Joint effect of insulin signaling genes on all-cause mortality

Objective: We have previously reported the combined effect of SNPs perturbing insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. Methods: We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. Results: In the first sample, individuals carrying 1 or ≥2 risk alleles had 33% (p = 0.06) and 51% (p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08–1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13–1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. Conclusion: Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.     

Contribution of rare variants in monogenic diabetes-genes to early-onset type 2 diabetes

AimThis study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D).MethodsA nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested.ResultsWhen all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08–2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87–22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01–1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02).ConclusionRare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.     

The SH2B1 obesity locus and abnormal glucose homeostasis: Lack of evidence for association from a meta-analysis in individuals of European ancestry

Background/AimsThe development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D.Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association.MethodsThe SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448).ResultsVariability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89–1.04) or in the meta-analysis (OR = 1.01; 0.98–1.05).ConclusionOur data exclude a role for the SH2B1 obesity locus in the modulation of AGH.     

Lack of replication of common EXT2 gene variants with susceptibility to type 2 diabetes in Lebanese Arabs

ObjectiveRecent genome-wide association studies and replication analyses have reported the association of variants of the exostosin-2 (EXT2) gene and risk of type 2 diabetes mellitus (T2DM) in some populations, but not in others. This study investigated the associations of EXT2 variants rs1113132, rs3740878 and rs11037909 with T2DM in a Lebanese Arab population.MethodsThis case-control study involved 995 T2DM patients and 1076 control subjects. Genotyping was done by the allelic exclusion method.ResultsWhile minor allele frequencies (MAFs) of rs11037909 (P = 0.028) and rs3740878 (P = 0.048), but not rs1113132 (P = 0.841), were higher in patients, this was lost after correcting for multiple testing. Apart from EXT2 rs1113132, which was marginally associated with T2DM in the additive model (P = 0.054), but not after adjustment for covariates, none of the tested EXT2 SNPs were associated with T2DM in any of the genetic models tested. However, variable associations of EXT2 variants with T2DM were noted according to BMI status. While the three tested EXT2 variants were not associated with T2DM in obese subjects, rs1113132 and rs11037909, but not rs3740878, were associated with T2DM in non-obese subjects. Meta-analysis revealed a significant association of rs11037909 and a marginal association of rs3740878 with T2DM in the fixed model. Using a common (GTA) haplotype as reference, three-locus (rs1113132/rs11037909/rs3740878) haplotype analysis demonstrated no association between any of the EXT2 haplotypes with T2DM, not even before correcting for multiple testing.ConclusionThis study demonstrated no association of rs1113132, rs3740878 and rs11037909 EXT2 variants with T2DM.     

Association of parental cardiovascular risk factors with offspring type 1 diabetes mellitus insulin sensitivity

AimThis study aimed to determine whether the insulin resistance (IR) and lipid profiles in Type 1 Diabetes (T1D) offspring are associated with IR and other cardiovascular risk factors in their parents.MethodsThis study included 99 T1D patients (19.6 ± 4.0 yrs.), 85 mothers and 60 fathers. Parents' IR was assessed by HOMA-IR, and the insulin sensitivity in T1D patients was assessed by the estimated Glucose Disposal Rate (eGDR).ResultsThe eGDR in the T1D offspring was negatively related to age (p = 0.023), weight (p = 0.004), LDL (p = 0.026), and microalbuminuria (p = 0.019). Maternal Type 2 Diabetes (p < 0.001) and HOMA-IR (p = 0.029) were negatively related to eGDR in their T1D offspring. The maternal HOMA-IR and the proband's eGDR were positively (p = 0.012) and negatively (p = 0.042) associated with the birth weight of the T1D offspring, respectively. We didn't find an association with the fathers' profiles.ConclusionsIn a cohort of offspring with T1D the insulin sensitivity was related to the IR, lipid profile, and the presence of T2D only in their mothers. Precocious screening and treatment of these risk factors beyond glycemic control will benefit T1D with this background.     

Common variants in SOCS7 gene predict obesity,disturbances in lipid metabolism and insulin resistance

Background and aimsSpecific Suppressor of Cytokine Signaling (SOCS) members, such as SOCS7, may play a role in the development of insulin resistance (IR) owing to their ability to inhibit insulin signaling pathways. The objective was to explore the association between common variants and related haplotypes in SOCS7 gene and metabolic traits related to obesity, lipid metabolism and IR.Methods and Results780 unrelated men were included in a cross-sectional study. We selected three tagged SNPs that capture 100% of SNPs with minor allele frequency ≥ 0.10. Analyses were done separately for each SNP and followed up by haplotype analysis. rs8074124C was associated with both obesity (p = 0.005) and abdominal obesity (p = 0.002) and allele C carriers showed, in comparison with TT carriers, lower BMI (p = 0.001) and waist circumference (p = 0.001). rs8074124CC- carriers showed lower fasting insulin (p = 0.017) and HOMA-IR (p = 0.018) than allele T carriers. rs12051836C was associated with hypertriglyceridemia (p = 0.009) and hypertriglyceridemic waist (p = 0.006). rs12051836CC- carriers showed lower fasting insulin (p = 0.043) and HOMA-IR (p = 0.042). Haplotype-based association analysis (rs8074124 and rs12051836 in that order) showed associations with lipid and obesity -related phenotypes, consistent with single locus analysis. Haplotype analysis also revealed association between haplotype CT and both decreased HDL-C (p = 0.026) and HDL-C (p = 0.014) as a continuous variable.ConclusionsWe found, for the first time, significant associations between SOCS7 common variants and related haplotypes and obesity, IR and lipid metabolism disorders.     

T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population

AimAdiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population.MethodsTwo polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n = 5212) and people with T2D in the DIABHYCAR study (n = 3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n = 230), and in controls who remained normoglycaemic (n = 226) throughout.ResultsIn a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04–1.18; P = 0.001) and 0.92 (95% CI: 0.87–0.98; P = 0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P = 0.03) and HbA_1c (P = 0.006), and lower plasma adiponectin levels (P = 0.03) in the D.E.S.I.R. participants. Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P = 0.03), HbA_1c (P = 0.02) and Fatty Liver Index (FLI; P ≤ 0.01), and higher plasma adiponectin levels (P = 0.002). Associations with HbA_1c, FLI and adiponectin levels persisted after adjusting for BMI.ConclusionCDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.     

Type 2 diabetes and polymorphisms on chromosome 9p21: a meta-analysis

Background and aimsGenome-Wide Association Studies found some variants on chromosome 9p21 associated with type 2 diabetes (T2D). We performed a meta-analysis to estimate strength, accuracy and feature of the association of polymorphisms in 9p21 with T2D.Methods and resultsArticles were retrieved screening electronic databases and cross references. Twenty-two publications were identified, for a total of 38,455 T2D patients and 60,516 controls. Twenty-one studies investigated the role of the SNP rs10811661; in some studies three additional SNPs (rs564398, rs10757278, rs1333040) were genotyped. Population attributable risk (PAR) was computed as: risk allele frequency1(OR-1)/OR, using the per-allele odds ratio (OR).The risk allele (T) of rs10811661 was associated with T2D in most of the studies. In meta-analysis the overall per-allele OR was 1.24 (95% CI: 1.21–1.27; P < 10^?15), with no difference according to ethnicity (P = 0.45), and low heterogeneity (P = 0.040) across studies partly explained by sample size. Modeling of inheritance suggested an additive effect of the T allele. PAR of T2D related to this polymorphism was 15% for Caucasians and 13% for Asians. The overall odds ratio for the T allele of the SNP rs564398 was 1.08 (95% CI: 1.05–1.12; PAR = 6%). The other SNPs showed negligible associations.ConclusionsThis meta-analysis provides accurate and comprehensive estimates of the association of some genetic variants at chromosome 9p21 and T2D. A relatively small but significant role of the T allele of the rs10811661 SNP in increasing by 21–27% the risk of T2D in an additive way was apparent.     

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms

BackgroundPrevious genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions.MethodsWe conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants.ResultsVariants at the CTRC (p = 1.22 × 10^?21) and SPINK1 (p = 6.59 × 10^?47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220.ConclusionsA shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.     

TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study

Aims/hypothesis  Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). Methods  We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. Results  As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10⁻⁷) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). Conclusions/interpretation  We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Association of the ENPP1 K121Q polymorphism with type 2 diabetes and obesity in the Moroccan population

AimThe ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme (ENPP1), which downregulates insulin signaling by inhibiting insulin-receptor tyrosine kinase activity, is encoded by the ENPP1 gene. A common functional ENPP1 K121Q polymorphism has been suggested to contribute to insulin resistance, obesity and type 2 diabetes (T2D) in various ethnic groups. For this reason, we assessed the association between the ENPP1 K121Q polymorphism in T2D and obesity phenotypes in the Moroccan population.MethodsUsing LightCycler^® technology, we genotyped the ENPP1 K121Q polymorphism in 503 subjects with T2D and 412 normoglycaemic individuals.ResultsThere was no evidence of an association between ENPP1 K121Q and T2D in either an additive (P = 0.99) or recessive mode of inheritance (P = 0.47). However, the Q121 variant was significantly more frequent in obese than in non-obese subjects after adjusting for age, gender and T2D status. We observed genetic heterogeneity between obese and non-obese T2D patients (P = 0.02). The K121Q polymorphism was associated with T2D in the presence of obesity in both additive (1.55 [95% CI 1.16–2.07]; P = 0.003) and recessive (2.31 [95% CI 1.34–3.97]; P = 0.002) modes of inheritance.ConclusionAlthough there was no evidence of an association between the ENPP1 K121Q variant and the general phenotype of T2D, we did find an association with adult obesity and T2D. The Q121 allele frequency in Morocco is 37.3%, placing it between European Caucasians (15%) and Black Africans (79%). This study is the first to report an association between K121Q and metabolic diseases in the Moroccan population.     

Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes

Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03–1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96–1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. Conclusions/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. D. Altshuler and L. Groop jointly supervised this project.     

Genome-wide gene and serum ferritin interaction in the development of type 2 diabetes in adults aged 40 years or older

Background and aimsElevated serum ferritin is associated with incident Type 2 diabetes (T2D), but the interactions between serum ferritin and genetic factors which may improve understanding underlying mechanism in the development of T2D are still unclear. We determined the gene–ferritin interactions on the development of T2D by genome-wide gene–ferritin interaction analyses.Methods and resultsA total of 3405 participants from two prospective cohorts of community living residents were included, and the median follow-time was 3.99 years. Genome-wide gene–ferritin interactions were analyzed using the joint test with two degrees of freedom and the interaction test with one degree of freedom. There were 18 SNPs selected in the joint test. Finally, four independent variants [rs355140 (LINC00312), rs4075576 (nearby PDGFA), rs1332202 (PTPRD), and rs713157 (nearby LINC00900)] with low pairwise linkage disequilibrium (r2 < 0.2) and located at least 1000 kb from the index SNP showed interactions with serum ferritin level. In the association analyses between serum ferritin levels (tertiles of ferritin and ferritin status) and the incidence of T2D according to genotype, the Incidence Rate Ratios (IRRs) in the highest tertile of ferritin level (vs. the lowest tertile) were greater for participants with heterozygotes of risk alleles of each of the four SNP than IRRs for those with wild type. Compared with the normal group, the elevated ferritin group also had a higher risk of T2D for all genetic variants of risk alleles, particularly its homozygotes.ConclusionSerum ferritin level interacts with genetic variants (rs355140, rs4075576, rs1332202, and rs713157) in the development of T2D.     

The STAT4 and not the IFNL3 variant is associated with hepatitis B virus clearance in a population from the Khyber Pakhtunkhwa region of Pakistan

Background and study aimsHost genetic modifiers of the risk and persistence of hepatitis B virus (HBV) infection in the Pakistani population have not been clearly elucidated. Recently, two genome-wide association studies described that STAT4 and IFNL3 variants are associated with different aspects of the course of HBV infection. However, the roles of these variants in the persistence of HBV infection have not been investigated in the HBV-infected population of Pakistan. Therefore, we examined the roles of the STAT4 and IFNL3 variants in a chronic HBV-infected population from the Khyber Pakhtunkhwa (KPK) region of Pakistan.Patients and methodsSTAT4 rs7574865 and IFNL3 rs12979860 genotyping were performed in 297 subjects (240 infected with HBV and 57 controls). Statistical analyses were performed using the chi-squared test, Student’s t-test, Hardy–Weinberg equilibrium tests and logistic regression models.ResultsAmong the 297 subjects, compared with the IFNL3 rs12979860 genotype [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.39–1.29, p = 0.2), the STAT4 rs7574865 genotype was independently associated with the risk of developing chronic HBV infection [OR = 1.9, 95% CI = 1.09–3.50, p = 0.02].ConclusionThe STAT4 rs7574865 and not the IFNL3 rs12979860 variant is associated with persistence of HBV infection in a Pakistani population from the KPK region.     

The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel

On chromosome 6q22.3, a cluster of single-nucleotide polymorphisms located in intron 5 of the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) gene were shown to confer susceptibility to type 2 diabetes in multiple ethnic groups. The diabetogenic role of CDKAL1 variants is suggested to consist in lower insulin secretion probably due to the insufficient inhibition of the CDK5 activity. In this study, we assessed the association of several SNPs of CDKAL1 with T2D in 772 Russian affected patients and 773 normoglycemic controls using a Taqman-based allelic discrimination assay. We showed association of the minor allele C of rs10946398 (Odds Ratio (OR) = 1.21, 95% CI = 1.04–1.4, P = 0.016), allele C of rs7754840 (OR = 1.18, 95% CI = 1.01–1.37, P = 0.038), and allele G of rs7756992 (OR = 1.21, 95% CI = 1.04–1.42, P = 0.017) with higher diabetes risk thereby replicating the predisposing role of CDKAL1 in etiology of T2D. These alleles contribute to three haplotypes (CCA, CGG, and CCG) related to higher diabetes risk (OR = 1.48, 2.12, and 1.95). Combinations of these haplotypes between each other form the group of high-risk haplogenotypes whose carriers had decreased HOMA-β compared to other CDKAL1 variants in both diabetic (38.6 ± 19.3 vs. 48.2 ± 21.2, P _adjusted = 0.019–0.044) and non-diabetic (91.8 ± 42.1 vs. 108 ± 47.2, P _adjusted = 0.0054–0.01) patients. The carriage of the risk haplogenotypes of CDKAL1 was associated with reduced response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. These data suggest that CDKAL1 is involved in the pathogenesis of T2D through impaired beta-cell function.     

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort

Background and aimsApoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed.Methods and resultsThe study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression.The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05–1.99) and female (OR = 2.22, 95%CI = 1.58–3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression).ConclusionA common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.