Lipid profiles and associated gene polymorphisms in young Asian Indian patients with acute myocardial infarction and the metabolic syndrome.

BACKGROUND: The objective of this study was to examine the association between serum lipid levels and the metabolic syndrome, together with polymorphisms in lipid-associated genes, in young Asian Indians with acute myocardial infarction (AMI). METHODS: The study population comprised 492 patients who were 45 years old or younger. We assessed lipid levels and the frequencies of the cholesteryl ester transfer protein (CETP) Taq-1 B, lipoprotein lipase (LPL)S447X, -93 T/G, apolipoprotein B (APO B) 96bp ins/del, lipoprotein(a) (LP[a]) pentanucleotide repeat, and apolipoprotein E (APO) E epsilon 2/3/4 polymorphisms in relation to the metabolic syndrome using both National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) definitions. RESULTS: The metabolic syndrome as defined by the NCEP ATP III criteria was found in 301 (61%) patients and in 295 (60%) patients according to the IDF criteria. Hypercholesterolemia (64.5%), hypertriglyceridaemia (78.7%), low high-density lipoprotein cholesterol (HDL-C) (70.1%), and raised non-HDL-C (68.0%) occurred significantly more frequently in patients with the metabolic syndrome defined by the NCEP ATP III criteria. Similar results were observed for the IDF definition. A significant relationship with the LPL -93 T/G polymorphism was found, with the minor G allele occurring more frequently in patients defined by the NCEP ATP III criteria (odds ratio [OR] 2.72; 95% confidence interval [CI] 1.07-8.16; P = 0.023). The X allele of the LPL S447X polymorphism was observed less frequently in metabolic syndrome patients (OR 0.52; 95% CI 0.34-0.78; P = 0.0009). Several genotypes, including the LPL S447X, APO E3/E3, and the CETP Taq1 B2B2, were associated with favorable lipid profiles. CONCLUSION: Dyslipidemia occurred with similar frequency in young Asian Indian patients with AMI and the metabolic syndrome, irrespective of the definition used. Significant associations were observed between LPL gene polymorphisms and the metabolic syndrome. Several lipid-associated genotypes exerted a favorable effect on lipid profiles.

TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies.

BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. FUNDING: German Research Foundation (DFG).

Genetic variants associated with insulin resistance and metabolic syndrome in young Asian Indians with myocardial infarction.

BACKGROUND: The objective of this study was to assess whether an association exists between the metabolic syndrome and polymorphisms in genes involved in insulin resistance in young Asian Indian patients presenting with acute myocardial infarction (AMI). METHODS: The study population comprised 467 patients who were 45 years or younger. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) definitions were used to assess the prevalence of metabolic syndrome. We examined the genotype and allele frequencies of the IRS-I G972R, PPAR-gamma P12A, KCNJ11 E23K, and TNF-alpha -308G/A polymorphisms in relation to the metabolic syndrome determined by both definitions. RESULTS: The metabolic syndrome as defined by the NCEP ATP III criteria was found in 282 (60.4%) patients, and in 278 (59.5%) patients according to the IDF criteria. This gave only a moderate level of agreement of 79% between the two definitions (Cohen's kappa = 0.554). No association was found between the IRS-I G972R, PPAR-gamma P12A, and KCNJ11 E23K, or TNF-alpha -308G/A polymorphic variants and the metabolic syndrome, or its components, for either definition. CONCLUSION: Although the metabolic syndrome is a common finding in young Asian Indian patients with AMI, there was only a moderate level of agreement between the NCEP ATP III and IDF definitions of the syndrome. Our findings do not support a role for any of the polymorphic variant alleles in the four insulin resistance-related genes examined in the etiology of insulin resistance and reinforces the notion of a multifactorial etiology for the metabolic syndrome.

The role of echocardiography and its comparison with NT-proBNP measurements in patients with acute myocardial infarction.

BACKGROUND: This study investigated the use of echocardiography in the early detection of regional wall motion abnormalities (RWMA) in patients presenting with acute myocardial infarction (AMI). The relationship between RWMA and mechanical complications, as assessed by two-dimensional echocardiography, and admission levels of amino terminal fragment of pro-brain natriuretic peptide (NT- proBNP) was also examined. MATERIAL/METHODS: The study population comprised 226 patients admitted to hospital with a diagnosis of AMI. Echocardiography and NT-proBNP measurements were performed on all patients. RESULTS: Sixty-eight percent of the patients with AMI were found to have RWMA on echocardiography. Significantly more patients had RWMA within any given range of ejection fraction (EF) (p<0.001), but this difference was most pronounced in those with left ventricular (LV) dysfunction. Mitral regurgitation was the most common complication (48%) seen on echocardiography. The majority of patients (84%) had elevated NT-proBNP levels on admission; this was evident in all categories of EF (p=0.003). In those with normal EF on echocardiography (58%), more patients had elevated levels regardless of the presence of RWMA. CONCLUSIONS: This study showed that echocardiography is useful in the detection of RWMA in the early stages of AMI. No significant relationship was demonstrated between NT-proBNP levels and RWMA in patients with normal or abnormal LV function. Admission plasma NT-proBNP may, however, be considered as an additional marker in the diagnosis of AMI, especially in those without RWMA.

The frequency of cytochrome P450 2E1 polymorphisms in Black South Africans.

Polymorphisms in the promoter region of the Cytochrome P4502E1 (CYP2E1) gene reportedly modify the metabolic activity of CYP2E1 enzyme, and have been associated with increased susceptibility to squamous cell carcinoma (SCC) of the oesophagus in high prevalence areas such as China. To assess the frequency of these polymorphisms in Black South Africans, a population with a high incidence of oesophageal SCC, this study examined genomic DNA from 331 subjects for restriction fragment length polymorphisms in the CYP2E1 (RsaI and PstI digestion). The frequency of the CYP2E1 c1/c1 and c1/c3 genotypes was 95% and 5% respectively. The frequency of the CYP2E1 allele distribution was found to be markedly different between Chinese and South African populations; hence it is important to place racial differences into consideration when proposing allelic variants as genetic markers for cancer.

Methylenetetrahydrofolate reductase gene polymorphisms in black South Africans and the association with preeclampsia.

BACKGROUND: A methylenetetrahydrofolate reductase (MTHFR) polymorphism (1317T --> C) that occurs commonly in black African individuals prompted this study to establish whether this polymorphism, alone or in association with other MTHFR variants, is associated with preeclampsia in black South African women. METHODS: A group of 204 black women with preeclampsia was examined for the 677C --> T, 1298A --> C and 1317T --> C MTHFR polymorphic alleles using standard techniques. Also examined were women with early-onset preeclampsia (n = 67) and gestational hypertension (n = 78). Results were compared with 338 ethnically matched normotensive pregnant women who had normal full-term gestations. RESULTS: No differences in the 677T --> C or 1298A --> C MTHFR alleles were found between the study groups and controls; very few women were homozygous for either variant allele. Significant differences were observed for the 1317T --> C polymorphism: only 39% of preeclamptics were homozygous for the T allele compared with 52% of the control group [p = 0.002; 0.59 (0.42-0.83)]. Heterozygotes occurred significantly more frequently in preeclamptics (51%), compared with controls (41%) [p = 0.019; 1.49 (1.07-2.08)]. Allele frequencies also differed significantly between preeclamptics and controls [p = 0.003; 0.69 (0.53-0.88)]. Allele frequencies in women with gestational hypertension were statistically indistinguishable from those in controls. CONCLUSION: The low frequencies of the 677C --> T and 1298A --> C MTHFR variant alleles in black South Africans imply little or no role for these mutations in preeclampsia in this population group. However, significant differences in the 1317T --> C allele in preeclamptics suggest that the MTHFR gene, or a closely associated gene, may still have some role, as yet undefined, in the pathogenesis of preeclampsia.

Hypertension-related gene polymorphisms in pre-eclampsia, eclampsia and gestational hypertension in Black South African women.

OBJECTIVE: To examine whether polymorphisms in the renin-angiotensin system (RAS) are associated with pregnancy-related hypertensive disorders in a black South African population. DESIGN: The angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen M235T and angiotensin II receptor type 1 1166A<--C polymorphisms were assessed in study groups comprising 204 women with pre-eclampsia, 120 with eclampsia, 67 with early onset pre-eclampsia and 78 with gestational hypertension. METHODS: Using chi analysis, results were compared with those obtained from 338 ethnically matched normotensive pregnant women following normal full term pregnancies. No significant differences in the distribution of any of these polymorphisms were found between patients with pre-eclampsia or eclampsia and the normal control subjects. Patients with gestational hypertension were less frequently homozygous for the ACE insertion polymorphism compared with controls (5 versus 13%, respectively; P = 0.049; odds ratio 0.36 [95% confidence interval (CI) 0.09-1.04]). CONCLUSION: The commonly occurring RAS polymorphisms are not predictive of pre-eclampsia or eclampsia in the Black South African population.

Haemostatic gene polymorphisms in young indian asian subjects with acute myocardial infarction.

BACKGROUND: The relationship between haemostatic gene polymorphisms and arterial disease remains unclear. Much of the evidence gathered so far has been obtained from small heterogeneous studies, resulting in inconsistencies. This study focuses on the South African Indian population which not only represents the largest Indian population outside the Indian subcontinent, but also constitutes a genetically discrete group in whom a high incidence of coronary heart disease occurs. MATERIAL/METHODS: We investigated the relationship between polymorphisms in the Factor V (Leiden), prothrombin (20210 GgA) and thrombomodulin (Ala455Val) genes in patients with a myocardial infarction (MI) <45 years of age (n=195) and in unaffected siblings (n=107) and unrelated healthy race-matched individuals drawn from the same community (n=300). RESULTS: The Factor V Leiden mutation was found to occur with a frequency of less than 1%, while the prothrombin 20210 GgA polymorphism was not observed in any of the individuals in this study. In contrast, the variant thrombomodulin Val allele occurred with a frequency similar to that reported in Caucasians. The frequency of this allele in both patients with MI and their siblings was marginally higher than in healthy controls, but the difference did not reach statistical significance. However, in patients who smoked, the thrombomodulin variant allele occurred significantly more frequently than in the non-smoking group (p=0.044). CONCLUSIONS: The Leiden Factor V and prothrombin 20210 GgA polymorphisms have no value in disease association studies in the Indian Asian population. In smokers, the thrombomodulin Ala455Val variant allele emerges as a significant risk factor for coronary heart disease.

Plasminogen activator inhibitor type 1 (PAI1) and platelet glycoprotein IIIa (PGIIIa) polymorphisms in Black South Africans with pre-eclampsia.

BACKGROUND: Association of fibrin abnormalities with pre-eclampsia prompted this study to examine whether polymorphisms in the plasminogen activator inhibitor Type 1 and platelet glycoprotein IIIa genes constitute risk factors for this condition. METHODS: A group of 151 Black Zulu-speaking pre-eclamptics was examined for 4G/5G plasminogen activator inhibitor Type 1 and PlA1/A2 platelet glycoprotein IIIa polymorphic alleles using standard techniques. Results were compared with those found in 217 ethnically matched healthy normotensive pregnant women who had normal full-term gestations. RESULTS: Pre-eclamptic patients had a slightly higher frequency of the 4G plasminogen activator inhibitor Type 1 allele (15%) compared with the controls (12%); this was reflected also in the heterozygote frequency (28% and 22%) for the patients and the controls, respectively. These differences were not significant. Only 2% of this population was found to be homozygous for the 4G allele. No differences were observed in the platelet glycoprotein IIIa polymorphism genotype and allele frequency distribution between the patients and the controls. CONCLUSIONS: Neither the 4G allele of the plasminogen activator inhibitor Type 1 nor the PlA2 allele of the platelet glycoprotein IIIa have any significant role as risk factors in the patho-etiology of pre-eclampsia in Black South Africans, although these genes cannot yet be excluded as contributory to this disorder. It is possible that the underlying causes of pre-eclampsia may vary between different ethnic populations.