Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis
1 Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, TzYou First Road, Kaohsiung, 80708, Taiwan
2 Department of Neurology, Kaohsiung Medical University, No. 100, TzYou First Road, Kaohsiung, 80708, Taiwan
3 Department of Medical Genetics, Kaohsiung Medical University, No. 100, TzYou First Road, Kaohsiung, 80708, Taiwan
4 Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, TzYou First Road, Kaohsiung, 80708, Taiwan
5 Section of Neurology, Taichung Veterans General Hospital, No. 160, Sec. 3, ChungKang Rd., Taichung, 40705, Taiwan
6 Department of Neurology, Kaohsiung Medical University Hospital, No.100, ShihChuan 1st Road, Kaohsiung, 80708, Taiwan
7 Department of Neurology, Kaohsiung Municipal Hsiao-Kang Hospital, No.482, Shanming Road, Kaohsiung, 81267, Taiwan
8 Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, TzYou First Road, Kaohsiung, 80708, Taiwan
9 Department of Neurology, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan
BMC Medical Genetics 2010, 11:93 doi:10.1186/1471-2350-11-93Published: 12 June 2010
The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis.
Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 ± 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index ≥ 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect.
In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index ≥ 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index ≥ 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27).
The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.