White European Ancestry Research Articles

Incidence of Late-Stage Age-Related Macular Degeneration in American Whites: Systematic Review and Meta-analysis

To estimate incidence of age-related macular degeneration (AMD) by subtype in American whites aged ≥50 years. Systematic review and meta-analysis. Prospective cohort studies of AMD incidence in populations of white European ancestry published in MEDLINE, EMBASE, and Web of Science. Fourteen publications in 10 populations that examined AMD incident cases were identified. Data on age-sex-specific incidence of late AMD, geographic atrophy (GA) and neovascular AMD (NVAMD), year of recruitment, AMD grading method, and continent were extracted. Annual incidence of late AMD, GA, and NVAMD by age-sex in American whites aged ≥50 years from a Bayesian meta-analysis of incidence studies was compared with incidence extrapolated from published prevalence estimates. Incidence rates from the review agreed with those derived from prevalence, but the latter were based on more data, especially at older ages and by AMD subtypes. Annual incidence (estimated from prevalence) of late AMD in American whites was 3.5 per 1000 aged ≥50 years (95% credible interval 2.5, 4.7 per 1000), equivalent to 293 000 new cases in American whites per year (95% credible interval 207 000, 400 000). Incidence rates approximately quadrupled per decade in age. Annual incidence GA rates were 1.9 per 1000 aged ≥50 years, NVAMD rates were 1.8 per 1000. Late AMD incidence was 38% higher in women vs men (95% credible interval 6%, 82%). Estimating AMD incidence from prevalence allows better characterization at older ages and by AMD subtype where longitudinal data from incidence studies are limited.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Abstract 47: Genetically Elevated Low-Density Lipoprotein Cholesterol is Associated with Aortic Valve Calcification and Incident Aortic Stenosis

Background: Although plasma low density lipoprotein cholesterol (LDL-C) appears to be a causative factor in animal models of aortic valve (AV) disease, randomized trials with cholesterol lowering therapies in established disease have failed to reduce progression. We sought to evaluate whether life-long genetic elevations in LDL-C, high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) are associated with AV disease. Methods: Using 144 single nucleotide polymorphisms associated with LDL-C, HDL-C or TG in genomewide association studies (GWAS), we constructed three separate genetic risk scores (GRS). We estimated the association between each GRS and (1) the presence of AV calcium determined by computed tomography in 6942 participants of white European ancestry from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium using summary level GWAS data and; (2) incidence of aortic stenosis in 28,585 participants from the Malmo Diet and Cancer Study (MDCS) over a mean follow-up time of 15.8 years. Results: The LDL-C GRS, but not the HDL-C or the TG GRS, was associated with presence of AV calcium (OR per predicted mmol/L LDL-C, 1.38 95% CI 1.09-1.74; p=0.007). The LDL-C GRS was also associated with incident aortic stenosis (HR per mmol/L LDL-C, 3.04 (1.34-6.91, p=0.008). In sensitivity analyses excluding SNPs also associated with HDL-C or TG to reduce pleiotropy, the LDL-C GRS remained associated with AV calcium (OR per predicted mmol/L LDL-C 1.39 95% CI 1.04-1.90; p=0.03) and aortic stenosis (HR per mmol/L LDL-C 3.85, 95% CI 1.37-10.79, p=0.01). Further analyses to exclude residual pleiotropic effects of HDL-C and TG, did not materially change these findings. Conclusions: Genetic predisposition to increased LDL-C is associated with presence of AV calcium and incidence of aortic stenosis, providing novel supportive evidence that LDL-C is a causal factor for the development of AV disease. Earlier intervention to reduce LDL-C merits further investigation to prevent AV disease.

Evidence That anHMGA1Gene Variant Associates with Type 2 Diabetes, Body Mass Index, and High-Density Lipoprotein Cholesterol in a Hispanic-American Population

High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans. This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI). In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047). As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency.

Association of common variants in KIF21B and ankylosing spondylitis in a Chinese Han population: a replication study

KIF21B polymorphisms were found associated with susceptibility to multiple sclerosis and ankylosing spondylitis (AS) in populations of white European ancestry. We aimed to replicate the association of polymorphisms around KIF21B and AS in a Chinese Han population. This case-control study included 665 patients with AS and 1,042 healthy controls genotyped for seven single nucleotide polymorphisms (SNPs) of KIF21B--rs12118246, rs4915464, rs502658, rs10494829, rs12089839, rs6687260, and rs957957--by TaqMan genotyping assay; statistical analyses involved the use of PLINK. We also estimated the linkage disequilibrium and haplotypes of these SNPs. Two SNPs--rs502658 (allelic p = 0.0002, odds ratio [OR] 0.60, 95 % confidence interval [95 % CI] 0.47-0.76) and rs10494829 (allelic p = 0.003, OR 1.30, 95 % CI 1.12-1.52)--were significantly associated with AS in the Chinese Han population. In addition, a linear regression test showed that they have independent contribution to disease susceptibility. For both SNPs, haplotype AT was strongly associated with AS and increased the risk of the disease (p = 0.045, OR 1.183, 95 % CI 1.004-1.395), and the genotype GC reduced the risk (p = 0.011, OR 0.715, 95 % CI 0.55-0.928). This work identified a significant association of two SNPs in KIF21B and AS in the Chinese Han population. KIF21B may play an important role in the pathogenesis of AS in the Chinese population and might be a new therapeutic target for AS.

Genetic Associations with Valvular Calcification and Aortic Stenosis

BackgroundLimited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.MethodsWe determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.ResultsOne SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10−8 and P=1.8×10−8, respectively), but the findings were not replicated consistently.ConclusionsGenetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Neurotrophic gene polymorphisms and response to psychological therapy

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR=0.60 (0.42–0.85), P=0.005). These effects remained even when other clinically relevant covariates were accounted for (OR=0.62 (0.41–0.92), P=0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions.

The complex interplay of genetic and lifestyle risk factors in type 2 diabetes: an overview.

Type 2 diabetes (T2D) is one of the scourges of modern times, with many millions of people affected by the disease. Diabetes occurs most frequently in those who are overweight or obese. However, not all overweight and obese persons develop diabetes, and there are those who develop the disease who are lean and physically active. Certain ethnicities, especially indigenous populations, are at considerably higher risk of obesity and diabetes than those of white European ancestry. The patterns and distributions of diabetes have led some to speculate that the disease is caused by interactions between genetic and obesogenic lifestyle factors. Whilst to many this is a plausible explanation, remarkably little reliable evidence exists to support it. In this review, an overview of published literature relating to genetic and lifestyle risk factors for T2D is provided. The review also describes the concepts and rationale that have motivated the view that gene-lifestyle interactions cause diabetes and overviews the empirical evidence published to date to support this hypothesis.

Gene Expression Profiling Reveals Renin mRNA Overexpression in Human Hypertensive Kidneys and a Role for MicroRNAs

The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3' untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4, and TNNT2 mRNAs and for miRNAs hsa-miR-21, hsa-miR-126, hsa-miR-181a, hsa-miR-196a, hsa-miR-451, hsa-miR-638, and hsa-miR-663. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3' untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology.

7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium

BackgroundUsing the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association...

Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population

BackgroundThe genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have...

Functional Variants of the &lt;emph type="ital"&gt;HMGA1&lt;/emph&gt; Gene and Type 2 Diabetes Mellitus

High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM). To examine the association of HMGA1 gene variants with type 2 DM. Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls. The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis. The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA. Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

Association of Variants at 1q32 and STAT3 with Ankylosing Spondylitis Suggests Genetic Overlap with Crohn's Disease

Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6×10−10, odds ratio (OR) = 0.74, 95% CI:0.68–0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6×10−4. OR = 0.86 (95% CI:0.79–0.93); rs744166, P = 2.6×10−5, OR = 0.84 (95% CI:0.77–0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2×10−5, OR = 0.65 (95% CI:0.54–0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2×10−5, OR = 0.83 (95% CI:0.76–0.91)), CDKAL1 (rs6908425, P = 1.1×10−4, OR = 0.82 (95% CI:0.74–0.91)), LRRK2/MUC19 (rs11175593, P = 9.9×10−5, OR = 1.92 (95% CI: 1.38–2.67)), and chr13q14 (rs3764147, P = 5.9×10−4, OR = 1.19 (95% CI: 1.08–1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.

Abstract A82: The FTO obesity gene and the risk of postmenopausal breast cancer among the medically underserved population in rural Pennsylvania

Abstract Purpose: Among all the established risk factors for postmenopausal breast cancer (PMBC), obesity, with 21 % risk, accounts for the largest share of potentially modifiable population attributable risk (PAR). The risk of PMBC from obesity is multifactorial and includes genetic, behavioral and environmental influences. Of all the genes associated with obesity, FTO has the highest risk (RR=1.67) and greatest PAR (&amp;gt; 20%), in the white European population. The risk of human adiposity has been associated with allele A (Adenine) in SNP rs9939609, and G (Guanine) in SNP rs1477196 and T(Thymidine) in SNP rs1861868. Central and northeastern counties in Pennsylvania (PA), of which 75% has been designates as medically underserved, is home to a relatively homogenous population of white European ancestry. This region experiences significantly above the national average age-adjusted breast cancer incidence and high prevalence of obesity. Elimination of health disparities across different segments of population is one of the objectives of the Healthy People of 2010. The notion of health disparities implies that the disease-specific risk for different sub-populations should be identified and resources should be allocated accordingly. Research on the genetic susceptibility of PMBC from obesity has been inconclusive. Therefore, we conducted a retrospective study with the primary objective of assessing prevalence of three SNPs [rs9939609, rs1861868, and rs1477196] of the FTO gene in group of women diagnosed with invasive breast cancer and their age-matched controls. Methods: The study benefits from an ongoing population-based biobanking project entitled “MyCode” at the GHS. A total of 201 women diagnosed with invasive breast cancer have donated blood samples to the project constitute the cases. Controls were 603 women with no medical history of breast cancer, who have also participated in the biobanking. SNPs have been genotyped using ABI TaqMan assays. Clinical and demographic data have been retrieved from medical records. Measures of associations were estimated using non-parametric statistics. All statistical analyses were performed using SAS v. 9.1 (SAS Institute, Cary, NC). Results: So far genotyping has been completed for a total of 50 cases and 99 controls with the mean age of 66 (±12) and 64 (±11) (P=.49) years, respectively. The difference in mean BMI between cases (32.23 ±7.23) and controls (33.52 ± 8.80) did not reach the level of statistical significance. Of the three SNPs, the SNP rs9939609 yielded a potential association with PMBC (OR= 2.04,95% CI .96-4.34, P=.0653). Conclusions: Preliminary findings suggest that one of the SNPs of FTO might increase the risk of PMBC. The FTO gene, in addition to its role in human adiposity, has been reported to encode a protein that is a member of the non-heme dioxygenase super family, involved in DNA repair pathway by reversing of alkylated damages to DNA and RNA. Discerning the association between the common SNPs of the FTO gene and PMBC offers the potential to identify at risk women that could benefit from targeted intervention strategies to reduce their risk of PMBC. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A82.

Association of the Vitamin D Metabolism Gene CYP24A1 With Coronary Artery Calcification

The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC). We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10(-6). A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.

FGF21 signalling pathway and metabolic traits – genetic association analysis

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest

BackgroundExisting studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.Methodology/Principal FindingsWe used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002–07, population ∼1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5×10−8). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10−4 and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).Conclusions/SignificanceA novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

NRG1 gene in recurrent major depression: No association in a large‐scale case–control association study

The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large-scale case-control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD.

Genetic Variants of theENPP1/PC-1Gene Are Associated With Hypertriglyceridemia in Male Subjects

Hypertriglyceridemia is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. Membrane glycoprotein PC-1 (also termed ENPP1) is a direct insulin receptor inhibitor, and certain polymorphisms of the ENPP1/PC-1 gene have been associated with insulin resistance, type 2 diabetes, obesity, and diabetic complications. We examined the effect of 3 ENPP1/PC-1 variants (K121Q, rs1044498, and IVS20delT-11, rs1799774, and A-->G+1044TGA, rs7754561) on plasma triglyceride levels in 1112 subjects of non-Hispanic American white European ancestry. Two of the ENPP1/PC-1 variants--A-->G+1044TGA (odds ratio [OR] 1.48, 95% confidence interval [CI], 1.54-1.82, P = 0.002) and IVS20delT-11 (OR 1.41, 95% CI, 1.08-1.84, P = 0.012)--were significantly associated with hypertriglyceridemia. Haplotype analyses also revealed an association with hypertriglyceridemia. In the variant analyses and in the haplotype analysis, the associations with hypertriglyceridemia were observed in male but not female subjects. Interestingly, the more widely studied K121Q ENPP1/PC-1 variant was not associated with hypertriglyceridemia in any group or subgroup analysis. In the present study, we find that genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects, and may contribute to the development of the insulin resistance/metabolic syndrome in this population.

Prediagnosis Reproductive Factors and All-Cause Mortality for Women with Breast Cancer in the Breast Cancer Family Registry

Studies have examined the prognostic relevance of reproductive factors before breast cancer diagnosis, but most have been small and their overall findings inconclusive. Associations between reproductive risk factors and all-cause mortality after breast cancer diagnosis were assessed with the use of a population-based cohort of 3,107 women of White European ancestry with invasive breast cancer (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, United States). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to breast cancer diagnosis, breastfeeding, age at menarche, and menopause and menopausal status at breast cancer diagnosis. Hazard ratios for all-cause mortality were estimated with the use of Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education, and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 and 5 years, before their breast cancer diagnosis were more likely to die. The unadjusted hazard ratio estimates were 2.75 [95% confidence interval (95% CI), 1.98-3.83; P < 0.001] and 2.20 (95% CI, 1.65-2.94; P < 0.001), respectively, and the adjusted estimates were 2.25 (95% CI, 1.59-3.18; P < 0.001) and 1.82 (95% CI, 1.35-2.46; P < 0.001), respectively. When evaluating the prognosis of women recently diagnosed with breast cancer, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.