Risk factor–gene interaction in carotid atherosclerosis: effect of gene polymorphisms of renin-angiotensin system

The risk factor–gene interaction in carotid atherosclerosis was investigated in 205 community-dwelling healthy subjects aged 50 years or more in Japan. The intima–media thickness (IMT) of the common carotid artery was evaluated by ultrasonography with a 7.5-MHz probe. Gene polymorphisms were determined for each subject with angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C, and apolipoprotein E (apoE) genotypes. There was no genotype-specific difference in carotid IMT among any genes examined. Combinations of genotypes did not increase carotid IMT compared with subjects without these genotypes. In the total population, multiple regression analysis showed that age, systolic blood pressure (SBP), sex, and body mass index (BMI) were significantly associated with carotid IMT. However, the association between risk factors and IMT was genotype-specific. Age was significantly associated with IMT in ACE D carriers, but not in subjects with the ACE II genotype. Analysis of covariance adjusted with other risk factors showed that the age-dependent change in IMT was significantly different between subjects with the ACE II genotype and the ACE D carriers (F[1.196] = 4.97; P = 0.027). Similarly, the regression of IMT on SBP was significantly different between AGT TT and AGT MT + MM (F[1.196] = 7.20; P = 0.0079). The regression of IMT on BMI was also significantly different between apo E4 carriers and noncarriers (F[1.196] = 6.78; P = 0.0099). Furthermore, general linear model analysis with risk factors, genotype, and risk factor-genotype interactions revealed that the age^*ACE genotype interaction, the SBP^*AGT genotype interaction, and the BMI^*apoE genotype interaction were significantly associated with IMT. These findings further support the role of risk factor-gene interaction in carotid atherosclerosis. Received: January 5, 2001 / Accepted: February 5, 2001     

脂蛋白脂酶Ser447Ter基因多态性与动脉硬化性脑梗死的相关研究

目的研究脂蛋白脂酶（lipoprotein lipase，LPL）Ser447Ter基因多态性与动脉粥样硬化性脑梗死（atherosclerotic cerebral infarction, CI）发病的关系及其对血脂水平、颈动脉斑块的影响。方法对166例CI患者及72名健康成人采用聚合酶链反应-限制性片段长度多态性方法检测LPL-Ser447Ter基因多态性，颈动脉超声多普勒检查颈总动脉内膜中层厚度（intima-media thickness，IMT）和颈动脉斑块（carotid artery plaque，CAP）的形状及大小。结果CI组CG＋GG基因型甘油三酯（triglyceride，TG）含量比CC基因型明显降低（P=0．1301），高密度脂蛋白胆固醇（high density lipoprotein cholesterol，HDL-C）含量明显增高（P=0．007）；对照组CG＋GG基因型TG含量比CC基因型低（P=0．041）；CI组G等位基因频率低于对照组（P=0．014）；LPLSer447Ter基因多态性与颈总动脉IMT和CAP分级无明显相关。结论LPL Ser447Ter基因多态性与血脂变化及脑梗死的关系密切，G等位基因可能引起血TG降低、HDL-C升高；G等位基因可能是脑梗死的保护基因型．     

Hepatic lipase promoter C-480T polymorphism is associated with serum lipids levels, but not subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study

The common C‐480T polymorphism (rs1800588) of the hepatic lipase gene (LIPC) has been associated with high‐density lipoprotein (HDL) cholesterol, atherosclerosis, and coronary artery disease. In this study, we examined whether the polymorphism is associated with serum lipid and lipoprotein concentrations, as well as with subclinical atherosclerosis in Young Finns. The participants comprised 2041 men and women (aged 24–39 years) enrolled in the Cardiovascular Risk in Young Finns Study with complete data concerning the rs1800588 polymorphism and serum lipids concentration. All participants underwent an ultrasound examination for brachial artery flow‐mediated vasodilatation (FMD) and carotid artery intima‐media thickness (IMT) measurement. The marker of arterial elasticity, carotid artery compliance (CAC), was also calculated by means of ultrasound and concomitant brachial blood pressure measurements. In all subjects, serum total cholesterol (p < 0.001), HDL cholesterol (p = 0.006), apolipoprotein AI (apoAI, p < 0.001), and triglyceride (p = 0.009) concentrations increased according to rs1800588 genotype in the order CC, CT, and TT. The same order applied only to apoAI after adjustment for age, body mass index, systolic and diastolic blood pressure, smoking, alcohol consumption, physical activity, diabetes, hypertension, contraceptive hormone use in women, and concentrations of glucose, insulin and C‐reactive protein in men and women separately (p = 0.007 and p = 0.003, respectively). The polymorphism was also associated with HDL cholesterol, total cholesterol, and triglyceride levels in women (adjusted p = 0.004, p = 0.007 and 0.02, respectively), but not in men (p was not significant for all). No significant association between the rs1800588 and brachial FMD, carotid IMT, or CAC was found among the entire study population or among women or men separately, with or without adjustment for the above‐mentioned factors. The rs1800588 is associated with serum lipid and apolipoprotein concentrations, especially in women, but does not seem to be a determinant of brachial artery FMD, carotid IMT, or CAC in young healthy adults.     

Association of interleukin‐10 promoter region polymorphisms with risk factors of Atherosclerosis

Atherosclerosis is considered as an inflammatory disease, and carotid artery intima‐media thickness (IMT) and carotid plaque are generally used as intermediated phenotype of atherosclerosis. The aim of this study was to investigate whether carotid IMT and plaque are associated with promoter region polymorphisms of interleukin 10 (IL‐10) gene. We recruited 135 subjects from a rural area of south‐eastern part of South Korea. Three polymorphisms in the promoter region of IL‐10 (?1082 A/G, ?819 T/C and ?592 A/C) were genotyped by pyrosequencing. Carotid IMT was measured at common carotid arteries, and carotid bulbs and cardiovascular risk factors such as cholesterol, blood pressure, uric acid and homocysteine were measured using blood samples. Subjects with the minor allele (C) of ?819 T/C or the minor allele (C) of ?592A/C showed lower values in carotid IMT than those with major allele homozygote of each polymorphism (P = 0.018 and P = 0.031, respectively). Subjects with carotid plaque were significantly older and showed higher values in carotid IMT, uric acid and homocysteine than those without plaque (P < 0.01, respectively). In conclusion, the promoter region polymorphisms of IL‐10 gene associate with carotid IMT and plaque. Further studies with larger samples are needed to provide stronger evidence to justify anti‐atheromatous properties of IL‐10.     

Relationship of angiotensin-converting enzyme gene polymorphism to carotid wall thickness in middle-aged men

The insertion/deletion (I/D) polymorphism of the human angiotensin-converting enzyme (ACE) gene is a major determinant of circulating ACE levels. The D allele has been suggested to be a potent risk factor for coronary artery disease; however, the effect of the ACE gene on carotid atherosclerosis remains controversial. We therefore studied the relationship between the ACE gene I/D polymorphism and carotid artery intima-media thickness (IMT). A random sample of 300 men aged 50-59 years living in southern Finland were selected, and 233 agreed to participate (74%). Data were collected in 219 subjects. Quantitative B-mode ultrasonography was used to measure the maximum near and far wall IMT of right and left common, bifurcation, and internal carotid artery. The mean maximum IMT (overall mean) was calculated as the mean of 12 maximum IMTs at 12 standard sites. Patients with an IMT higher than 1.7 mm in at least one of 12 standard sites were assumed to have carotid atherosclerosis. The I/D polymorphism was determined by polymerase chain reaction. Overestimation of the frequency of the DD genotype was eliminated by insertion-specific primer and the inclusion of 5% dimethylsulfoxide. No significant differences were found in carotid wall thickness between the three genotypes; the overall mean IMT were 1.18 +/- 0.30, 1.22 +/- 0.24, and 1.08 +/- 0.40 mm in genotypes of II, ID, and DD, respectively. Similarly, the ACE genotypes and allele frequencies did not differ significantly between the subjects with and those without carotid atherosclerosis. There was no association in the subgroups among only nonsmoking subjects or subjects without chronic medication. The present data indicate that the I/D polymorphism of the ACE gene is not related to carotid IMT and is unlikely to play a major role in carotid atherosclerosis.     

Association of MTHFR C677T polymorphism with elevated homocysteine level and disease development in vitiligo

Increasing evidence on the association of MTHFR gene polymorphism and serum homocysteine levels with autoimmune diseases such as vitiligo has made the MTHFR gene a very interesting candidate to be evaluated in different ethnicities and populations. We aimed to evaluate the levels of serum homocysteine and vitamin B12 and their associations with MTHFR C677T polymorphism in the Iranian population. This case–control study included 104 patients with vitiligo and 100 age‐ and sex‐matched healthy control subjects. Serum vitamin B12 and homocysteine levels were measured by a chemiluminescence assay. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis was used for genotyping the polymorphism. The mean serum homocysteine levels were significantly higher in cases than controls and associated with disease activity (p < .001). Furthermore, the homozygous MTHFR C677T variant genotype was associated with vitiligo development (adjusted OR: 3.52, 95% CI: 1.09–11.32, p = .02) and elevated homocysteine level (p < .001). There was no association between serum vitamin B12 levels and the MTHFR C677T genotype. The homozygous variant MTHFR C677T may be considered as a risk factor for both elevated homocysteine levels and the development of vitiligo in the Iranian population. Although these results are not conclusive, they could elucidate the contribution of genetic and immune‐mediated inflammatory factors to the pathogenesis of vitiligo.     

Association of the MTHFR C677T polymorphism and bone mineral density in postmenopausal women: a meta-analysis

Osteoporosis is a condition characterized by low bone mineral density (BMD) and micro-architectural changes in the bone tissue. The risk of osteoporosis is partly determined by genetic factors. The role of C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene has been investigated in postmenopausal osteoporosis. However, the relationship between MTHFR polymorphism and BMD is still controversial. We carried out a meta-analysis of 5,833 subjects to evaluate the association of MTHFR and BMD in postmenopausal women. Databases of MEDLINE, Web of Science, Scopus and CNKI were retrieved for all publications relating to MTHFR polymorphism and BMD in postmenopausal women. Five eligible studies were selected for meta-analysis. All these articles studied the association of MTHFR polymorphism and BMD of the femoral neck and lumbar spine in postmenopausal women. Our analysis suggested that postmenopausal women with the TT genotype had lower femoral neck BMD than the women with the CC/CT genotype, and the weighted mean difference (WMD) was -0.01 g/cm² [95% confidence interval (CI): (-0.01, -0.01), P < 0.01]. However, BMD of the lumbar spine of postmenopausal women with the TT genotype was not significantly different from that of women with the CC/CT genotype. In the random effects model, the WMD between the TT and TC/CC genotype was -0.01 g/cm² [95% CI: (-0.04, 0.01), P = 0.32]. The C677T polymorphism of the MTHFR gene is associated with BMD of the femoral neck in postmenopausal women. Women with the TT genotype of the MTHFR gene have lower BMD, suggesting that the TT genotype may be a risk factor for postmenopausal osteoporosis.     

A study of gene--environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach

Introduction: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene–environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness.

Methods: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products.

Results: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r² = 0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers.

Discussion: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis.

     

The C677T mutation in the methylene tetrahydrofolate reductase gene increases serum uric acid in elderly men

A common mutation, C677T, in the methylene tetrahydrofolate reductase gene (MTHFR) reduces the activity of MTHFR and increases total homocysteine levels in plasma. Increased homocysteine levels are reportedly associated with high serum uric acid levels. The relationship between the MTHFR mutation and uric acid metabolism remains unclear, however. To investigate whether the C677T MTHFR mutation is a risk factor for hyperuricemia, we performed MTHFR genotyping and clinical laboratory determinations, including serum uric acid, in 271 elderly Japanese men (age range, 40–79 years; mean, 52.6 years). The mean uric acid levels for the C/C, C/T, and T/T genotypes were 5.67, 6.00, and 6.39 mg/dl, respectively (P = 0.012). The T/T genotype was more frequent in subjects with high uric acid levels than in those with low uric acid levels (P = 0.038). These findings suggest that the C677T MTHFR mutation contributed to higher uric acid levels in subjects enrolled in this study. In conclusion, the mutation of the MTHFR gene may be a risk factor for hyperuricemia in elderly men. Received: February 28, 2000 / Accepted: February 29, 2000     

Genetics of C‐reactive protein and complement factor H have an epistatic effect on carotid artery compliance: The Cardiovascular Risk in Young Finns Study

Atherosclerosis is characterized by a prominent inflammatory component and C‐reactive protein (CRP) has been implicated to modulate the complement activity in atherosclerotic arteries via complement factor H (CFH) binding. In this study, we examined whether the gene‐gene interactions between CRP haplotypes and CFH Tyr402His functional polymorphism exerted an effect on early atherosclerosis. Single nucleotide polymorphisms (SNPs) in CFH (Tyr402His) and CRP (?717A > G, ?286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped in the participants of the Cardiovascular Risk in Young Finns Study (n = 1698, aged 24–39 years). The CRP SNPs were further constructed into haplotypes and their interactive effects with the CFH Tyr402His polymorphism on the early atherogenic vascular changes [i.e. carotid artery compliance (CAC) and intima‐media thickness (IMT)] were examined. After risk factor adjustment, a significant gene‐gene interaction (P = 0·007) on CAC was observed between CRP haplotype ATGTG and CFH Tyr402His polymorphism in males. Furthermore, logistic regression analysis verified the risk‐modifying interactive effect on CAC between these loci (OR 3·70, 95% CI 1·37–10·02, P = 0·010). No effects on CAC were observed in females and no effects on IMT were detected in either sex. We conclude that the combined presence of CRP haplotype ATGTG and CFH 402His allele may be disadvantageous to carotid artery elasticity in males.     

CRP and FCGR2A genes have an epistatic effect on carotid artery intima‐media thickness: the Cardiovascular Risk in Young Finns Study

The role of the inflammatory mediator C‐reactive protein (CRP) in atherosclerosis is recognized although its specific functions are not entirely clear. CRP binds to the Fcγ receptor2A (FcγR2A) and its polymorphism, FCGR2A (Arg131His), strongly influences the binding. We wanted to evaluate the CRP‐mediated proatherogenic process on early atherosclerosis and investigated whether CRP and FCGR2A show an interactive effect on carotid intima‐media thickness (IMT). Polymorphisms of FCGR2A (Arg131His) and CRP (–717A > G, –286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped and their effects on IMT were analyzed in 2260 young adults participating in the Cardiovascular Risk in Young Finns Study. CRP haplotypes were constructed based on the CRP polymorphisms. The FCGR2A(Arg131His) polymorphism did not have an independent effect on IMT but a significant gene‐gene interaction, epistasis, between FCGR2A and CRP genetics on IMT was found. The epistatic effect was seen in men at haplotype and genotypic level; both CRP haplotype GCGCG (–717, –286, +1059, +1444 and +1846) and CRP–717A > G polymorphism interacted with FCGR2A(Arg131His) on IMT. After adjustment with classical risk factors the P‐values for interaction were P = 0.013 and P = 0.010, respectively. No associations were observed in women. In conclusion, this study showed that the effect of CRP genetics on early atherosclerotic changes is modulated by the FCGR2A genetics.     

LDL、Hcy、D-二聚体及颈动脉粥样硬化与急性缺血性脑卒中相关性研究

目的 研究LDL、Hcy、D-二聚体及颈动脉粥样硬化与急性缺血性脑卒中的相关性。方法 选取我院2016年12月~2018年12月急性缺血性脑卒中患者57例作为研究组,比较不同NIHSS评分患者LDL、Hcy、D-二聚体水平及颈动脉不稳定斑块比例情况;同时选取正常体检者52例作为对照组,比较两组LDL、Hcy、D-二聚体、颈动脉内膜中层厚度（IMT）及颈动脉不稳定斑块例数。结果 研究组患者LDL（4.11±0.42）mmol/L、Hcy（23.29±4.34）μmol/L、D-二聚体（1.62±0.38）mg/L均高于对照组的（3.05±0.37）mmol/L、（7.78±4.15）μmol/L、（0.25±0.05）mg/L,差异有统计学意义（P＜0.05）;研究组颈动脉粥样硬化及颈动脉不稳定斑块者多于对照组,差异有统计学意义（P＜0.05）;NIHSS评分＞10分的患者的LDL、Hcy、D-二聚体水平均高于NIHSS评分≤10分的患者,且评分高的颈动脉不稳定斑块的比例高于评分低的患者,差异具有统计学意义（P＜0.05）。结论 LDL、Hcy、D-二聚体升高及颈动脉粥样硬化对于诊断急性缺血性脑卒中具有极高的临床价值,能反映患者病情的严重程度,对于临床诊断及治疗具有重要意义。     

Association of longevity with IL-10 −1082 G/A and TNF-α−308 G/A polymorphisms

Cytokines are crucial for the regulation of inflammation development in humans. Many studies have shown that variations in cytokine genes might play a role in determining human longevity. This study examined the changes in the gene pool relevant to the −308 G/A polymorphism in the promoter region of the proinflammatory cytokine tumour necrosis factor (TNF)-α gene and the −1082 G/A polymorphism in the promoter region of anti-inflammatory cytokine interleukin (IL)-10 gene with aging and survival selection occurs in the Jordanian population. IL-10 −1028 G/A and TNF-α−308 G/A were genotyped in 119 randomly selected elderly subjects (41 women and 78 men) with a mean age of 90.2 years and young control subjects of 118 (46 women and 72 men) with a mean age of 31.9 years. No significant differences were found in the genotype and allele frequencies of TNF-α gene variants between the two groups (P > 0.05) while the IL-10 genotype and allele frequencies were significantly associated with longevity in men (P < 0.05) but not in women (P < 0.05). Thus, IL-10 −1028 G/A polymorphism seems to play a role in the pathway to longevity in Jordanian men.     

An association analysis between <Emphasis Type="Italic">ApoA1</Emphasis> polymorphisms and the high-density lipoprotein (HDL) cholesterol level and myocardial infarction (MI) in Japanese

Association studies were performed to confirm the effect of polymorphisms in apolipoprotein A1 (ApoA1) on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI). A sequence analysis identified nine polymorphisms in ApoA1. After considering linkage disequilibrium, four polymorphisms in ApoA1 and four polymorphisms in the 5-flanking regions and 3-flanking regions from the JSNP database were determined in 1,880 subjects recruited from the Suita study, which represents the general population in Japan. Of the eight polymorphisms tested, the ApoA1 T84C polymorphism had the greatest effect on the levels of HDL-C (P=0.0005, P _c=0.0040 corrected by the Bonferroni method) and triglyceride (P<0.0001, P _c=0.0008). The ApoA1 MspI polymorphism was not associated with HDL-C or triglyceride levels. We confirmed that the ApoA1 T84C polymorphism was associated with the HDL-C level but not the triglyceride level in patients with MI (n=637). Moreover, this polymorphism was associated with the incidence of MI in male subjects (P=0.0326). A logistic analysis indicated that the frequency of MI in the CC genotype was lower than that in the CT+TT genotype (P=0.0145, OR=0.4955, 95% CI: 0.2746–0.8525). The ApoA1 T84C polymorphism is an important marker for the HDL-C level and may be a new risk marker for MI in Japanese.This study was supported by the Program for the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research of Japan.     

Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: A systematic review and meta-analysis

Familial hypercholesterolemia (FH) is a common genetic disorder of lipoprotein metabolism leading to premature atherosclerosis. From early onset, status and progression of atherosclerosis of the large peripheral arterial walls can be quantified by ultrasound intima-media thickness (IMT) measurements. Here we describe differences in IMT in treated and untreated FH patients versus unaffected controls over a broad age range. We conducted a systematic literature search using MEDLINE, EMBASE and Trials.gov up to April 2020 for studies addressing IMT in FH patients and controls. Our search yielded 558 articles of which 42 (6,143 participants) were included. Meta-analysis showed a mean (95%CI) difference between FH patients vs controls of 0.11 (95%CI 0.06-0.15) mm in carotid IMT (p<0.001), and 0.47 (0.19-0.74) mm in femoral IMT (p <0.001). We found a smaller mean (95%CI) difference in carotid IMT in treated FH patients vs controls: 0.05 (0.03-0.08) mm (p <0.001), than in untreated FH patients vs controls 0.12 (0.03-0.21) mm (p=0.009). When plotted against age, the mean (95%CI) difference in carotid IMT between FH patients vs controls increases with 0.0018 (-0.0007-0.0042) mm/year. This increase was smaller in treated vs untreated FH patients, when compared to controls (0.0023 (0.0021 to 0.0025) mm/year vs 0.0104 (0.0100-0.0108) mm/year, respectively). Our findings suggest that more robust earlier treatment initiation and achieving treatment targets could be beneficial to reduce cardiovascular risk in patients with FH.     

Minimal nocturnal oxygen saturation predicts future subclinical carotid atherosclerosis: the Wisconsin sleep cohort

Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO₂) and cardiovascular disease (CVD) risk factors with carotid intima‐media thickness (IMT) and plaques. We used data on 689 Wisconsin sleep cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (SD) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B‐mode ultrasound. Bilateral common, bifurcation and internal carotid artery segments were evaluated for plaque score. Participants (8) were aged 56 years (55% male); 32% had hypertension and mean body mass index (BMI) was 31 (7) kg m². Mean and minimum nocturnal SaO₂ were 95% (2) and 86% (7), respectively. Mean percentage sleep time with SaO₂ < 90% was 2% (8). Both mean (odds ratio [OR]: 0.60 lower plaque count per 5% higher mean SaO₂, 95% confidence interval [CI]: 0.38–0.96, P = 0.033) and minimum SaO₂ (OR: 0.88 lower plaque count per 5% higher minimum SaO₂, 95% CI: 0.80–0.97, P = 0.013) predicted carotid plaque score after adjusting for age, sex and BMI. Minimum SaO₂ predicted future plaque score after adding adjustment for traditional CVD risk factors (OR: 0.90 lower plaque count per 5% higher minimum SaO₂, 95% CI: 0.81–0.99, P = 0.038). Mean SaO₂ was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO₂ is an independent predictor of future carotid plaque burden. Other nocturnal SaO₂ parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors.     

Genetic study of Apolipoprotein E gene,alpha‐1 antichymotrypsin gene in sporadic Parkinson disease

Several lines of evidence have suggested some common genetic risk factors for Alzheimer disease (AD) and Parkinson disease (PD) because there are some overlapping pathologies in these two neurodegenerative diseases. In the present study, we investigated the role of Apolipoprotein E gene polymorphism and the signal peptide polymorphism in alpha‐1 antichymotrypsin (ACT) gene in idiopathic sporadic PD. The study was performed in a sample consisting of 68 PD cases and 160 healthy subjects in Shanghai China. We found no significant differences of ACT gene polymorphic distribution between PD cases and controls. The ApoE gene ε2/ε4 genotype was significantly more frequent in PD subjects (χ² = 7.126, df = 1, P = 0.008) and conferred a 12.70 times susceptibility for PD (OR = 12.62, 95% CI: 1.445–110.17, χ² = 5.259, P < 0.05, AF = 4.59%). No interaction of ApoE and ACT genes was detected in PD. Therefore, our data suggested that the ApoE ε2/ε4 genotype might be a susceptibility variant of moderate effect for sporadic idiopathic PD in our samples, whereas the ACT gene signal peptide polymorphism might not. © 2002 Wiley‐Liss, Inc.     

ADCYAP1R1 genotype associates with post‐traumatic stress symptoms in highly traumatized African‐American females

Pituitary adenylate cyclase‐activating polypeptide (PACAP) and its receptor (PAC1) play a critical role in biological processes that mediate stress response and have been implicated in psychological outcome following trauma. Our previous work [Ressler et al. (2011); Nature 470:492–497] demonstrated that a variant, rs2267735, in the gene encoding PAC1 (ADCYAP1R1) is associated with post‐traumatic stress disorder (PTSD) in a primarily African‐American cohort of highly traumatized females. We sought to extend and replicate our previous finding in a similarly trauma‐exposed, replicate sample of 1,160 African‐American adult male and female patients. Self‐reported psychiatric measures were collected, and DNA was obtained for genetic analysis. Using linear regression models to test for association with PTSD symptom severity under an additive (allelic) model, we found a genotype × trauma interaction in females (P < 0.001), but not males (P > 0.1); however, there was no main effect of genotype as in our previous study. The observed interaction suggests a genetic association that increases with the degree of trauma exposure in females only. This interaction remained significant in females, but not males, after controlling for age (P < 0.001), income (P < 0.01), past substance abuse (P < 0.001), depression severity (P = 0.02), or child abuse (P < 0.0005), and all five combined (P = 0.01). No significant effects of genotype (or interactions) were found when modeling depression severity when controlling for comorbid PTSD symptom severity (P > 0.1), demonstrating the relative specificity of this variant for PTSD symptoms. A meta‐analysis with the previously reported African‐American samples revealed a strong association between PTSD symptom severity and the interaction between trauma and genotype in females (N = 1424, P < 0.0001). © 2013 Wiley Periodicals, Inc.     

Impact of inflammation and oxidative stress on carotid intima‐media thickness in obstructive sleep apnea patients without metabolic syndrome

Obstructive sleep apnea (OSA) increases the risk of cardiovascular diseases, and carotid intima‐media thickness (IMT) is a good indicator of the severity of atherosclerotic disease. This study tested the hypothesis that inflammation and oxidative stress determined carotid IMT in patients with OSA. The carotid IMT, mean systolic and diastolic pressure (night and morning) were significantly higher and the level of thiols and high‐density lipoprotein were significantly lower in our 121 OSA patients than in 27 controls (P < 0.05). The apnea/hypopnea index was correlated positively with E‐selectin (r = 0.222, P = 0.014), total cholesterol (r = 0.185, P = 0.042), low‐density lipoprotein (r = 0.264, P = 0.003) and HbA1c levels (r = 0.304, P = 0.001), but inversely with high‐density lipoprotein level (r = −0.203, P = 0.025) in the 121 patients with OSA. In OSA subjects, multiple linear regression analysis revealed that age, systolic blood pressure and intercellular cell adhesion molecule‐1 level associated independently with carotid IMT. Besides both age and systolic blood pressure, our study demonstrated that intercellular cell adhesion molecule‐1 level was associated significantly with carotid IMT in those patients who had OSA but without metabolic syndrome.     

An interaction between the TaqIB polymorphism of cholesterol ester transfer protein and smoking is associated with changes in plasma high-density lipoprotein cholesterol levels in Turks

Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for atherosclerosis. We investigated the effects of the TaqIB polymorphism of cholesterol ester transfer protein (CETP) on CETP activity and plasma HDL-C levels in random nondiabetic and self-reported diabetic subjects in a population with very low HDL-C levels. The rare B2B2 genotype was associated with significantly higher HDL-C levels and lower CETP activity in random subjects and with higher HDL-C in diabetic subjects. After stratification of random subjects by smoking status, the common B1B1 genotype was associated with lower HDL-C levels than the B2B2 genotype. Although smoking was associated with lower HDL-C, especially in men, HDL-C levels between smokers and nonsmokers were not different in subjects with the B1B2 or B2B2 genotypes. However, smoking (20+ cigarettes/day) was associated with a marked reduction in HDL-C in the B1B1 subjects. The B1B1/smoking interaction was not reflected in a difference in CETP activity. High triglycerides and elevated body mass index (BMI) lower HDL-C. The B2B2 genotype was associated with the highest HDL-C levels, and these levels were significantly lower in the hypertriglyceridemic subjects (>or=50th percentile). The lowest HDL-C levels were seen in hypertriglyceridemic subjects with the B1B1 genotype. Although BMI (>or=50th vs<50th percentile) did not affect HDL-C in B2B2 subjects, a high BMI was associated with markedly lower HDL-C in B1B1 subjects. Thus, HDL-C levels in Turks may be modulated by an interaction between the CETP TaqIB polymorphism and smoking, as well as an interaction with hypertriglyceridemia and BMI.