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PubMed2004

Common variants in glutamine:fructose-6-phosphate amidotransferase 2 (GFPT2) gene are associated with type 2 diabetes, diabetic nephropathy, and increased GFPT2 mRNA levels.

Increased flux of glucose through the hexosamine biosynthetic pathway has been implicated in insulin resistance, altered insulin secretion, and diabetic nephropathy. Glutamine:fructose-6-phosphate amidotransferase (GFPT), the rate limiting enzyme in hexosamine biosynthesis, is encoded by the unlinked but highly homologous genes GFPT1 and GFPT2. We tested the hypothesis that GFPT2 sequence variation contributed to the susceptibility to type 2 diabetes mellitus (T2DM) and diabetic nephropathy in Caucasian and African-American individuals. We identified 11 single nucleotide polymorphisms (SNPs), of which seven were common. A single variant in exon 14, I471V, altered the amino acid sequence, is conserved between human and mouse genes, and was associated with T2DM among Caucasians (P = 0.05). A trend to an association was noted with diabetic nephropathy among African-American individuals (P = 0.15). Several variants in the 3' untranslated region (UTR) and exon 18 were also associated with T2DM in Caucasian individuals (P < 0.05), and the SNP in the 3' UTR was associated with diabetic nephropathy in African-American subjects (P = 0.047). GFPT2 mRNA levels in transformed lymphocytes from study subjects were significantly increased among African-American subjects compared with Caucasian individuals, regardless of diagnosis. Furthermore, the associated allele of the 3' UTR SNP was approximately 2-fold overexpressed. We propose that the 3' UTR variant results in increased GFPT2 mRNA levels with resultant increased hexosamine flux. The I471V variant may contribute to altered protein function or may simply be in linkage disequilibrium with the 3' UTR.

3' Untranslated Regions↗

PubMed2006

Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.

AIMS AND HYPOTHESIS: India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population. MATERIALS AND METHODS: We genotyped type 2 diabetes patients (n = 955) and ethnically matched control subjects (n = 399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in TCF7L2. RESULTS: We observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI = 1.24-1.82], p = 4.0 x 10(-5)), rs4506565 (OR 1.48 [95% CI = 1.24-1.77], p = 2.0 x 10(-5)) and rs7903146 (OR 1.46 [95% CI = 1.22-1.75], p = 3.0 x 10(-5)). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI = 1.40-3.72] vs OR 1.43 [95% CI = 1.11-1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p = 0.001), higher 2-h plasma glucose (p = 0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p = 0.012) in non-diabetic subjects. CONCLUSIONS: Our study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.

Adult↗

PubMed2003

Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate.

Uric acid nephrolithiasis (UAN) is a common disease with an established genetic component that presents a complex mode of inheritance. While studying an ancient founder population in Talana, a village in Sardinia, we recently identified a susceptibility locus of approximately 2.5 cM for UAN on 10q21-q22 in a relatively small sample that was carefully selected through genealogical information. To refine the critical region and to identify the susceptibility gene, we extended our analysis to severely affected subjects from the same village. We confirm the involvement of this region in UAN through identical-by-descent sharing and autozygosity mapping, and we refine the critical region to an interval of approximately 67 kb associated with UAN by linkage-disequilibrium mapping. After inspecting the genomic sequences available in public databases, we determined that a novel gene overlaps this interval. This gene is divided into 15 exons, spanning a region of approximately 300 kb and generating at least four different proteins (407, 333, 462, and 216 amino acids). Interestingly, the last isoform was completely included in the 67-kb associated interval. Computer-assisted analysis of this isoform revealed at least one membrane-spanning domain and several N- and O-glycosylation consensus sites at N-termini, suggesting that it could be an integral membrane protein. Mutational analysis shows that a coding nucleotide variant (Ala62Thr), causing a missense in exon 12, is in strong association with UAN (P=.0051). Moreover, Ala62Thr modifies predicted protein secondary structure, suggesting that it may have a role in UAN etiology. The present study underscores the value of our small, genealogically well-characterized, isolated population as a model for the identification of susceptibility genes underlying complex diseases. Indeed, using a relatively small sample of affected and unaffected subjects, we identified a candidate gene for multifactorial UAN.

Amino Acid Sequence↗

PubMed1968

Hemoglobin variant common to Chinese and North American Indians: alpha-2-beta-22 Glu-Ala.

An electrophoretically slow hemoglobin variant, in which the structural change involves the replacement of a glutamyl residue by alanyl at position beta-22, was reported in two groups of North American Indians: hemoglobin-G Coushatta, in Alabama-Coushatta Indians in Texas; and hemoglobin-G Saskatoon, in descendants of Santee Indians living in Canada. Hemoglobin-G Hsin-Chu, found in Taiwan in a Chinese from the northern Chinese province of Liaoning, is now shown to have the same structural anomaly.

Alanine↗

PubMed1998

Plasma leptin levels: interaction of obesity with a common variant of insulin receptor substrate-1.

Obesity is associated with insulin resistance and other major cardiovascular risk factors. A common amino acid polymorphism at codon 972 of the insulin receptor substrate-1 (IRS-1) has been shown to interact with obesity in the expression of insulin resistance. The plasma concentration of the adipocyte-specific hormone leptin is increased in obesity and is correlated with adipose tissue mass. Because in vitro studies demonstrated inhibitory effects of leptin on insulin signaling, leptin may be involved in obesity-associated insulin resistance. To gain insight into the relationship between insulin and leptin in obesity, we studied plasma leptin levels and several cardiovascular risk factors, as well as their modification by the IRS-1 codon 972 genotype, in 156 obese individuals and 131 lean control subjects. In both groups, 10% of the subjects were heterozygous for the IRS-1 codon 972 variant. Obese individuals harboring the IRS-1 variant displayed significantly lower plasma concentrations of leptin than obese subjects without the polymorphism (means, 26.7 versus 37.8 ng/mL, P<0.0293). In a subgroup of obese patients, leptin mRNA abundance was measured in the adipose tissue and was significantly lower in carriers of the IRS-1 variant than in subjects with the wild-type variant (P<0.0291). Our data suggest that insulin signaling influences plasma leptin concentrations at the mRNA expression level and argue against leptin as a major causative factor of insulin resistance.

Adult↗

PubMed2004

Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis.

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

Aged↗

PubMed2003

CD99 expression in hepatocellular carcinoma: an immunohistochemical study in the fibrolamellar and common variant of the tumour.

Histological diagnosis of hepatocellular carcinoma (HCC) in biopsy and fine needle aspiration material can pose difficult problems. This is particularly so in the fibrolamellar variant of the tumour (FLHCC) which has biological features distinctly different from those of common HCC (CHCC). Expression of CD99, a membrane localised glycoprotein which is known to be a feature of diagnostic importance in several malignant neoplasms was looked for in immunohistochemical preparation of tissue material from 18 cases of HCC, 6 FLHCC and 12 CHCC accessioned in our department. Positive staining of variable degrees and intesity was observed in all 18 cases. Non-neoplastic hepatocytes, normal or others and all the 18 other cases of non-HCC cancers outside the liver or metastatic within the liver were negative. In some cases, mostly of FLHCC, a definitive diagnosis could be suggested on the basis of CD99 positivity. It is concluded that in cases of HCC, particularly in small specimens and in FLHCC, immunostaining for CD99 will be of significant help in diagnosis.

12E7 Antigen↗

PubMed1988

Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C).

Data on the distribution of beta thalassemia among over 6,000 Melanesians reveals a major difference in the carrier rates between populations in the malarious coastal regions of New Guinea and those living in the historically malaria-free Highlands. The island of Maewo in Vanuatu has a particularly high incidence of beta + thalassemia associated with a single restriction enzyme haplotype. Direct cloning into a plasmid vector and sequence analysis demonstrate that the mutation is a G to C transversion at position 5 of intron 1 of the beta-globin gene. Oligonucleotide probe surveys indicate that this variant accounted for all cases of beta thalassemia studied from Maewo. It is also common in coastal Papua New Guinea where haplotype and oligonucleotide probe data suggest that the molecular basis of beta thalassmia is more heterogeneous.

Alleles↗

PubMed1993

The common variant of cystic fibrosis transmembrane conductance regulator is recognized by hsp70 and degraded in a pre-Golgi nonlysosomal compartment.

The most common cause of cystic fibrosis is deletion of Phe-508 (delta F508) from the cystic fibrosis transmembrane conductance regulator (CFTR). Previous studies have suggested that delta F508 CFTR is an unstable protein that retains a pattern of glycosylation specific to the endoplasmic reticulum. This report examines the mechanism responsible for the mislocalization of delta F508 CFTR in a human cystic fibrosis epithelial cell line overexpressing recombinant CFTR by virtue of adenovirus-mediated gene transfer. Immunoelectron microscopy confirmed that wild-type CFTR is delivered to the plasma membrane of these cells and that delta F508 CFTR is retained in the endoplasmic reticulum. Pulse-chase studies showed that newly synthesized CFTR complexes with the chaperone hsp70. The wild-type protein dissociates from hsp70 before its transport to the Golgi, and the protein is subsequently degraded in lysosomes. By contrast, the complex formed between delta F508 CFTR and hsp70 is retained in the endoplasmic reticulum and delta F508 CFTR is rapidly degraded in a pre-Golgi nonlysosomal compartment. Thus, hsp70 discriminates between the normal form of CFTR and the form of the protein that most commonly causes cystic fibrosis (delta F508). These findings clarify the mechanism by which mutation causing delta F508 affects the intracellular trafficking of CFTR and suggest another function for hsp70 in ensuring quality control during the biosynthesis of plasma-membrane proteins.

Biological Transport↗

PubMed2003

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.

ATP Binding Cassette Transporter 1↗

PubMed2005

The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment.

OBJECTIVE: Our objective was to investigate the interactions between common polymorphisms in ABCB1, CYP3A4, and CYP3A5 genes and the lipid-lowering efficacy and safety of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin. METHODS: One hundred sixteen hypercholesterolemic patients were prospectively screened by physical examination, medical history, and clinical laboratory evaluation and were included in this study. Subjects entering the study were treated with 20 mg/d simvastatin. Plasma lipid and lipoprotein levels were measured before treatment, after 2 months of treatment, and after 6 months of treatment. Ninety-nine patients completed the 6-month follow-up and were included in the association analysis for treatment efficacy. Seventeen subjects who had adverse drug reactions (ADRs) to simvastatin (ADR group) could not complete the 6-month follow-up and were included in the association analyses for safety. Myalgia was observed in 15 of 17 subjects and was the only ADR included in the association analyses, but other common ADRs were also observed. Myalgia was defined as proximal or diffuse muscle pain, tenderness, or weakness, or both pain and weakness, with normal or slightly increased serum creatine phosphokinase levels. ABCB1 (1236C>T, 2677G>A/T, and 3435C>T), CYP3A4 (-392A>G), and CYP3A5 (6986A>G) allele variants were determined by polymerase chain reaction and restriction mapping. RESULTS: After adjustment for covariates, carriers of the ABCB1 1236T variant allele had a greater reduction in total cholesterol and low-density lipoprotein cholesterol with simvastatin treatment, as compared with homozygotes with the wild-type allele (-29.0% [95% confidence interval (CI), -25.9 to -32.5] versus -24.2% [95% CI, -19.0 to -29.3] [P = .042] and -39.6% [95% CI, -35.8 to -44.0] versus -33.8% [95% CI, -27.4 to -40.2] [P = .042], respectively). Similar results were observed for the 2677G>A/T polymorphism and haplotype data. The 1236T, 2677non-G, and 3435T alleles were less frequent in ADR cases than in the non-ADR group (P < .05 for all single-nucleotide polymorphisms). Haplotype analyses also demonstrated a reduction of the T-non-G-T haplotype frequency (20%) in patients in whom myalgia developed during simvastatin treatment, as compared with the non-ADR group (41.4%) (P = .03). No significant associations were observed between the CYP3A4 -392A>G and CYP3A5*3 allele variants and the efficacy or tolerability of simvastatin. CONCLUSIONS: Our data suggest an association of ABCB1 gene polymorphisms and the efficacy and safety of simvastatin.

ATP Binding Cassette Transporter 1↗

PubMed2006

Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia.

DTNBP1 was first identified as a putative schizophrenia-susceptibility gene in Irish pedigrees, with a report of association to common genetic variation. Several replication studies have reported confirmation of an association to DTNBP1 in independent European samples; however, reported risk alleles and haplotypes appear to differ between studies, and comparison among studies has been confounded because different marker sets were employed by each group. To facilitate evaluation of existing evidence of association and further work, we supplemented the extensive genotype data, available through the International HapMap Project (HapMap), about DTNBP1 by specifically typing all associated single-nucleotide polymorphisms reported in each of the studies of the Centre d'Etude du Polymorphisme Humain (CEPH)-derived HapMap sample (CEU). Using this high-density reference map, we compared the putative disease-associated haplotype from each study and found that the association studies are inconsistent with regard to the identity of the disease-associated haplotype at DTNBP1. Specifically, all five "replication" studies define a positively associated haplotype that is different from the association originally reported. We further demonstrate that, in all six studies, the European-derived populations studied have haplotype patterns and frequencies that are consistent with HapMap CEU samples (and each other). Thus, it is unlikely that population differences are creating the inconsistency of the association studies. Evidence of association is, at present, equivocal and unsatisfactory. The new dense map of the region may be valuable in more-comprehensive follow-up studies.

Alleles↗

PubMed2005

The common variant N372H in BRCA2 gene may be associated with idiopathic male infertility with azoospermia or severe oligozoospermia.

OBJECTIVE: To explore the possible association between the common single nucleotide polymorphism N372H in human breast cancer susceptibility gene 2 (BRCA2) and the idiopathic male infertility with azoospermia or severe oligozoospermia. STUDY DESIGN: The study included 240 infertile patients with idiopathic azoospermia or severe oligozoospermia and 250 fathered controls. The allele and genotype frequencies of the polymorphism N372H in BRCA2 gene were investigated in both patients and controls using denaturing high performance liquid chromatography analysis (DHPLC). RESULTS: The frequency of allele H of the polymorphism N372H in patients was significantly higher than that of the controls (23.5% versus 17.6%, OR = 1.49, 95% CI 1.06-1.97, P = 0.02) and the subjects bearing rare allele H (NH + HH) significantly increased in patients compared with controls (41.7% versus 32.4%, 95% CI 1.03-2.15, P = 0.03). CONCLUSION: The results of this study suggested that the polymorphism N372H in BRCA2 gene may be associated with idiopathic male infertility with azoospermia or severe oligozoospermia.

Chromatography, High Pressure Liquid↗

PubMed2006

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors.

Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth factor 1 (IGF-1) levels among post-menopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p = 0.02), free estradiol (p = 0.04), total testosterone (p = 0.04), free testosterone (p = 0.006) and decreased levels of sex hormone-binding globulin (p = 0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.

Black or African American↗

PubMed2001

Identification of a common variant in the lipoprotein lipase gene in a large Utah kindred ascertained for coronary heart disease: the -93G/D9N variant predisposes to low HDL-C/high triglycerides.

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage.

Aged↗

PubMed1999

Nonpathogenic common variants of IFNGR1 and IFNGR2 in association with total serum IgE levels.

Atopy is an immune disorder in which a Th2 dominant mechanism leads to high IgE levels and the clinical disorder asthma. It has been postulated that the Th1 cytokine IFNgamma, acting through its heterodimeric receptors, IFNgammaR1 and IFNgammaR2, in the induction/proliferation of Th1 cells, might suppress the Th2 responses that may underlie atopic asthma. However, neither murine nor human variants of IFNgamma associate with atopy. Several dysfunctional mutations have been identified in IFNgamma receptor genes (IFNGR1 and IFNGR2) in relation to severe and selective infections with poorly pathogenic organisms. However, little is known about common polymorphisms and their functional role in atopy. To test whether such variants of IFNGR1 and IFNGR2 relate to atopic asthma, we conducted a genetic association study in both British (n = 300) and Japanese (n = 200) populations. An intronic variant of IFNGR1 showed marginal association with total serum IgE levels in the British population compared with those with total IgE levels <30 IU/ml and those with >120-500 IU/ml [odds ratio = 2.00 (95% CI 1. 00-4.07), P = 0.048]. A coding variant, Gln64Arg of the IFNGR2, also associated with total serum IgE levels in the British population [chi(2) = 5.08, P = 0.024]. Further genetic and functional analyses are needed to clarify the role of variants of IFNgamma receptor genes in atopic immune disorder among different ethnic groups.

Asthma↗

PubMed1998

A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current.

We have cloned HERG USO, a C-terminal splice variant of the human ether-à-go-go-related gene (HERG), the gene encoding the rapid component of the delayed rectifier (IKr), from human heart, and we find that its mRNA is approximately 2-fold more abundant than that for HERG1 (the originally described cDNA). After transfection of HERG USO in Ltk- cells, no current was observed. However, coexpression of HERG USO with HERG1 modified IKr by decreasing its amplitude, accelerating its activation, and shifting the voltage dependence of activation 8.8 mV negative. As with HERG USO, HERGDeltaC (a HERG1 construct lacking the C-terminal 462 amino acids) also produced no current in transfected cells. However, IKr was rescued by ligation of 104 amino acids from the C terminus of HERG1 to the C terminus of HERGDeltaC, indicating that the C terminus of HERG1 includes a domain (</=104 amino acids) that is critical for faithful recapitulation of IKr. The lack of this C-terminal domain not only explains the finding that HERG USO does not generate IKr but also indicates a similar mechanism for hitherto-uncharacterized long QT syndrome HERG mutations that disrupt the splice site or the C-terminal. We suggest that the amplitude and gating of cardiac IKr depends on expression of both HERG1 and HERG USO.

Alternative Splicing↗

PubMed2002

Interaction between a common variant of the cholesteryl ester transfer protein gene and the apolipoprotein E polymorphism: effects on plasma lipids and lipoproteins in a cohort of 7-year-old children.

BACKGROUND AND AIM: Common variations in genes, such as apolipoprotein E (apo E) and cholesteryl ester transfer protein (CETP), are major determinants of plasma lipid and lipoprotein levels. As both apo E and CETP contribute to the reverse transport of cholesterol to the liver, the effects of variations at the CETP locus may very well interact with the apo E genotype. METHODS AND RESULTS: As part of an ongoing study, the combined effects of the apo E genotype and heterogeneity at the CETP gene locus on plasma lipids and lipoproteins were studied in a birth cohort sample of 257 Dutch prepubescent boys and girls (aged 6.7-8.1 years). The children with an apo E2E3 genotype (carrying the epsilon 2 allele; arg158-->cys) had lower concentrations of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) than those with an apo E4E3 (carrying the epsilon 4 allele; cys112-->arg) or apo E3E3 genotype (homozygous for the parent epsilon 3 allele). These associations were statistically significant in children who were homozygous (p = 0.004 for LDL; p = 0.002 for apo B) or heterozygous (p < 0.0001 for LDL and apo B) for the absence of the Taq-IB polymorphism at the CETP gene locus (B2 allele), but not in those homozygous for the presence of this variant (B1B1). The highest plasma high-density lipoprotein cholesterol (HDL-C) concentrations were observed in children with the CETP B2B2 genotype. The difference in HDL-C levels between the CETP genotype groups was statistically significant only in E2E3 carriers (p = 0.01). The LDL/HDL ratio was significantly lower in E2E3 carriers, but not when combined with a CETP B1B1 genotype. CONCLUSION: These findings indicate that the apo E genotype and heterogeneity at the CETP gene locus have an additive and interactive influence on plasma lipid and lipoprotein levels in children.

Analysis of Variance↗