Polymorphisms of the apolipoprotein B and E genes and their relationship to plasma lipid variables in healthy Chinese men

In this study we have analysed the apolipoprotein (Apo) E polymorphism and polymorphisms of the ApoB gene, including the ApoB/Xba I and ApoB/4311 diallelic polymorphisms and a hypervariable region (HVR) situated in the 3 region of the gene (ApoB/3HVR), in a sample of healthy male subjects from Taiyuan (northern People's Republic of China). In comparison to Caucasian populations, in the Chinese sample, the Xba I2 allele (presence of cutting site; frequency 6.1%; and 95% confidence interval, 3.3–8.9) and the long HVR alleles (9.4%; 6.0–12.8) were rare, whereas the ApoB/4311 (Ser) allele (70.8%; 65.4–76.2) and the 34-repeat allele of the HVR (HVR34; 62.4%; 56.8–68.0) were frequent. In subjects having none, one, or two HVR34 alleles, the mean levels of plasma triglycerides were 2.32±1.44 (SD), 1.45+0.74, and 1.75±1.07 g/l, respectively (P < 0.007). Similar trends were observed for very low density lipoprotein (VLDL) cholesterol, LpE:B, and LpCIII:B. The frequencies of the ApoE alleles were similar to those reported in other populations of Asian origin; E2 (7.4%; 4.2–10.6), E3 (84.4%; 80.2–88.6), and E4 (8.2%; 5.0–11.4). Individuals carrying the E2 allele had a lower mean level of ApoB than E33 individuals: 0.87±0.16 and 1.00±0.22 g/l, respectively (P < 0.007). Individuals carrying the E4 allele had higher levels of ApoE than E33 individuals: 0.140±0.084 and 0.094±0.052 g/l, respectively (P < 0.004); similar trends were observed for VLDL cholesterol, triglycerides, LpE:B, and LpCIII:B. The ApoB/ HVR34 and ApoE/E4 polymorphisms accounted for 10% to 15% of the variability of the plasma levels of VLDL cholesterol, ApoE, triglycerides, LpE:B, and LpCIII:B. Several lipid variables appeared to be favourably affected by specific forms of ApoB and ApoE that are particularly frequent in this Chinese population.     

The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects

Thymidylate synthase (TYMS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) may compete for their common cofactor 5,10-methylenetetrahyhdrofolate (5,10-meTHF). Limiting 5,10-meTHF results in elevated homocysteine, especially in individuals homozygous for the T allele of the MTHFR C677T polymorphism. The TYMS gene has a tandem repeat polymorphism (two repeats or three repeats, designated 2R or 3R, respectively), which may also affect homocysteine concentrations. The 3R allele is subject to increased translational efficiency in vitro and the 3R3R genotype is associated with both decreased serum folate and elevated plasma homocysteine (tHcy) in a population of Singapore Chinese. We assessed the relationship between TYMS genotype and key biochemical and genetic variables in a random sample of 392 healthy young Northwestern European men and women. The tHcy concentrations for 3R3R homozygotes (median 8.5 mol/l) did not differ significantly from those for 2R2R homozygotes (median 8.7 mol/l) or 2R3R heterozygotes (median 9.3 mol/l) in the population as a whole (P=0.43), or in subsets of subjects with low serum folate (P=0.60) or the MTHFR 677TT genotype (P=0.90). Furthermore, there was no trend toward elevated tHcy in 3R3R homozygotes. Similarly, the TYMS tandem repeat polymorphism was not associated with serum folate concentrations. Our findings indicate that the TYMS 3R3R genotype is not a determinant of homocysteine in this sample of healthy young Caucasian adults from Northern Ireland.     

Protection of Neurons from Apoptosis by Apolipoprotein E-containing Lipoproteins Does Not Require Lipoprotein Uptake and Involves Activation of Phospholipase C��1 and Inhibition of Calcineurin

Apolipoprotein E-containing lipoproteins (LpE) are generated in the central nervous system by glial cells, primarily astrocytes, and are recognized as key players in lipid metabolism and transport in the brain. We previously reported that LpE protect retinal ganglion neurons from apoptosis induced by withdrawal of trophic additives (Hayashi, H., Campenot, R. B., Vance, D. E., and Vance, J. E. (2007) J. Neurosci. 27, 1933–1941). LpE bind to low density lipoprotein receptor-related protein-1 and initiate a signaling pathway that involves activation of protein kinase Cδ and inhibition of the pro-apoptotic glycogen synthase kinase-3β. We now show that uptake of LpE is not required for the neuroprotection. Experiments with inhibitors of phospholipase Cγ1 and RNAi knockdown studies demonstrate that activation of phospholipase Cγ1 is required for the anti-apoptotic signaling pathway induced by LpE. In addition, the protein phosphatase-2B, calcineurin, is involved in a neuronal death pathway induced by removal of trophic additives, and LpE inhibit calcineurin activation. LpE also attenuate neuronal death caused by oxidative stress. Moreover, physiologically relevant apoE3-containing lipoproteins generated by apoE3 knock-in mouse astrocytes more effectively protect neurons from apoptosis than do apoE4-containing lipoproteins. Because inheritance of the apoE4 allele is the strongest known genetic risk factor for Alzheimer disease, the reduced neuroprotection afforded by apoE4-containing LpE might contribute to the neurodegeneration characteristic of this disease.The lipoprotein composition of cerebrospinal fluid differs from that of plasma because the blood-brain barrier prevents the movement of lipoproteins from the peripheral circulation into the central nervous system (CNS)³ (1). The CNS contains a distinct population of lipoprotein particles that are generated within the CNS and are thought to play important roles in the metabolism and transport of lipids within the brain. These lipoproteins are the size and density of plasma high density lipoproteins and contain apolipoprotein (apo) E and apoJ as their major protein constituents (2–5). The apoE-containing lipoproteins (LpE) in the CNS are generated by non-neuronal glial cells, primarily astrocytes (5). Astrocytes are thought to provide nutrient support for neurons by delivering lipoproteins to neurons for axonal growth (6) and synaptogenesis (7). Interest in the function of apoE in the nervous system has blossomed recently because after nerve injury the synthesis of apoE dramatically increases (by up to 150-fold) (6, 8). In addition, inheritance of the ϵ4 allele of apoE instead of the more common ϵ3 allele is the strongest genetic risk factor known for development of late-onset Alzheimer disease (9, 10). Furthermore, apoE3-containing lipoproteins have been reported to stimulate axon growth more efficiently than those containing apoE4 (11, 12). Thus, it has been proposed that LpE assist in repairing neurons after injury.Our laboratory has reported that astrocyte-derived LpE stimulate axon extension of retinal ganglion cells (RGCs; CNS neurons) by binding to a neuronal receptor of the low density lipoprotein receptor family on axons (13). Neurons in the CNS express several receptors of this superfamily for which apoE is a ligand (2, 14, 15). Some of these receptors can function both in the endocytosis of ligands (16) and in signaling pathways that are required for normal brain development (17, 18). Recently, we demonstrated that glia-derived LpE strikingly protect cultured RGCs from apoptosis induced by withdrawal of trophic additives (19). The prevention of neuronal apoptosis was promoted by LpE binding to the multifunctional low density lipoprotein receptor-related protein-1 (LRP1) whereupon a signaling pathway was initiated that involved activation of protein kinase Cδ and inactivation of the pro-apoptotic kinase, glycogen synthase kinase-3β (19).The aim of the present study was to dissect further the mechanism by which LpE protect RGC from apoptosis. We demonstrate that uptake of LpE is not required for the prevention of apoptosis. Furthermore, a signaling pathway induced upon binding of LpE to LRP1 requires the action of phospholipase Cγ1 upstream of protein kinase Cδ. Our data also show that glial LpE containing apoE3 are more protective against apoptosis than are apoE4-containing lipoproteins.     

Association of the SDF1-3′A polymorphism with susceptibility to myocardial infarction in Chinese Han population

SDF-1 has been demonstrated to be involved in the pathophysiology of atherosclerosis. This study was aimed to investigate whether the SDF1-3′A polymorphism (rs1801157) is associated to myocardial infarction (MI) in a sample of Chinese Han population. A total of 560 patients with MI and 532 controls were enrolled in the study. The SDF1-3′A polymorphism was determined by polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) analysis. A significant difference in genotype distribution and allele frequency was observed between patients and controls (P = 0.003 and P = 0.001, respectively). The A allele carriers had a significantly reduced MI risk compared with the GG homozygotes (OR, 0.69; 95% CI, 0.52–0.92; adjusted P = 0.007) in a logistic regression model after controlling conventional risk factors. The present study showed a significant association between the SDF1-3′A polymorphism and MI in Chinese Han population.     

Interactions of the apolipoprotein A5 gene polymorphisms and alcohol consumption on serum lipid levels

Background

Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5–1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.

Methodology/Principal Findings

A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05–0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between –1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The –1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the –1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05–0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05–0.01).

Conclusions

The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption.     

Apolipoprotein E phenotypes and hyperlipidemia

Summary Apolipoprotein E phenotypes were determined in 361 patients with hyperlipidemia and in controls. The E2 isoform was significantly more frequent in the group of hyperlipidemics (P<0.0005). This was not due to a higher frequency of E-2/2 homozygotes with type III hyperlipoproteinemia, but rather to a significantly higher frequency of E2 heterozygotes (P<0.0005). Subgrouping of hyperlipidemics into patients with a) hypertriglyceridemia, b) hypercholesterolemia and c) mixed hyperlipidemia revealed i) that isoform E2 was significantly more frequent in patients with hypertriglyceridemia (0.001>P>0.005), ii) that isoform E4 was significantly more frequent in patients with hypercholesterolemia (0.01>P>0.005) and iii) that isoforms E2 (P>0.005) and E4 (0.05>P>0.025) were both more frequent in patients with mixed hyperlipidemia. Roughly 20% of patients with mixed hyperlipidemia had one of the rare phenotypes E-4/4,-4/2 or-2/2. We conclude that alleles 2 and 4 both contribute to the susceptibility for, and/or phenotypic expression of hyperlipidemia. Whereas the gene 2 seems to exert its influence on plasma lipoproteins by an abnormal gene product (E2) that has reduced binding activity to lipoprotein receptors, the mechanism underlying the association of the 4 gene with hyperlipidemia is presently unclear.     

A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations

Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3UTR del/del subjects (434 g/l) compared with either ins/ins (282 g/l) or ins/del (298 g/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component.     

Association of the HindIII Polymorphism of the Lipoprotein Lipase Gene with Myocardial Infarction and the Life Span in Elderly Patients with Coronary Heart Disease

Allele and genotype frequencies of the HindIII polymorphism of the lipoprotein lipase (LPL) gene were studied in patients with myocardial infarction (MI) and stable angina of effort (SAE), including long-lived people (over 90). The polymorphism proved to be associated with MI and with the life span, genotype H+/H+ being predisposing to MI and allele H– being protective. The allele and genotype frequencies of long-lived people differed significantly from the Hardy–Weinberg proportions and from those of SAE patients aged up to 90. An excess of heterozygotes in this group suggests a selective pressure which eliminates homozygotes. Possibly, heterozygotes H+/H– have an adaptive advantage, which provides for their longevity.     

Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese

The homozygous deletion allele (DD) of the angiotensin-I converting enzyme (ACE) gene and the T235 homozygote of the angiotensinogen (AGT) gene have been reported to be correlated with an increased prevalence of coronary artery disease (CAD) and myocardial infarction (MI). The importance of the DD genotype and T235 homozygote as genetic risk factors for CAD in Chinese remains uncertain. This study included 426 patients who underwent coronary angiography and 180 healthy subjects without clinical evidence of CAD. Coronary angiography identified 268 patients with CAD (CAD group) and 158 patients without CAD. The healthy subjects and patients without angiographic evidence of CAD constituted the control group. Three polymorphisms were studied: an insertion/deletion (I/D) polymorphism of the ACE gene and the T174 M and M235T polymorphisms of the AGT gene. No association was found between any of the three studied polymorphisms and the risk of CAD or MI in Chinese using univariate or multivariate analysis. In multivariate analysis, the relative risks were 1.20 (95% confidence interval = 0.91–1.61, P = 0.20) for the DD genotype, 1.05 (95% CI = 0.82–1.35, P = 0.69) for the T174 homozygote, and 1.19 (95% CI = 0.91–1.55, P = 0.20) for the T235 homozygote. Similarly, no significant difference was found in the frequencies of the DD genotype and the T174 and T235 homozygotes between the control group, the CAD group, the non-MI group, and the MI group when analyzed according to sex, age, or degree of risk. Our data suggest that neither the DD genotype of the ACE I/D polymorphism nor the T174 and T235 homozygotes of the AGT gene confer significant risk for CAD or MI in Chinese. Received: 18 December 1996 / Accepted: 27 February 1997     

Investigation of KIF6 Trp719Arg in a Case-Control Study of Myocardial Infarction: A Costa Rican Population

Background and Methodology

The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations.

Principal Findings

Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR = 1.12; 95%CI, 0.98–1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non-fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01–1.34), but this association would not be significant after a multiple testing correction.

Conclusions/Significance

We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in a case-control study of Costa Ricans living in the Central Valley of Costa Rica.     

Association between a rare novel TP53 variant (rs78378222) and melanoma,squamous cell carcinoma of head and neck and lung cancer susceptibility in non‐Hispanic Whites

Recently, several studies have investigated the association between a newly reported rare functional single nucleotide polymorphism (SNP) in TP53 (rs78378222) and cancer risk, but generated inconsistent findings. The present study further investigated this association with risk of melanoma, squamous cell carcinoma of head and neck (SCCHN) and lung cancer. Using volunteers of non‐Hispanic Whites recruited for three large case–control studies, we genotyped the TP53 rs78378222 SNP in 1329 patients with melanoma, 1096 with SCCHN, 1013 with lung cancer and 3000 cancer‐free controls. Overall, we did not observe any variant homozygotes in this study population, nor significant associations between the TP53 rs78378222AC genotype or C allele and risk for melanoma (P = 0.680 and 0.682 respectively) and lung cancer (P = 0.379 and 0.382 respectively), but a protection against SCCHN (P = 0.008 and 0.008 respectively), compared with the AA genotype or A allele. An additional meta‐analysis including 19,423 cancer patients and 54,050 controls did not support such a risk association either. Our studies did not provide statistical evidence of an association between this rare TP53 variant and increased risk of melanoma, nor of lung cancer, but a possible protection against SCCHN.     

Association of polymorphisms at restriction enzyme recognition sites of apolipoprotein B and E gene with dyslipidemia in children undergoing primary nephrotic syndrome

Background Dyslipidemia, a common complication, is very prevalent in children with primary nephrotic syndrome (PNS). Recent studies have shown that genetic basis may be involved in the onset of HLP secondary to PNS. ApoB and E have been identified as the important candidate genes for lipid abnormalities. Objective: To investigate the association of apolipoprotein B (apoB) and E (apoE) genetic polymorphisms (Xba I, EcoR I, Msp I, and Hha I) with parameters describing the serum lipid profiles in children undergoing PNS. Methods: Genomic DNA was extracted from 250 children diagnosed with PNS and 200 healthy controls with neither allergic nor renal disease. ApoB (Xba I, EcoR I, and Msp I) and apoE (Hha I) genotypes were determined by PCR-restriction fragment length polymorphism (RFLP) analysis. The fasting serum lipoprotein (a) [Lp(a)], total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), apoB, and total protein from a 24-h urine sample were measured. Results: No significant differences in genotypes and alleles frequencies were observed for the apoB Xba I, EcoR I, Msp I and the apoE Hha I restriction sites in PNS patients as compared to controls (P > 0.05). Patients and controls with X + allele exhibited significantly higher serum levels of Lp(a), TC, nonHDL-C, LDL-C, LDL-C/HDL-C ratio, and apoB than that with X− allele (P < 0.05), whereas for apoA1/B ratio the opposite was found (P < 0.01). E−/E− carriers had significantly higher Lp(a), TC, HDL-C, and apoA1 concentrations than did E+/E− or E+/E+ carriers in control group (P < 0.05). Healthy children carrying the rare EcoR I allele had higher mean Lp(a), TC, and HDL-C levels than homozygotes for E+ (P < 0.05). Higher Lp(a) serum concentrations were observed in patients with E− allele (P < 0.05). No significant differences in lipid parameters were determined for the apoB Msp I and apoE Hha I the polymorphisms study (P > 0.05). When genetic variations were compared with urinary protein excretion, the Xba I X− allele was more frequent in patients with elevated proteinuria (P < 0.01). Conclusion: Presence of Xba I X+ allele and/or EcoR I E− at the apoB gene may be risk factors for lipid abnormalities secondary to childhood PNS.     

Polymorphism of the Apolipoprotein E Gene and Risk of Myocardial Infarction

The apolipoprotein E (ApoE) gene polymorphism resulting from nucleotide substitutions in exon 4 was analyzed in Russian and Tatar patients with myocardial infarction (MI) from Bashkortostan. Alleles 2, 3, and 4 were identified by PCR. The genotype frequency distribution proved to be age-dependent in healthy Russians, genotype 2/3 increasing in frequency in subjects over 45. Russians who suffered MI under 45 had lower frequencies of genotype E3/3 (50.00% vs. 75.47% in controls of the same age, = 0.013, OR = 0.33) and allele 3 (72.12% vs. 85.85%, = 0.020, OR = 0.43) and a higher frequency of allele 4 (22.12% vs. 10.38%, = 0.030, OR = 2.45). Russians who suffered MI complicated by cardiogenic shock (CS) had a significantly higher frequency of genotype 3/4 and lower frequencies of genotype 3/3 and allele 3 as compared with MI patients without CS. In Tatars, genotype 4/4 occurred at a frequency of 14.29% in patients who suffered MI under 45, and was not detected in healthy subjects of the same age ( = 0.024, OR = 17.85). Thus, the ApoE polymorphism was associated with higher risk of MI in Russians and Tatars under 45.     

Genetic Analysis of the Relationship between Bone Mineral Density and Low-Density Lipoprotein Receptor-Related Protein 5 Gene Polymorphisms

Background

A number of studies have examined the association between the polymorphisms of the low-density lipoprotein receptor-related protein 5 gene (LRP5), but previous results have been inconclusive. Thus we performed a meta-analysis of studies on the association between the LRP5 polymorphisms and bone mineral density (BMD) to assess their pooled effects.

Methods

Published literature from PubMed, EMBASE and ISI web of science were searched for eligible publications. Weighted mean difference (WMD) and 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

A total of 19 studies with 25773 subjects were considered in this meta-analysis. Of them, 17 examined the association between the A1330V polymorphism and BMD, 8 were focused on the V667M polymorphism, and 2 analyzed the Q89R polymorphism. Individuals with the A1330V AA genotype showed significantly higher BMD than those with the AV/VV genotypes [at lumbar spine (LS): WMD = 0.02g/cm², 95% CI = 0.01-0.03, P < 10^-4; at femur neck (FN): WMD = 0.01g/cm², 95% CI = 0.00-0.02, P = 0.01] or VV genotype (at LS: WMD = 0.02g/cm², 95% CI = 0.01-0.04, P = 0.01). Significant associations were also detected in the analysis for V667M (VV vs. VM/MM: WMD at LS = 0.02g/cm², 95% CI = 0.02-0.03, P < 10^-5; WMD at FN = 0.01g/cm², 95% CI = 0.01-0.02, P = 0.0002). As for Q89R, subjects with the QQ genotype tended to have higher BMD than those with the QR/RR genotypes at FN (WMD = 0.03g/cm², 95% CI = 0.01-0.05, P = 0.005).

Conclusion

This meta-analysis demonstrated that the LRP5 polymorphisms may be modestly associated with BMD of LS and FN.     

Allelotyping of Hras1Minisatellite: Formation of Carcinogenic Risk Groups and Prognosis of the Clinical Course of Non-Small Cell Lung Cancer

PCR-based typing of Hras1minisatellite alleles was carried out in 226 non-small cell lung cancer (NSCLC) patients and 207 unaffected controls. Application of this method permitted detection of four common (a1toa4) and 25 other alleles, differing from any common allele by one or more repeat units. Depending on their frequency in control group, these alleles were defined as intermediate or rare (the frequency over 0.5% or less than 0.5%, respectively). It was established that the frequency of rare alleles in the group of NSCLC patients (7.1%) was statistically significantly higher than in healthy individuals (2.2%, P= 0.002), while the difference in the distribution of common and intermediate alleles between the compared groups was not statistically significant. In addition, rareHras1alleles were more frequent (P= 0.02) among nonsmoking patients (P= 0.02) compared to the patients subjected to of tobacco carcinogens. The presence of heavy (a3–a4) alleles was associated with an increased risk of low-differentiated and/or actively metastasizing tumors and also with the risk of lung cancer in the patients under 50 years of age (P< 0.05). These data indicate that an approach including application of modern highly sensitive techniques ofHras1allele typing in combination with preliminary examination of healthy control population can be employed for identifying carcinogenic risk groups as well as for prognosis of the NSCLC clinical course.     

A resistin gene polymorphism is associated with body mass index in women

The potential association of resistin (RETN) gene variability with obesity-related phenotypes was investigated in 585 non-diabetic individuals of European descent. The polymorphism studied (–420 C>G) is located in the RETN gene 5-flanking region. A significant association between the polymorphism and body mass index and waist circumference was observed in the women subsample (n=356), where the G allele was somewhat less frequent in the overweight/obese group than in normal-weight individuals (0.25 vs. 0.32; p=0.040; OR=0.70 [0.50–0.98]). Female carriers of the G-allele presented a lower mean BMI than C/C homozygotes (25.5 vs. 26.8 kg/m²; p=0.010). Furthermore, when women were stratified by menopausal status, the association was restricted to premenopausal women (C/C homozygotes, mean BMI=26.3 kg/m²; G-carriers, 24.4 kg/m²; p=0.014). Our findings suggest that RETN gene variation has gender-specific effects on BMI and warrants further investigation of its implications for the development of obesity.     

Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial

Objective

Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI.

Methods

371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01217307","term_id":"NCT01217307"}}NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging.

Results

Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001).

Conclusion

LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.     

ACE and AGTR1 Polymorphisms in Pathogenesis of Human Left Ventricular Hypertrophy

The A2350G polymorphism of exon 17 of the angiotensin I-converting enzyme gene (ACE) and the A1166C polymorphism of the 3-untranslated region (3-UTR) of the angiotensin II type 1 receptor gene (AGTR1) were tested for association with left ventricular hypertrophy (LVH) in patients with essential hypertension (EH) or arterial hypertension (AH) combined with diabetes mellitus type 2 (DM2). The patients with EH or AH + DM2 did not differ significantly in ACE or AGTR1 allele or genotype frequencies from healthy subjects. Both polymorphisms were associated with LVH in EH. AGTR1 allele 1166C was more frequent in patients with LVH than without (33.6 vs. 20.7%) and affected the left ventricular mass index (LVMI) in patients with EH (p = 0.007). The frequency of ACE allele 2350G in EH patients with LVH was 1.5 times higher, and that of genotype GG was 3.5 times higher, than in patients without LVH. LVMI differed significantly (p = 0.002) between patients with different ACE genotypes, being maximum in homozygotes GG and minimum in homozygotes AA. Thus, AGTR1 allele 1166C and ACE allele 2350G were identified as predisposing to LVH in EH. The two polymorphisms were not associated with the incidence or severity of LVH in patients with AH and DM2.     

Unusual scarcity of restriction site polymorphism in the human thyroglobulin gene. A linkage study suggesting autosomal dominance of a defective thyroglobulin allele

Summary Chromosomal DNA prepared from 90 unrelated individuals, mainly of Caucasian origin, was screened for restriction fragment length polymorphisms in the 3 220 kilobase pairs (kb) of the human thyroglobulin (Tg) gene. The probes used were Tg cDNA fragments and subcloned single-copy genomic segments, isolated from a human cosmid library. All in all, 1164 nucleotides were screened using 15 different restriction enzymes. The average number of nucleotides screened was 354 per individual. Only one polymorphism was found in these 1164 nucleotides, with a minor allele frequency of 2.2%. This polymorphism, which is located in an intervening sequence, was found in healthy individuals and in a family with hereditary congenital hypothyroidism due to a defect in the synthesis and structure of thyroglobulin. The Mendelian segregation of polymorphism and goiter in ten family members suggests that the rare variant is linked to a normal Tg allele and provides strong evidence for autosomal dominant inheritance of this Tg synthesis defect.     

Post-stroke memory impairment among patients with vascular mild cognitive impairment

Background

The American Stroke Association/American Heart Association recommended the criteria for diagnosis of vascular cognitive impairment and memory impairment (MI) is a feature in the classification of vascular mild cognitive impairment (VaMCI). VaMCI patients with MI may differ in terms of infarct location or demographic features, so we evaluated the clinical characteristics associated with MI in patients with VaMCI.

Methods

A prospective multicenter study enrolled 353 acute ischemic stroke patients who underwent evaluation using the Korean Vascular Cognitive Impairment Harmonization Standard Neuropsychological Protocol at three months after onset. The association between MI and demographic features, stroke risk factors, and infarct location was assessed.

Results

VaMCI was diagnosed in 141 patients, and 58 (41.1%) exhibited MI. Proportions of men and of left side infarcts were higher in VaMCI with MI than those without (75.9 vs. 57.8%, P?=?0.03, 66.7 vs. 47%, P?=?0.02). Multiple logistic analyses revealed that male sex (odds ratio [OR] 3.07, 95% confidence interval [95% CI] 1.12-8.42), left-side infarcts (OR 3.14, 95% CI 1.37-7.20), and basal ganglia/internal capsule infarcts (OR 4.53, 95% CI 1.55-13.22) were associated with MI after adjusting other demographic variables, vascular risk factors, and subtypes of stroke.

Conclusions

MI is associated with sex and infarct location in VaMCI patients.