French Caucasians Research Articles

Differential influence of race and environment on indeterminate reactivities to non-treponemal and treponemal antigens by immuno-chromatographic dual syphilis rapid test.

IntroductionSyphilis rapid test results may be influenced by numerous environmental and genetic factors.MethodsThe proportion of false positive syphilis non-treponemal (NT) and treponemal (T) test results using immuno-chromatographic dual syphilis rapid test on serum from Cameroonian blacks (n=103) versus French blacks (n=104) or French caucasians (n=51), all HIV-negative and free of clinical syphilis, was examined.ResultsBlack individuals in Cameroon had a significantly higher frequency of false positive NT or T tests than black individuals in France. black individuals in France had a higher frequency of indeterminate NT tests as compared to caucasians in France.ConclusionBoth racial and environmental factors may affect immuno-chromatographic dual syphilis rapid testing.

Discovery and Functional Annotation of PRSS1 Promoter Variants in Chronic Pancreatitis.

Recently, our resequencing of the promoter region of PRSS1 in French Caucasian individuals led to the identification of a functional variant (c.-204C > A) that is in perfect linkage disequilibrium with the "chronic pancreatitis (CP)-protective" PRSS1 c.-408C > T variant. Here, we extended the resequencing to 626 French Caucasians (242 idiopathic CP patients and 384 controls). We discovered three additional variants (c.-184G > A, c.-173C > T, and c.-147C > T), each being found only once in either patients or controls. We analyzed these three variants, together with a known PRSS1 promoter variant (c.-30_-28delTCC) long considered to be causative for CP, by luciferase promoter reporter assay in AR42J cells treated with dexamethasone. This analysis revealed that c.-30_-28delTCC resulted in reduced rather than increased PRSS1 gene expression, suggesting that it is not a CP risk factor as originally claimed. We provide evidence that c.-147C > T probably confers protection against CP by reducing the affinity of an ATF4 transcription factor binding site.

Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk.

It has recently been suggested that the low-frequency c.136–14_136–13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136–14_136–13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136–14_136–13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.

Association of sirtuin 1 (SIRT1) gene SNPs and transcript expression levels with severe obesity.

Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40 kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.

C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: Results from a large french cohort and meta-analysis

Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc. The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed. Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset. These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.

Arachidonic acid ω-hydroxylase CYP4A11: inter-ethnic variations in the 8590T>C loss-of-function variant

The human Cytochrome P450 4A11 (CYP4A11) is a major ω-hydroxylase involved in the regulation of blood pressure in the kidney through the conversion of arachidonic acid into 20-hydroxyeicosatetraenoic acid (20-HETE). Previous studies have reported a significant association between the 8590T>C genetic variant of CYP4A11 and hypertension. Interestingly, several population-based studies have reported ethnic differences in the prevalence of hypertension, with the highest prevalence in African populations. The aim of this work was to determine the frequency and inter-ethnic comparison of the CYP4A11 (8590T>C) functional polymorphism, in five new ethnic groups: European (99 French Caucasians), African (36 Gabonese and 50 Senegalese), South American (60 Peruvians) and North African (53 Tunisians) populations, using polymerase chain reaction-single strand conformational polymorphism and sequencing strategies. We confirmed that the CYP4A11 (8590T>C) functional polymorphism exhibits inter-ethnic frequency differences. Noteworthy, the highest 8590C allele frequency was observed in the Tunisian (30.2%), followed by Senegalese (20%) populations. In addition, the CC genotype was only found in the Gabonese and Tunisian populations (5.6% and 8.4%, respectively). These populations may be of major interest to help to clarify the linkage between hypertension and CYP4A11 (8590T>C) genotype in African populations. These findings provide data for further studies that investigate the potential association of CYP4A11 (8590T>C) variant with an incidence of hypertension genesis in respect of ethnicity.

Genetic Variability at the Six Transmembrane Protein of Prostate 2 Locus and the Metabolic Syndrome: The Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study

The six-transmembrane protein of prostate 2 (STAMP2) has been shown to be involved in insulin resistance in animal models, but in humans, its role is far from understood. Our hypothesis was that genetic variation of STAMP2 could be associated with insulin resistance phenotypes such as the metabolic syndrome (MetS) in humans. Our objective was to search for associations between STAMP2 polymorphisms and the MetS in humans. Nine single-nucleotide polymorphisms (SNPs) were tested for associations with the International Diabetes Federation-defined MetS and its constituent parameters in 5212 French Caucasians from the prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR), with a 9-yr follow-up. Methods included logistic regression and analysis of covariance adjusting for confounding variables and testing for interactions. None of the SNPs was significantly associated with the prevalence or the incidence of the MetS. The rs12386756 was marginally associated with two parameters of the MetS [triglycerides (P = 0.04) and fasting glucose (P = 0.05)]. An interaction effect between this SNP and fat intake was observed on high-density lipoprotein-cholesterol levels (P = 0.01) and systolic blood pressure (P = 0.03) that is consistent with an interrelation between STAMP2 and nutrition. Three SNPs were associated with insulin levels, but these SNPs were not associated with other features of the MetS. These findings suggest that the common polymorphisms of STAMP2 are unlikely to significantly contribute to the risk of the MetS in the general population, but relationships with insulin and interactions with fat intake need to be replicated.

417 GENETIC VARIABILITY WITHIN 8Q24 CONFERS ENHANCED RISK OF UROTHELIAL CELL CARCINOMA OF THE UPPER URINARY TRACT

You have accessJournal of UrologyUrothelial Cancer: Upper Tract Tumors1 Apr 2010417 GENETIC VARIABILITY WITHIN 8Q24 CONFERS ENHANCED RISK OF UROTHELIAL CELL CARCINOMA OF THE UPPER URINARY TRACT Morgan Roupret, Eva Comperat, Sarah Drouin, Géraldine Cancel-Tassin, Cecile Gaffory, Mathilde Sibony, Marc-Olivier Bitker, and Olivier Cussenot Morgan RoupretMorgan Roupret More articles by this author , Eva ComperatEva Comperat More articles by this author , Sarah DrouinSarah Drouin More articles by this author , Géraldine Cancel-TassinGéraldine Cancel-Tassin More articles by this author , Cecile GafforyCecile Gaffory More articles by this author , Mathilde SibonyMathilde Sibony More articles by this author , Marc-Olivier BitkerMarc-Olivier Bitker More articles by this author , and Olivier CussenotOlivier Cussenot More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.487AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently, genome-wide association studies have led to discoveries of variants in the human genome that confer risk of common diseases, including cancers. Many genes have been implicated in development of urothelial carcinomas (UC) of the bladder and notably on chromosome 8q24. Upper Urinary Tract-Urothelial Cell Carcinomas (UUT-UCCs) are very rare tumours that account for only 5% of all urothelial carcinomas. It has been demonstrated that a functional polymorphism located on allele T of rs9642880 was linked with enhanced risk of urinary bladder cancer. Therefore, the purpose of this study was to determine whether this polymorphism on the 8q24 locus is associated with enhanced susceptibility to UUT-UCC. METHODS We genotyped the constitutional DNA of 268 patients with UUT-UCC and 268 healthy controls matched for age, gender, tobacco consumption and ethnicity (population of French Caucasians). Polymorphisms at rs9642880 on chromosome 8q24, 30 kb upstream of MYC, were determined using the 5' nuclease polymerase chain reaction method, with the specific primers and probes. Frequencies were compared between cases and controls. RESULTS Genotypes were in Hardy-Weinberg equilibrium for both patient cases and healthy controls. The mean age was 68.7 for both patients and controls. The allele frequency of 8q24 rs942880 was significantly higher in UUT-TCC patients than healthy controls (p=0.03). The G/T genotype and the T/T genotype conferred a significantly higher risk of UUT-TCC (OR=2.18; 95% CI 1.28-3.69) (p=0.004). CONCLUSIONS Our results strongly suggest that a polymorphism in 8q24 rs9642880 allele is a risk factor for UUT-UCC. Our results are in line with those published previously regarding bladder tumours. This study supports the idea that there are common carcinologic pathways between urothelial tumours of the upper and of lower urinary tract. Paris, France© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e164-e165 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Morgan Roupret More articles by this author Eva Comperat More articles by this author Sarah Drouin More articles by this author Géraldine Cancel-Tassin More articles by this author Cecile Gaffory More articles by this author Mathilde Sibony More articles by this author Marc-Olivier Bitker More articles by this author Olivier Cussenot More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose

Estrogen receptor 1 (ESR1) mediates effects of estrogens on glucose homeostasis. Polymorphisms in intron 1, 2, and 4 of the ESR1 gene have been found to be associated with type 2 diabetes (T2D) in Hungarian, Chinese, and African-American and European-American cohorts. The aim of this study was to investigate the association between ESR1 polymorphisms and T2D as well as quantitative phenotypes related to glucose homeostasis in French and Swedish Caucasians. The French cohort included 941 normoglycemic controls and 988 T2D patients. The Swedish cohort consisted of 1045 controls with normal glucose tolerance, 324 participants with impaired glucose tolerance, and 276 T2D patients. A total of 20 single nucleotide polymorphisms (SNPs) distributed across the ESR1 gene were genotyped. SNPs in introns 3 and 4 of the ESR1 gene associated significantly with T2D in the French cohort (rs3020314, rs985694, P = 0.0009-0.001) and with fasting plasma glucose in Swedish men (rs9397456, rs3020314 rs3020317, P = 0.0002-0.0022) after Bonferroni correction for the analysis of 20 SNPs. In addition, nominal association of ESR1 rs1884051 (P=0.011) with T2D in the French cohort replicates a previously observed association in Finns (empirical P=0.024) (http://www.broad.mit.edu/diabetes/). This study provides further evidence that ESR1 genetic polymorphisms are associated with T2D and with fasting plasma glucose. No current evidence that the investigated SNPs are functional is present, thus, we suggest that the association between T2D and ESR1 variants may be because of other unidentified ESR1 polymorphisms that regulate glucose homeostasis.

BO-HGD survey

The prostacyclin synthase enzyme (CYP8A1, EC 5.3.99.4) is the unique member of family 8 in the cytochrome P450 superfamily. Inheritable interindividual differences in prostacyclin production may be implicated in the pathogenesis of human vascular diseases. Recently, we functionally characterized a variable number of tandem repeat (VNTR) polymorphism in the 5′-proximal regulatory region of CYP8A1. In this study, we extended the CYP8A1 VNTR polymorphism analysis using a panel of DNA samples from distinct ethnic populations: Tunisians, Gaboneses and French Caucasians. A total of nine VNTR were detected, three of which represent new variants in the CYP8A1 promoter region. Differences among the three ethnic panels in the frequency of the VNTR variants were observed.This study represents the first multi-population-based analysis of the frequency and distribution of VNTR polymorphism affecting the CYP8A1 promoter.

Association Analysis of Krüppel-Like Factor 11 Variants with Type 2 Diabetes in Pima Indians

Krüppel-like factor 11 (KLF11) is a transcription factor of the zinc finger domain family that has been shown to regulate expression of the insulin gene. An initial study reported that a KLF11 variant predicting a Q62R was associated with type 2 diabetes (T2D) in French Caucasians; however, subsequent studies have failed to identify an association between this variant and T2D in subjects from a similar Northern-European ancestry. We sought to determine whether the Q62R or other variants within KLF11 were associated with T2D in Pima Indians, a population with an extremely high prevalence of this disease. KLF11 was sequenced in 24 Pima Indians to identify potentially novel variants. There were 18 variants genotyped in a family-based sample of 1337 Pima Indians to analyze the linkage disequilibrium pattern of this gene and identify representative variants. Four representative variants were further genotyped in a population-based sample of 3501 full-heritage Pima Indians for association analyses. Among these subjects, 413 had undergone metabolic studies when they were nondiabetic to measure traits that predict T2D. Neither the Q62R nor any other common variant in KLF11 was associated with T2D in the Pima population. In addition, no variant was associated with insulin secretion or insulin-stimulated glucose disposal rate. Common variation in KLF11 variation does not appear to influence the population-based risk for developing T2D among full-heritage Pima Indians. Thus, KLF11 is unlikely to play a major role in the etiology of T2D among this Native American population.

Evaluation of the association of IGF2BP2 variants with type 2 diabetes in French Caucasians.

OBJECTIVE—We performed a comprehensive genetic association study of common variation spanning the IGF2BP2 locus in order to replicate the association of the “confirmed” type 2 diabetes susceptibility variants rs4402960 and rs1470579 in the French Caucasian population and to further characterize the susceptibility variants at this novel locus.RESEARCH DESIGN AND METHODS—We genotyped a total of 21 tagging single nucleotide polymorphisms spanning the IGF2BP2 locus in our type 2 diabetes case-control cohort comprising 3,093 French Caucasian subjects.RESULTS—IGF2BP2 variants rs4402960 and rs1470579 were not associated with type 2 diabetes in the present study (P = 0.632 and P = 0.896, respectively). Meta-analysis of genotype data from over 34,000 subjects demonstrated that our inability to replicate rs4402960/rs1470579 was consistent with the findings from several previous genome-wide association study (GWAS) datasets that were underpowered to detect this modest association signal (odds ratio [OR] 1.14). We obtained novel evidence that rs9826022, a borderline rare variant (5% minor allele frequency) in the 3′ downstream region, was associated with type 2 diabetes (P = 0.0002; OR 1.53 [95% CI 1.22–1.91]). This result was corroborated by the meta-analysis of 10,542 genotypes from the current study and GWAS datasets using both fixed (P = 9.47 × 10−6; 1.30 [1.16–1.46]) and random effects (P = 0.001; 1.30 [1.11–1.52)] calculations.CONCLUSIONS—We were unable to replicate the confirmed rs4402960/rs1470579 susceptibility variants but found novel evidence for a rare variant in the 3′ downstream region of IGF2BP2. Further genetic and functional studies are required to identify the etiological IGF2BP2 variants.

AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia

OBJECTIVE—The gene encoding the α2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia. RESEARCH DESIGN AND METHODS—The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and β-2-adrenergic receptor polymorphisms were investigated. RESULTS—The −469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or Pcorr = 0.04 and Pcorr = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study −469T>G remained significant (odds ratio 0.90 [95% CI 0.84–0.97]; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P = 0.003 and Pcorr = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post–oral glucose tolerance test serum insulin release (P = 0.02, Pcorr = 0.1 for fasting and P = 0.04, Pcorr = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol · l−1 · pmol−1 · l−1; P = 0.01, Pcorr = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations. CONCLUSIONS—Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.

Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis

Quantitative fluorescent multiplex PCR (QFM-PCR) was established in order to make possible the rapid and efficient mutational analysis of the pancreatic secretory trypsin inhibitor ( SPINK1) gene. Using QFM-PCR, a novel heterozygous deletion encompassing the entire SPINK1 gene was identified in one of nine newly recruited French Caucasian families with chronic pancreatitis. The breakpoints were fully characterized and the ∼30 kb deletion was termed c.1-15969_c.240+7702del30588bp. Whilst sequences with the potential to form non-B DNA structures were found to span both the 5′ and 3′ deletion breakpoints, the generation of this gross deletion is potentially explicable in terms of non-homologous end-joining facilitated by the presence of a 1-bp microhomology at the two ends. The SPINK1 gene deletion identified in the index patient was also detected in her affected father and paternal uncle but not in 50 healthy French Caucasians. Remarkably, in all three affected individuals, the SPINK1 deletion was found to be co-inherited with a heterozygous p.L997F missense mutation in the unlinked CFTR gene, a lesion previously reported to be associated with a variety of cystic fibrosis-related diseases including idiopathic pancreatitis. Given that the SPINK1 deletion constitutes a clear-cut disease-causing factor, it may be that the CFTR missense mutation acts as a disease modifier in the context of this particular family.

Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

Background7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits.MethodsWe screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort.ResultsWe did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort.ConclusionSGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.

Molecular analysis of the CYP2F1 gene: Identification of a frequent non-functional allelic variant

The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR–SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, * 3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer.

Association of ITGAV supports a role of angiogenesis in rheumatoid arthritis

Motivated by linkage data and the hypothesis that angiogenesis plays a functional role in rheumatoid arthritis (RA), Jacq and colleagues present a family-based, multi-stage, candidate gene association study in French and European Caucasians in a paper on the association of the ITGAV rs3738919-C variant allele with RA (C-containing genotypes: odds ratio 1.94, confidence interval 1.3 to 2.9, P = 0.002). Support comes from a recent genome-wide study, which on its own would have missed identifying the association. Further research into the associating variant will require detailed haplotype analysis, verification in further studies, and research involving intermediate phenotypes or direct functional experiments. This new RA risk factor supports the role of angiogenesis in the disease.

No contribution of angiotensin-converting enzyme (ACE) gene variants to severe obesity: a model for comprehensive case/control and quantitative cladistic analysis of ACE in human diseases

Candidate gene analyses are often inconclusive owing to genetic or phenotypic heterogeneity, low statistical power, selection of nonfunctional SNPs, and inadequate statistical analysis of the genetic architecture. Angiotensin-converting enzyme (ACE) is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Associations between body mass index (BMI) and ACE polymorphisms have been reported in general populations, but the contribution to severe obesity of this gene, which is located under an obesity genome-scan linkage peak on 17q23, is unknown. ACE is one of the most studied genes and markers responsible for variation in circulating ACE enzyme levels have been extensively characterised. Eight of these variants were genotyped in 1054 severely obese cases and 918 nonobese controls, as well as 116 nuclear families from the genome scan (n=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) after minimal correction for multiple testing. Quantitative analysis of clades and diploclades for BMI, waist-to-hip ratio, or ZBMI in children were also not significant. This rigorous, large-scale study of common, well-defined, severe polygenic obesity provides strong evidence that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with severe obesity in French Caucasians. Such a study design exemplifies the strategy needed to clearly define the contribution of the ACE gene to the plethora of complex genetic diseases where weak associations have been previously reported.

Bardet-Biedl Syndrome Gene Variants Are Associated With Both Childhood and Adult Common Obesity in French Caucasians

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity.

The PPARG Pro12Ala Polymorphism Is Associated With a Decreased Risk of Developing Hyperglycemia Over 6 Years and Combines With the Effect of the APM1 G-11391A Single Nucleotide Polymorphism

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested.