([Ca²⁺]_i) in platelets is also proposed as an intermediate phenotype for hypertension in spontaneously hypertensive rats (SHR). Increased [Ca²⁺]_i in platelets is hypothesized to contribute to atherothrombotic events. Platelet hyperactivity is frequently associated with cardiovascular disease.

Methods In a genome scan, we performed the quantitative trait loci (QTL) mapping for [Ca²⁺]_i in back-crossed rats derived from SHR and normotensive Fischer 344 rats, which demonstrated a single major QTL for hypertension on chromosome 1. Thrombin-stimulated [Ca²⁺]_i in Ca²⁺-free and in Ca²⁺-containing buffers was measured in platelets using the Fura-2 method.

Results Among the parental strains, systolic blood pressure and thrombin-stimulated [Ca²⁺]_i were significantly greater in SHR than in Fischer 344 and F₁ rats. The sarco(endo)plasmic reticulum Ca²⁺-dependent ATPase II gene locus (Serca2) between D12Mgh5 and D12Mgh6 showed the significant linkage for thrombin-stimulated [Ca²⁺]_i in Ca²⁺-free and Ca²⁺-containing buffers. The peak logarithm of the odds scores were 3.6 and 3.3, respectively. These QTL explained 19.8% and 17.4% of the total variances, respectively. D3Mit13 and DXMgh1 showed suggestive linkage for thrombin-stimulated [Ca²⁺]_i in Ca²⁺-free and in Ca²⁺-containing buffers, respectively. The peak logarithm of the odds scores were 2.6 and 2.1, respectively.

Conclusions A significant QTL for [Ca²⁺]_i was mapped near Serca2 on chromosome 12, and suggestive QTL were identified near D3Mit13 and DXMgh1 in a genome scan. Genetic abnormalites in platelet [Ca²⁺]_i may contribute to cardiovascular disease via platetet hyperactivity, independent of blood pressure elevation.