HindIII Genotype Research Articles

Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

Complement blockade by eculizumab is clinically effective in hemolytic paroxysmal nocturnal hemoglobinuria. However, the response is variable and some patients remain dependent on red blood cell transfusions. In 72 patients with hemolytic paroxysmal nocturnal hemoglobinuria on eculizumab we tested the hypothesis that response may depend on genetic polymorphisms of complement-related genes. We found no correlation between the complement component C3 genotypes and the need for blood transfusions. On the other hand, we found a significant correlation with the HindIII polymorphism of a complement regulatory gene, the complement receptor 1 (CR1) gene. At this locus two co-dominant alleles are known, of which H (common) is associated with high expression, whereas L (rare) is associated with low expression of CR1 on red blood cells. Patients who still needed blood transfusion on eculizumab accounted for 18% of the H/H homozygotes, 33% of the H/L heterozygotes and 68% of the L/L homozygotes (P=0.016). Thus, patients with paroxysmal nocturnal hemoglobinuria who have the L/L genotype are seven times more likely to be sub-optimal responders to eculizumab. Both in vitro and in vivo we found that the CR1 HindIII genotype correlates with the abundance of paroxysmal nocturnal hemoglobinuria red cells that have bound C3, and with the kinetics of C3 binding. These results are consistent with the notion that by affecting C3 binding the CR1 genotype influences the response to eculizumab treatment, and this emerges as a novel example of pharmacogenetics.

The gene–diet interaction, LPL PvuII and HindIII and carbohydrate, on the criteria of metabolic syndrome: KMSRI-Seoul Study

ObjectiveThe objective of this study was to investigate the effects of the interaction between lipoprotein lipase (LPL) PvuII and HindIII haplotypes and carbohydrate intakes on the components of metabolic syndrome (MetSyn) in Koreans. MethodsLPL PvuII and HindIII genotype, LPL mass, triglyceride, high-density lipoprotein cholesterol, blood pressure (BP), waist circumference (WC), insulin, and Homeostasis Model of Assessment - Insulin Resistance were determined using a cross-sectional design in 269 controls and 280 MetSyn patients. ResultsLPL mass was significantly lower in patients with PvuII and HindIII mutant alleles (P2 and H2) and decreased as the number of MetSyn components increased in all PvuII and HindIII haplotypes. Both LPL mass-adjusted WC and systolic BP (SBP) were positively associated with a ratio of percent energy from carbohydrate to percent energy from fat in individuals with P2H2 haplotype. After adjustment for age, sex, and LPL mass, the odds ratio (OR) for excessive WC was higher in carriers of P2H2 in the highest carbohydrate intake tertile compared with carriers of P1H1 in the lowest carbohydrate intake tertile (OR, 6.94; 95% confidence interval [CI], 1.39–34.62). Moreover, the OR for high SBP were higher in carriers of P1H2/P2H1 in the highest carbohydrate intake tertile (OR, 7.84; 95% CI, 1.79–34.46) and in carriers of P2H2 in the highest carbohydrate intake tertile (OR, 4.24; 95% CI, 1.16–15.48) than P1H1 carriers. ConclusionThis study suggests that P2H2 carriers in the highest carbohydrate intake tertile may be at risk for MetSyn because they had increased odds of excessive WC and high SBP.

Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke

Statins reduce the risk of cardiovascular events by lowering the blood cholesterol. Many genes involved in the pharmacodynamic pathway of statins have been part of pharmacogenetic research in patients with hypercholesterolemia, with an emphasis on genes involved in the cholesterol pathway. The present study was carried out with an aim to evaluate the association between the genetic variants of lipoprotein lipase gene [HindIII (+/+)/HindIII (-/-)], multiple drug resistance gene (C3435T) and endothelial nitric oxide synthase gene (4a/4b) with clinical outcome including an increased risk of recurrent stroke or death in ischemic stroke patients on atorvastatin therapy. 525 stroke patients and 500 healthy controls were involved in the study. Follow-up telephone interviews were conducted with patients post-event to determine stroke outcome. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. A significant association of MDR1 and LPL gene variants with bad outcome in stroke patients on atorvastatin therapy was found. However, there was no significant association of 27bp VNTR polymorphism of eNOS gene with outcome. MDR analysis was carried out to analyze gene-gene interaction involving these gene variants contributing to clinical outcome of patients on stratin therapy but no significant interaction between these variants was observed. In conclusion the individuals with HindIII (-/-) genotype of LPL and CC genotype of MDR1 gene would benefit more from atorvastatin therapy.

Six lipoprotein lipase gene polymorphisms, lipid profile and coronary stenosis in a Tunisian population

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoprotein particles (Chylomicrons and very-low-density lipoprotein). LPL polymorphisms' effects on lipids and coronary artery disease are controversial among studies and populations. Our aim was to study the association between six polymorphisms, haplotypes and significant coronary stenosis (SCS), disease severity and lipid parameters in Tunisian patients. LPL PvuII, 93 T/G, 188 G/E, HindIII, N291S and D9N polymorphisms were analyzed in 316 patients who underwent coronary angiography. Assessment of coronary angiograms identified SCS as the presence of stenosis >50 % in at least one major coronary artery. The stenosis severity was determined by using Gensini score and vessels number. A significant association of SCS with TT of the HindIII polymorphism was showed (odds ratio (OR): 2.84, 95 % CI, 1.19-7.40, p = 0.017) and TG (OR: 1.77, 95 % CI, 1.99-2.82, p = 0.033). The mutated HindIII genotype was significantly associated with increased TG and ApoB/ApoA-I ratio and with decreased HDL-C. Haplotype analysis showed that OR of SCS associated with the CTGTAG haplotype was 2.12 (95 % CI 1.05-4.25, p = 0.032) and with CGGGAA was 0.71 (95 % CI 0.26-1.95, p = 0.022) compared to the CTGTAA. Significant difference in Gensini score was observed among HindIII genotype and haplotypes. A significant association between the mutated genotype of HindIII polymorphism and decreased HDL-C level and increased ApoB/ApoA-I ratio and TG level was showed. Our results suggest that HindIII and D9N polymorphisms and CTGTAG haplotype seem to be considered as marker of predisposition to coronary stenosis. In another hand, HindIII and haplotypes were related to stenosis severity.

DNA Polymorphisms of the Lipoprotein Lipase Gene and Their Association with Coronary Artery Disease in the Saudi Population

Coronary heart disease (CHD) is a major health problem and a major cause of death in most countries. Evidence has been presented that gene polymorphisms (HindIII, PvuII and Ser447Ter) of lipoprotein lipase (LPL) are risk factors of coronary artery disease (CAD).AimOur objective of the present investigation was to determine whether 3 LPL polymorphisms (LPL-HindIII, LPL-PvuII and LPL-Ser447Ter) can be considered as independent risk factors for CAD in the Saudi population.MethodsWe recruited 120 CAD subjects, confirmed angiographically with identical ethnic backgrounds and 65 control subjects. Polymerase chain reaction-restriction fragment length polymorphisms (RFLP) technique was used to detect the polymorphisms of the LPL gene.Results and conclusionFor the HindIII genotype, within the CAD group, the frequencies of the H+H+ were found in 50.8%, whereas 44.2% carried the H−H+ genotype, and 5% carried the H−H− genotype. Within the control group, the H+H+ genotype was found in 44.6%, whereas 35.4% carried the H−H+ genotype, 20% carried the H−H− genotype. The odds ratio (OR) of HindIII genotype H+H+ vs. H−H− genotype at 95% Confidence Interval (CI) were 4.6 (1.57–13.2) and p < 0.005, hence showing no significant association with CAD. For the PvuII genotype, within the CAD group the frequencies of the P+P+ found in 41.7% whereas 43.3.2% carried the P−P+ genotype, and 15% carried the P−P− genotype. Within the control group the P+P+ was found in 38.5%, 43.0% carried the P−P+ genotype, and 18.5% carried the P−P− genotype. The OR of PvuII genotype P+P+ vs. P−P− genotypes (95% CI) is 1.33 and p = 0.52; hence, it was also insignificant to show association with the disease. For the Ser447Ter genotype, within the CAD group, the frequencies of the C/C found in 83.3%, whereas 16.7% carried the C/G genotype. Within the control group, the C/C was found in 87.7% and 12.3% carried the C/G genotype. We did not get any GG genotypes in control as well as patients for this gene. It can be concluded that C allele of gene masks the presence of G allele in the Saudi population. The OR of CG + GG vs. CC (95% CI) is 1.43 from 0.59 to 3.44 which is insignificant. Hence this gene also has no significant association with CAD in the Saudi population.

Association of LPL gene variant and LDL, HDL, VLDL cholesterol and triglyceride levels with ischemic stroke and its subtypes

Lipoprotein lipase (LPL) plays an important role in lipid metabolism by hydrolyzing triglycerides in chylomicrons and very low density lipoproteins. An increasing number of studies have suggested an association of LPL gene variants with the risk of cardiovascular and cerebrovascular diseases. The aim of this study was to test whether HindIII polymorphism of LPL gene is associated with ischemic stroke and its subtypes as well as plasma lipid levels in a South Indian population from Andhra Pradesh. Five hundred and twenty five ischemic stroke patients and 500 controls were enrolled in this case–control study. The LPL HindIII polymorphism was determined by PCR-RFLP technique and the lipid levels were estimated using commercially available kits. We found significant difference in the genotypic distribution between patients and controls [for HindIII (+/+) vs. HindIII (−/−), χ2=4.916; p=0.02; Odds ratio=1.59 (95%CI; 1.054–2.413); HindIII (+/+) vs. HindIII (−/−) and HindIII (+/−), χ2=5.25; p=0.02; Odds ratio=1.24 (95%CI; 1.03–1.503)]. A stepwise multiple logistic regression analysis confirmedthese findings. The relationship between HindIII genotypes and plasma levels of HDL, LDL, VLDL and triglycerides was analyzed using ANOVA and further confirmed by Post-hoc analysis. The levels of triglycerides were found to be elevated in individuals bearing HindIII (+/+) genotype in comparison with HindIII (−/−) genotype. HDL levels were found to be significantly reduced and triglyceride levels significantly elevated in HindIII (+/+) genotype in comparison with HindIII (−/−). However, there was no difference in the levels of LDL and VLDL between the two genotypes. Examining the association of LPL gene HindIII polymorphism with stroke subtypes, we found significant association of HindIII polymorphism with Intracranial large artery atherosclerosis [Odds ratio=2.12 955CI (1.656–2.848); p=0.009]. Our results suggest that the HindIII polymorphism of LPL is significantly associated with ischemic stroke risk and elevated levels of plasma triglycerides and reduced HDL levels. Further, this polymorphism is significantly associated with intracranial large artery atherosclerosis which is the most frequent subtype in our region.

Association analysis of genetic polymorphisms and potential interaction of the osteocalcin (BGP) and ER-α genes with body mass index (BMI) in premenopausal Chinese women

To investigate whether estrogen receptor alpha (ER-alpha) PvuII and osteocalcin (also known as bone Gla protein, or BGP) HindIII genetic polymorphisms and their potential interactions are associated with body mass index (BMI) variation. Data on BMI and ER-alpha PvuII and BGP HindIII genotypes were obtained from 328 healthy premenopausal Chinese women in east China. The study subjects were unrelated, at least 21 years old (mean age of 33.2+/-5.9 years), and had an average BMI of 21.58+/-2.59. All subjects were genotyped at the ER-alpha PvuII and BGP HindIII loci using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The BGP HindIII genotypes were significantly associated with BMI (P=0.003). Carriers of the HH and Hh genotypes had approximately 2.73% and 1.27% higher BMI than those of the hh genotype, respectively. In contrast, the ER-alpha PvuII polymorphism was not significantly associated with BMI (P=0.454). In addition, there was no evidence of potential interactions between the ER-alpha and BGP genes in our subjects (P>or=0.013). The HindIII polymorphism of the BGP gene, but not the PvuII polymorphism of the ER-alpha gene or their potential interaction, was associated with BMI in premenopausal Chinese women.

The association between osteocalcin gene polymorphism and dental fluorosis among children exposed to fluoride in People's Republic of China

Excessive fluoride intake has been shown to affect dentin and cementum mineralization throughout life. Some studies indicated that a HindIII polymorphism, of osteocalcin (OC) gene, was associated with bone metabolism-related diseases. Therefore, it is possible that the variation in OC genotypes will be associated with dental fluorosis (DF) status and/or serum caciotropic hormone level. A case-control study was conducted among children aged 8–12 years in Henan Province, PR China to investigate the association between dental fluorosis, serum calciotropic hormone level, and polymorphisms in the OC gene. HindIII polymorphism in OC gene was genotyped using the PCR-RFLP procedure. OC and calcitonin (CT) level in serum was detected using radioimmunoassay. No significant difference was observed for OC HindIII genotypes among the cases with dental fluorosis, the controls from endemic fluorosis area (EFA) and the controls from non-endemic fluorosis area (NEFA). A significant negative correlation was observed between serum calcium and OC level. No significant relationship was found between OC HindIII polymorphisms and the level of OC and CT. In conclusion, OC HindIII polymorphisms may not be a useful genetic marker for differential risk of dental fluorosis among children in PR China.

Lipoprotein lipase HindIII polymorphism influences HDL-cholesterol levels in statin-treated patients with coronary artery disease

HDL-cholesterol (HDL-C) is a recognized athero-protective factor and low levels of HDL-C occur frequently in patients with coronary artery disease. Regulation of HDL-C level most probably results from the interaction of genes involved in lipoprotein metabolism and also from non-genetic factors. We studied associations and interactions among HindIII polymorphisms of the lipoprotein lipase gene LPL and selected non-genetic factors with respect to HDL-C levels in patients with coronary artery disease. 288 Slovak patients (35% women) with documented coronary artery disease, age (mean +/- SEM) 60 +/- 1 years and BMI 29 +/- 0.3 kg/m(2), were examined and genotyped for LPL HindIII (rs320) using a PCR/RFLP method. HDL-C levels were determined in a direct enzymatic assay. In the sample overall there were no significant differences across the LPL genotypes in adjusted HDL-C levels or in other lipids, although a trend toward higher HDL-C and lower triglycerides in H-H- homozygotes was observed. Multiple linear regression identified a significant interaction between LPL HindIII and statin treatment, which together with sex and diabetes explained 12.1% of HDL-C variance. Accordingly, in statin-treated patients we observed significant stepwise increments of the HDL-C level related to the increasing number of H- alleles (P = 0.04 for linear trend), whereas no such association was observed in patients without hypolipidemic treatment. H-H- homozygotes had a 16% (0.19 mmol/l) higher level of HDL-C than the H+H+ homozygotes (P = 0.06). HDL-C may be influenced by an interaction between statin treatment and LPL HindIII genotype. However, the effect of this interaction appears to be small when compared with the effect of non-genetic factors. This finding requires replication in a pharmacogenetic study.

Genotypic variation and presence of rare genotypes among Douglas-fir tussock moth multicapsid nucleopolyhedrovirus ( OpMNPV) isolates in British Columbia

The Douglas-fir tussock moth ( Orgyia pseudotsugata) multicapsid nucleopolyhedrovirus ( OpMNPV) is periodically applied to suppress Douglas-fir tussock moth populations in British Columbia and in the western United States. The strain of OpMNPV in the product currently used for suppression is not genetically distinct from naturally occurring OpMNPV. To separate the mortality caused by the applied virus from that caused by the naturally occurring virus, a rare and genetically distinct strain of OpMNPV must be applied. To learn more about the genotypic diversity of OpMNPV populations in BC and to identify rare strains in this region, viral DNA was extracted from larvae reared from 208 field-collected egg masses found in five geographic regions of British Columbia and subjected to REN analysis. Nine, 12, and 9 different genotypes were detected using PstI, SalI, and HindIII, respectively. When the PstI, SalI, and HindIII profiles for each pure (single strain) isolate were grouped and considered as a combined PstI– SalI– HindIII genotype, 23 different genotypes were identified among 185 isolates. Nine rare OpMNPV genotypes were selected as ideal candidates for use as a potential ‘marker strain’ to accurately determine the efficacy of the treatment.

Lipoprotein lipase locus and progression of atherosclerosis in coronary-artery bypass grafts

Purpose: Our aim was to test whether polymorphisms in the lipoprotein lipase (LPL) gene were associated with the progression of atherosclerosis in grafts examined in the Post-Coronary Artery Bypass Graft Trial (Post-CABG Trial).Methods: 843 subjects in the post-CABG trial were genotyped for the LPL-D9N, N291S, PvuII, (TTTA)n, and HindIII polymorphisms. Associations between genotype and angiographically measured progression of atherosclerosis in grafts, medical history, and family history were examined.Results: Greater progression of atherosclerosis was observed in subjects with LPL-HindIII 2/2 (56% versus 42% of those with other LPL HindIII genotypes, P = 0.025) and with LPL (TTTA)n 4/4 (63% versus 43% of those with other (TTTA)n genotypes, P = 0.020). Mantel-Haenszel analysis yielded an odds ratio of 1.84 for the effect of LPL HindIII 2/2 genotype on the progression of atherosclerosis in grafts (P = 0.015) and demonstrated that the effect of genotype on progression was of the same magnitude as, but independent of, the effect of drug treatment.Conclusion: The LPL-HindIII 2/2 genotype is a marker for genetic variation in the 3′-end of LPL that acts as an independent risk factor for the progression of atherosclerosis in grafts examined in the Post-CABG Trial.

Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population.

Previous studies reported an association of certain polymorphisms in the lipoprotein lipase (LPL) gene with the risk of coronary artery disease (CAD); however, these studies were small and inconsistent. In addition, none of these studies attempted to establish such an association in the Arab population. To determine whether 2 LPL polymorphisms (LPL-HindIII and LPL-PvuII located on introns 8 and 6, respectively, of the LPL gene) can be considered as independent risk factors or as predictors for CAD in Arabs. We used polymerase chain reaction and restriction enzyme digestion to determine the distribution of the LPL-HindIII and LPL-PvuII polymorphisms among healthy blood donors of Arabic origin (BD group) and angiographically confirmed CAD patients (CAD group) with identical ethnic backgrounds. For the HindIII genotypes, within the BD group (n = 410), the +/+ genotype was found in 206 individuals (50.2%), 173 (42.2%) carried the +/- genotype, and 31 (7.6%) carried the -/- genotype. Within the CAD group (n = 352), the +/+ genotype was found in 189 individuals (53.7%), 138 (39.2%) carried the +/- genotype, and 25 (7.1%) carried the -/- genotype. P values of.38,.45, and.92 were obtained for the +/+, +/-, and -/- genotypes, respectively. For the PvuII genotypes, within the BD group (n = 511), the +/+ genotype was found in 182 individuals (35.6%), 248 (48.5%) carried the +/- genotype, and 81 (15.9%) carried the -/- genotype. Within the CAD group (n = 431), the +/+ genotype was found in 138 individuals (32%), 225 (52.2%) carried the +/- genotype, and 68 (15.8%) carried the -/- genotype. P values of.28,.29, and.98 were obtained for the +/+, +/-, and -/- genotypes, respectively. The distribution and the allele frequency of these 2 LPL variants were similar in CAD and BD study groups and followed the Hardy-Weinberg equilibrium. There was no difference in the distribution of both LPL polymorphisms between the healthy group and the CAD group. Therefore, these 2 LPL polymorphisms cannot be considered as independent risk factors or as predictors for CAD in this population.

Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population.

Abstract Context.—Previous studies reported an association of certain polymorphisms in the lipoprotein lipase (LPL) gene with the risk of coronary artery disease (CAD); however, these studies were small and inconsistent. In addition, none of these studies attempted to establish such an association in the Arab population. Objective.—To determine whether 2 LPL polymorphisms (LPL-HindIII and LPL-PvuII located on introns 8 and 6, respectively, of the LPL gene) can be considered as independent risk factors or as predictors for CAD in Arabs. Design.—We used polymerase chain reaction and restriction enzyme digestion to determine the distribution of the LPL-HindIII and LPL-PvuII polymorphisms among healthy blood donors of Arabic origin (BD group) and angiographically confirmed CAD patients (CAD group) with identical ethnic backgrounds. Results.—For the HindIII genotypes, within the BD group (n = 410), the +/+ genotype was found in 206 individuals (50.2%), 173 (42.2%) carried the +/− genotype, and 31 (7.6%) carrie...

Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men.

Physical activity has been identified as a protective factor against the occurrence and progression of coronary heart disease. The lipoprotein lipase (LPL) HindIII polymorphism has been associated with changes in triglyceride and high density lipoprotein (HDL)-cholesterol levels. We have investigated whether the association between the LPL HindIII genetic polymorphism and lipid levels is modified by physical activity. We have also tested the hypothesis that physical activity may interact with smoking and the LPL HindIII polymorphism to determine an individual's plasma lipid concentrations. A total of 520 men were selected from a representative sample used in a population study conducted in Gerona, Spain. The median value (291 kcal/day) of energy expenditure in leisure-time physical activity of the studied sample was selected as a cut-off to define sedentary or active subjects. Serum HDL-cholesterol was positively and significantly associated with the amount of daily energy expenditure in physical activity, whereas inverse associations were seen between physical activity and triglyceride concentration and with the triglyceride to HDL-cholesterol ratio. These effects were consistent across LPL HindIII genotypes. There was a statistically significant interaction between LPL genotype and smoking on lipid concentrations. No statistically significant differences were observed in lipid levels of active or sedentary non-smokers between H- carriers and H+H+ homozygotes for the LPL HindIII polymorphism. In smokers, sedentary H+H+ homozygotes showed significantly higher triglyceride and lower HDL-cholesterol concentrations than sedentary H- carriers. These differences were smaller and not statistically significant when lipid values of active H+H+ homozygotes were compared with active H- carriers. Among all subgroups, sedentary smokers with the H+H+ genotype had the most adverse lipid profile, which was considerably less adverse in H+H+ smokers who were physically active. These findings suggest that the presence of the H+H+ genotype has a deleterious effect on lipid profile in an adverse environment such as smoking, and that the expenditure of more than 291 kcal/day in physical activity attenuates this effect.

Osteocalcin gene polymorphism is related to bone density in healthy adolescent females.

Recently a polymorphism was found in the human osteocalcin gene, and its association with bone mass was investigated in healthy postmenopausal Japanese women. The osteocalcin gene allelic variant HH was found to be overrepresented in women with osteopenia. The purpose of this study was to investigate whether the previously demonstrated polymorphism of the osteocalcin gene was related to bone mineral density (BMD; g/cm2) or osteopenia in a group of 97 healthy Caucasian adolescent females (aged 16.9 +/- 1.2 years, mean +/- SD). BMD of the left humerus, right femoral neck, lumbar spine and total body was measured using dual-energy X-ray absorptiometry. The relation between the allelic variants and bone density was analyzed as presence or absence of the H allele. Presence of the H allele was found to be related to a lower BMD of the humerus (0.97 vs 1.02, p = 0.03). There was also a strong tendency towards significance at the femoral neck (p = 0.06) and total body (p = 0.11). Using a multiple linear regression and including physical activity, weight, height and years since menarche, presence of the H allele was found to be an independent predictor of humerus BMD (beta = -0.21, p < 0.05) and femoral neck BMD (beta = -0.23, p < 0.01). Using logistic regression, presence of the H allele was also independently associated with a 4.5 times increased risk of osteopenia (p = 0.03) in the whole group. Osteopenia was defined as at least 1 SD lower bone density than the mean for the whole group of at least one of the BMD sites measured. We have demonstrated that the osteocalcin HindIII genotype is independently related to bone density in healthy adolescent females. The present study also suggests that presence of the H allele is predictive of osteopenia at an early age.

Relationship of abdominal adiposity and dyslipemic status in women with a common mutation in the lipoprotein lipase gene

Abdominal obesity constitutes an important risk factor for cardiovascular disease. Hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterol concentration constitute the major lipid alterations observed in obesity. A common variant of the lipoprotein lipase (LPL) gene, the HindIII polymorphism, has been found to be associated with changes in triglyceride and HDL-cholesterol levels. We have investigated the impact of the LPL HindIII polymorphism on the relationship between abdominal adiposity and lipoprotein concentrations in 156 randomly selected women in a cross-sectional study conducted in the province of Gerona, in the northeast of Spain. The waist-to-hip ratio was used as an estimate of regional fat distribution. Serum lipid and lipoprotein measurements as well as lipoprotein lipase- HindIII genotypes were determined. Percentile 50 of waist-to-hip ratio (WHR) (0.81) was used as a cutoff to define low or high WHR groups, which significantly differed in blood pressure and lipid trait concentrations. Serum triglyceride concentrations and mean log triglyceride-to-HDL-cholesterol ratio were significantly higher in H+ homozygous women compared with H− carriers. Whereas no statistically–significant differences were observed in HDL-cholesterol concentration and log triglyceride-to-HDL-cholesterol ratio of H− carriers between WHR groups, H+ homozygous women showed significant differences in these lipid traits. It is noteworthy that high-WHR H− carrier women showed a mean HDL-cholesterol value similar to those of both genotypes in the low WHR group. A statistically significant interaction between WHR and genotype was observed for HDL-cholesterol concentration ( P=0.027) and log triglyceride-to-HDL-cholesterol ratio ( P=0.040). These results stress the compensating effects that weight loss may have on women with adverse genetic factors. From a complementary viewpoint, the presence of the H− allele seems to confer a protective lipid profile, even when an adverse anthropometric factor such as abdominal adiposity is present.

Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.

Antinuclear autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Autoantibodies to HRES-1/p28, a 28 000 M(r) nuclear protein, commonly occur in patients with SLE. HRES-1 is a single-copy endogenous retroviral element mapped to human Chromosome 1 at q42. A polymorphic Hin dIII site defines two different allelic forms of the genomic locus. The HRES-1/1 probe [5.5 kilobases (kb)] anneals to three polymorphic fragments and three genotypes can be differentiated: I, 5.5 kb fragment only; II, 3.7 kb and 1.8 kb fragments only; and III, all three polymorphic fragments. By cloning of the HRES-1 locus from homozygous type I and type II human DNA samples, the polymorphic Hin dIII site was identified as a G to C transition at position 653 of the long terminal repeat region. Family studies showed that Hin dIII genotypes of the HRES-1 locus are inherited in a Mendelian pattern. The relative frequency of genotype I with respect to genotype III was 3.1-fold lower in patients with SLE (14:40=0.35) in comparison to 100 ethnically matched control donors (47:43=1.09; P=0.0084). Frequency of genotype I vs genotype II alleles was lower in SLE (68/52) than in normal donors (137/63; P=0.033), suggesting that a genotype I allele of the HRES-1 locus may be protective against SLE. Western blot seroreactivity with recombinant HRES-1/p28 was noted in 4/14 (29%) of genotype I patients and 13/19 (68%) of genotype III patients (P<0.025). These data raise the possibility that the HRES-1 element or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE.

The Lipoprotein Lipase HindIII Polymorphism: Association with Total Cholesterol and LDL-Cholesterol, but not with HDL and Triglycerides in 342 Females

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of core triglycerides in chylomicrons and VLDL. We investigated the association between the HindIII polymorphism of the LPL gene and fasting glucose, lipid, and lipoprotein concentrations in 683 Caucasians. We first stabilized the study subjects, using an 8-day diet and exercise intervention program before obtaining blood samples. The use of this standardization period reduced the variance of all glucose and lipid concentrations. In our study, the HindIII allele frequencies for females and males were 0.29 and 0.34 for H- and 0.71 and 0.66 for H+, respectively. We found in females, but not in males, a significant association between the HindIII genotype and total cholesterol (P = 0.007) and LDL-cholesterol (P = 0.018), with females homozygous for the rare H- allele having the lowest, heterozygotes (H-/+) having intermediate, and women homozygous for the common H+ allele having the highest of each of these lipid traits. With regard to triglycerides, HDL-cholesterol, and glucose, no significant effect of the HindIII genotype was noted in either gender. These results suggest that in a gender-specific manner, the rare LPL HindIII H- allele has a cholesterol-lowering and, therefore, potentially cardioprotective effect compared with the common H+ allele.

A novel polymorphism in the promoter region for the human osteocalcin gene: the possibility of a correlation with bone mineral density in postmenopausal Japanese women.

We present a polymorphism of the human osteocalcin gene (also known as BGP, for bone Gla protein) due to a 1 base pair (bp) substitution from cytosine to thymine at position 298 nucleotides (nt), which is at position 198 nt upstream from the BGP exon 1. This mutation was detected by single-strand conformation polymorphism analysis after polymerase chain reaction for the osteocalcin gene fragment (326 bp) and sequencing analysis. The cytosine/thymine polymorphism can be defined by restriction fragment length polymorphism analysis using a modified primer pair and the restriction endonuclease HindIII. The osteocalcin genotype was determined in 160 postmenopausal Japanese women (age 48-80 years). Osteocalcin alleles were designated according to the absence (H) or presence (h) of the HindIII restriction site. There were 12 HH, 49 Hh, and 99 hh individuals, and the allele frequencies were 22.8% for H and 77.2% for h. To determine if genetic variation influences bone mineral density (BMD) and thus can be a determinant of susceptibility to osteoporosis in older women, we examined the association of BMD with the osteocalcin genotypes found in the present study. The subjects with genotype HH had the smallest BMD and those with hh had the greatest BMD among subjects, but these differences did not reach statistical significance. The HindIII genotype showed a significant effect on the prevalence of osteopenia in the subjects, that is, women with genotype HH had a 5.74 times greater risk for osteopenia (p < 0.05) and those with genotype Hh had a 1.59 times greater risk than women with genotype hh. We identified the osteocalcin gene polymorphism, detected with the HindIII genotype, which was suggested to influence bone density and is a possible genetic marker for bone metabolism.

Physical Activity, Fibrinogen Plasma Level and Gene Polymorphisms in Postmenopausal Women

The relations between habitual physical activity (PA), fibrinogen gene polymorphisms and plasma fibrinogen were investigated in 191 postmenopausal women. Subjects who reported PA at least 4 times/week had lower fibrinogen level (3.19 g/l; 95% CI 3.10; 3.27) than women reporting PA 2-3 times/week (3.43 g/l; 3.29; 3.58) or sedentary subjects (3.64 g/l; 3.33; 3.94). There were no differences in plasma fibrinogen across the alpha-fibrinogen (RsaI, TaqI) or beta-fibrinogen (MnlI, BclI, HindIII) genotypes, the frequencies of which were in a Hardy-Weinberg equilibrium. An interaction between RsaI, which was in complete linkage disequilibrium with TaqI, and PA on plasma fibrinogen was observed, even after adjustments for BMI, smoking and medication (p = 0.024). Among women homozygous for the common RsaI allele, the physically most active had lower fibrinogen level (p <0.001) compared to the physically less active subjects. These results suggest that, in postmenopausal women, the relation between physical activity and plasma fibrinogen is modulated by genetic variation in the alpha-fibrinogen gene.