PON1Q192R polymorphism is associated with lipid profile in Mexican men with Mayan ascendancy

Paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) that prevents low-density lipoprotein (LDL) oxidation. PON1Q192R polymorphism is associated with a risk of coronary heart disease and low HDL levels in case-control studies, but the issue is yet unresolved. Mexico has shown an increase in cardiovascular diseases, and some genetic factors may play a role. Our purpose was to evaluate the association between PON1Q192R and L55M polymorphisms and serum lipid profile in a healthy Mexican population. Ninety unrelated male inhabitants from southeastern Mexico with Mayan ascendancy agreed to participate. Demographic characteristics, lifestyle and medical history were obtained by questionnaire. Lipid profile was determined by enzymatic methods, PON1 activity by using paraoxon and phenylacetate and PON1 genotype by real-time PCR. HDL-cholesterol (HDL-C) levels were associated with genotype: 192RR homozygote subjects had lower HDL-C levels than 192QQ homozygotes, and individuals with 192RR and 192QR genotypes had an odds ratio (OR) = 7.05 (95% confidence interval (CI) = 1.29-38.34) of having HDL-C < 60 mg/dL. Individuals with higher paraoxonase activity (> 600.18 U/L) had a slight risk (OR = 4.9, 95% CI = 0.83-22.02) of having HDL-C < 60 mg/dL. PON155LM polymorphism was associated with higher LDL-cholesterol. PON1Q192R polymorphism showed a role in modulating lipid profile: 192RR homozygotes showed the least favorable lipoprotein levels.     

A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common autosomal codominant hereditary disease caused by defects in the LDL receptor (LDLR) gene, and one of the most common characteristics of affected subjects is premature coronary heart disease (CHD). In heterozygous FH patients, the clinical expression of FH is highly variable in terms of the severity of hypercholesterolaemia and the age of onset and severity of CHD. Identification of mutations in the ATP binding cassette transporter 1 (ABCA1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol and apolipoprotein A1 concentrations and premature coronary atherosclerosis, has led us to hypothesise that ABCA1 could play a key role in the onset of premature CHD in FH. In order to know if the presence of the R219K variant in the ABCA1 gene could be a protective factor for premature CHD in FH, we have determined the presence of this genetic variant by amplification by PCR and restriction analysis in a group of 374 FH subjects, with and without premature CHD. The K allele of the R219K variant was significantly more frequent in FH subjects without premature CHD (0.32, 95% CI 0.27 to 0.37) than in FH subjects with premature CHD (0.25, 95% CI 0.21 to 0.29) (p<0.05), suggesting that the genetic variant R219K in ABCA1 could influence the development and progression of atherosclerosis in FH subjects. Moreover, the K allele of the R219K polymorphism seems to modify CHD risk without important modification of plasma HDL-C levels, and it appears to be more protective for smokers than non-smokers.     

The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma

Melanocyte stimulating hormone (MSH) plays an important role in determining the cutaneous response to ultraviolet radiation and may also influence melanoma progression. We have previously shown that variants of the melanocortin receptor present on melanocytes, MC1R, are associated with sun sensitivity and red hair in a UK population and therefore now consider the gene as a candidate for melanoma susceptibility. We have compared the frequency of known MC1R variants in the second and seventh transmembrane domains in 43 melanoma cases and 44 controls. MC1R variants were more common in cases than controls (chi 2 = 6.75, 1 d.f.; P = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91 (95% c.l.: 1.48-10.35), and a population risk attributable to carriers of 34.6% (95% c.i. 10.7-52.1%). The Asp84Glu variant was only present in melanoma cases and appears to be of particular significance. The contribution of variant MC1R alleles was largely independent of skin type. Variants of the MC1R gene are likely to be causally associated with the development of melanoma.      

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P=0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P=0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.     

Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma

BACKGROUND: A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma. OBJECTIVE: To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant. METHODS: We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13. RESULTS: The variant showed a lower affinity with the IL-13 receptor alpha2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant. CONCLUSION: These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo.     

ICAM1 R241 is not associated with celiac disease in the Spanish population

Celiac disease (CD) is a chronic intestinal inflammatory disease that develops in genetically susceptible individuals after gluten ingestion. The ICAM1 gene, located in the CD linkage region 19p13, encodes an intercellular adhesion molecule (ICAM-1) involved in inflammatory processes. Increased levels of ICAM-1 were observed in intestinal biopsies and in sera of CD patients. In addition, an association between the ICAM1 polymorphism G241R and CD patients has been recently described in a French population. Our aim in this study was to analyze the role of ICAM1 polymorphisms in CD susceptibility in the Spanish population. We performed a case-control study with 608 CD patients and 537 healthy control individuals and a family study including 231 trios. Four ICAM1 single nucleotide polymorphisms (SNPs) were analyzed: three nonsynonymous, R478W (rs5030400), P352L (rs1801714) and G241R (rs1799969); and one intronic, rs281432. Despite having above 98% statistical power to detect the association described in the French population (odds ratio = 1.7), we did not find any differences in genotypic or allelic frequencies of the G241R polymorphism between our CD patients and controls, and no differences were observed when the other SNPs were analyzed. Therefore, in our population our results discard the important previously described role of ICAM1 G241R in celiac disease.     

A1166C variant of angiotensin II type 1 receptor gene is associated with severe hypertension in pregnancy independently of T235 variant of angiotensinogen gene

Hypertension in pregnancy (HP) is a multifactorial disease manifested due to a complex combination of environmental factors and several predisposing genes including factors in the renin angiotensin system. The aim of this study was to assess the association between the A1166C variant of the angiotensin II type 1 receptor (AT1) gene and severe HP. We carried out association studies and multivariate analyses including other candidate causal factors of HP such as the M235T variant of the angiotensinogen (AGT) gene, prepregnancy body mass index (BMI), and family history of hypertension in Japanese subjects. One hundred and fourteen patients with severe HP and 291 normal pregnancy controls were genotyped. Among primiparous subjects, the frequency of AC+CC genotype of AT1 was significantly higher in severe HP than in the controls. A multivariate analysis with AC+CC genotype of AT1 and TT genotype of AGT revealed that these were independently associated with primiparous severe HP. However, when family history of hypertension and prepregnancy BMI 25 were added as factors examined in the multivariate analysis, only TT genotype of AGT and family history of hypertension were found to be independent potent factors. The present results suggest that the C1166 allele of the AT1 gene may be concerned with the predisposition to essential hypertension independently of the T235 allele of the AGT gene.     

A common functional variant in the interleukin-6 gene is associated with increased body mass index in subjects with type 2 diabetes mellitus

Circulating levels of interleukin-6 (IL-6) are raised in insulin resistant states such as obesity, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). Growing evidence suggests that IL-6 is not only produced by fat cells but is also capable of inducing insulin resistance in these cells. The expected result of this in vivo, would be to increase adipose mass and subsequently body mass index (BMI). The IL-6 -174G > C common functional gene variant has consistently been associated with increased plasma IL-6, insulin resistance, and increased cardiovascular risk. We looked at the association between genotype and BMI in 571 Caucasian subjects with T2DM. There was a significant linear association between genotype and BMI: Median (interquartile range) GG 28.8 kg/m2 (26.0-31.6) vs GC; 29.4 kg/m2 (26.3-32.5) vs CC; 30.4 kg/m2 (26.1-33.0), p=0.05. When the group was divided by the median BMI (29.1 kg/m2), 62% of -174CC subjects were in the higher group compared to 38% in the lower group (p=0.008). By contrast, in 2,652 non-diabetic Caucasian men with a median BMI of 26.1 kg/m2, there was no difference in genotype distribution (p=0.288). The frequency of the -174C allele was lower in type 2 diabetes compared to the non-diabetic men (-174C allele frequency: 0.35[0.33-0.38] vs 0.43[0.42-0.45], p <0.00001; -174CC homozygotes: 12.3 vs 18.3%, respectively). The -174C allele is associated with higher BMI in type 2 diabetes, but not amongst healthy subjects. The increased cardiovascular risk associated with the -174C allele may account for the lower frequency of this allele in those with type 2 diabetes.     

The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women

Melanocortin-4 receptor (MC4R) plays critical roles in regulating food intake and energy balance. Recent genome wide scans found common variants near MC4R were related to obesity and insulin resistance. We examined the associations of the reported variants rs17782313 (T>C) and rs17700633 (G>A) with dietary intakes, weight change and diabetes risk in 5724 women (1533 with type 2 diabetes) from a prospective cohort. Under an additive inheritance model, SNP rs17782313 was significantly associated with high intakes of total energy (P = 0.028), total fat (P = 0.008) and protein (P = 0.003). Adjustment for age, BMI, diabetes status and other covariates did not appreciably change the associations. The SNP was also associated with significantly increasing trend of percentage of energy from total fat (P for trend = 0.037). The associations between SNP rs17782313 and higher BMI (P = 0.002) were independent of dietary intakes. In addition, carriers of allele-C had 0.2 kg/m(2) greater 10-year increase in BMI from cohort baseline 1976 to 1986 (P = 0.028) compared with the non-carriers. Moreover, per allele-C of rs17782313 was associated with 14% (2-32%) increased risk of type 2 diabetes, adjusting for BMI and other covariates. SNP rs1770833 was not significantly associated with either dietary intakes or obesity traits. In conclusion, the common SNP rs17782313 near MC4R gene was significantly associated with higher intakes of total energy and dietary fat. In addition, the SNP was related to greater long-term weight change and increased risk of diabetes in women.     

A functional variant of IRS1 is associated with type 1 diabetes in families from the US and UK

A collection of 767 multiplex type 1 diabetes families from the US and UK were tested for linkage to the IRS1 gene and for allelic association with a specific variant of IRS1, G972R. Pedigree disequilibrium testing revealed preferential transmission of the 972R allele to affected offspring in these families (P = 0.02). Linkage analyses conditioning on status at IRS1 position 972 suggest the possibility of interaction with an unidentified locus on chromosome 8.     

The D allele of the ACE I/D common gene variant is associated with Type 2 diabetes mellitus in Caucasian subjects

The deletion D allele of the angiotensin-I converting enzyme (ACE) I/D gene variant is associated with higher ACE activity in Caucasians and previous studies in non-Caucasian samples have suggested an association between the D allele and type 2 diabetes (Type 2DM). The aim of this study was to compare the genotype distribution between Caucasian subjects with Type 2DM and non-diabetic Caucasian men. Genotype distribution was compared between 574 Caucasian subjects with Type 2DM, recruited from the UCL Diabetes and Cardiovascular Disease Study and 2413 non-diabetic Caucasian men, recruited from the second Northwick Park Heart Study. Within both samples, genotype distributions were in Hardy-Weinberg equilibrium. The genotype distributions in those with Type 2DM compared to the non-diabetic men (II/ID/DD) was 18%/50%/32% vs. 23%/49%/27%, p=0.004. In accordance with this, the frequency of the D allele was higher in those with Type 2DM (0.574 [0.55-0.60] vs. 0.519 [0.50-0.53], p=0.001). On combining the two samples, the odds ratio (OR) for Type 2DM was significantly higher in D allele carriers compared to II subjects (OR=1.55, p=0.02, after adjustment for age, sex, BMI, blood pressure, and lipids). In those with diabetes, there was a significant association between genotype and a family history of diabetes. The odds ratio for a family history of diabetes in DD compared to II subjects was 1.52 [0.89-2.60], p=0.03. This study clearly shows an association between the ACE I/D common gene variant and Type 2DM.     

A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes in the Danish population

Genome-wide association scans in type 2 diabetes (T2D) have identified a risk variant, rs13266634 (Arg325Trp), in SLC30A8 on chromosome 8. SLC30A8 encodes a β-cell specific zinc-ion transporter and rs13266634 has been shown to affect insulin secretion. Recently, autoantibodies for Slc30A8 with high predictive value were demonstrated in individuals with type 1 diabetes (T1D), making this gene an interesting T1D candidate gene. We genotyped rs13266634 in 3008 cases and controls and 246 families from Denmark. Association to T1D could not be demonstrated.     

The interleukin 1B-511 polymorphism is associated with the risk of developing restenosis after coronary stenting in Mexican patients

Inflammation is the primary response to vessel wall injury caused by stent placement in coronary arteries. Cytokines of the interleukin-1 family are central regulators in immunoinflammatory mechanisms. The objective of this study was to test for association between IL-1 family gene polymorphisms and risk for restenosis after coronary stent placement. The IL-1B-511, IL-1F10.3, RN.4T>C, RN.6/1C>T, RN.6/2C>G, and IL-1RN VNTR polymorphisms were analyzed by 5' exonuclease TaqMan genotyping assays and polymerase chain reaction in a group of 165 patients who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed in search of angiographic predictors of restenosis and follow-up angiography was analyzed in search of binary restenosis. Patients with IL-1B-511 TT genotype had a 1.89-fold increased risk of developing restenosis. The analysis considering the lesions treated demonstrated that the lesions of patients with IL-1B-511 TT genotype had a 3.44-fold increased risk of developing restenosis. When the analysis considered the type of stent, the risk of developing restenosis was increased in lesions of patients with TT genotype (odds ratio = 4.50) who underwent coronary bare-metal stent implantation. Multiple logistic analysis identified IL-1B-511 TT genotype as an independent predictor for restenosis. The results suggest that IL-1B-511 polymorphism could be involved in the risk of developing restenosis after coronary stent placement.     

The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures

Background  

Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated. We attempted to replicate this study in our cohort of patients with TLE. Furthermore, we also analyzed the coding sequence of this gene and searched for disease-causing mutations.     

The MTHFD1 1958G>A variant is associated with elevated C-reactive protein and body mass index in Canadian women from a premature birth cohort

MTHFD1 1958G>A, a polymorphism in folate metabolism, increases risk of pregnancy complications. A mouse model exhibited developmental defects, increased weight and decreased leukocyte counts. To examine the latter associations, we genotyped 651 women from a premature birth cohort. Prematurity and 1958G>A were not associated. Increases in the inflammatory marker CRP (logistic regression, p = 0.055) and BMI (chi-square, p = 0.0113) were associated with AA genotype in women with low folate. MTHFD1 1958G>A may influence immune function and obesity.