European Reference Populations Research Articles

The Effect of Genome Parametrization and SNP Marker Subsetting on Genomic Selection in Autotetraploid Alfalfa.

Alfalfa, the most economically important forage legume worldwide, features modest genetic progress due to long selection cycles and the extent of the non-additive genetic variance associated with its autotetraploid genome. To improve the efficiency of genomic selection in alfalfa, we explored the effects of genome parametrization (as tetraploid and diploid dosages, plus allele ratios) and SNP marker subsetting (all available SNPs, only genic regions, and only non-genic regions) on genomic regressions, together with various levels of filtering on reading depth and missing rates. We used genotyping by sequencing-generated data and focused on traits of different genetic complexity, i.e., dry biomass yield in moisture-favorable (FE) and drought stress (SE) environments, leaf size, and the onset of flowering, which were assessed in 143 genotyped plants from a genetically broad European reference population and their phenotyped half-sib progenies. On average, the allele ratio improved the predictive ability compared with other genome parametrizations (+7.9% vs. tetraploid dosage, +12.6% vs. diploid dosage), while using all the SNPs offered an advantage compared with any specific SNP subsetting (+3.7% vs. genic regions, +7.6% vs. non-genic regions). However, when focusing on specific traits, different combinations of genome parametrization and subsetting achieved better performances. We also released Legpipe2, an SNP calling pipeline tailored for reduced representation (GBS, RAD) in medium-sized genotyping experiments.

HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank

ObjectivesHFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in...

Natural clines and human management impact the genetic structure of Algerian honey bee populations

BackgroundThe Algerian honey bee population is composed of two described subspecies A. m. intermissa and A. m. sahariensis, of which little is known regarding population genomics, both in terms of genetic differentiation and of possible contamination by exogenous stock. Moreover, the phenotypic differences between the two subspecies are expected to translate into genetic differences and possible adaptation to heat and drought in A. m. sahariensis. To shed light on the structure of this population and to integrate these two subspecies in the growing dataset of available haploid drone sequences, we performed whole-genome sequencing of 151 haploid drones.ResultsIntegrated analysis of our drone sequences with a similar dataset of European reference populations did not detect any significant admixture in the Algerian honey bees. Interestingly, most of the genetic variation was not found between the A. m. intermissa and A. m. sahariensis subspecies; instead, two main genetic clusters were found along an East–West axis. We found that the correlation between genetic and geographic distances was higher in the Western cluster and that close-family relationships were mostly detected in the Eastern cluster, sometimes at long distances. In addition, we selected a panel of 96 ancestry-informative markers to decide whether a sampled bee is Algerian or not, and tested this panel in simulated cases of admixture.ConclusionsThe differences between the two main genetic clusters suggest differential breeding management between eastern and western Algeria, with greater exchange of genetic material over long distances in the east. The lack of detected admixture events suggests that, unlike what is seen in many places worldwide, imports of queens from foreign countries do not seem to have occurred on a large scale in Algeria, a finding that is relevant for conservation purposes. In addition, the proposed panel of 96 markers was found effective to distinguish Algerian from European honey bees. Therefore, we conclude that applying this approach to other taxa is promising, in particular when genetic differentiation is difficult to capture.

Mendelian Randomization as a Tool for Cardiovascular Research

ImportanceMendelian randomization (MR) is a statistical approach that has become increasingly popular in the field of cardiovascular disease research. It offers a way to infer potentially causal relationships between risk factors and outcomes using observational data, which is particularly important in cases where randomized clinical trials are not feasible or ethical. With the growing availability of large genetic data sets, MR has become a powerful and accessible tool for studying the risk factors for cardiovascular disease.ObservationsMR uses genetic variation associated with modifiable exposures or risk factors to mitigate biases that affect traditional observational study designs. The approach uses genetic variants that are randomly assigned at conception as proxies for exposure to a risk factor, mimicking a randomized clinical trial. By comparing the outcomes of individuals with different genetic variants, researchers may draw causal inferences about the effects of specific risk factors on cardiovascular disease, provided assumptions are met that address (1) the association between each genetic variant and risk factor and (2) the association of the genetic variants with confounders and (3) that the association between each genetic variant and the outcome only occurs through the risk factor. Like other observational designs, MR has limitations, which include weak instruments that are not strongly associated with the exposure of interest, linkage disequilibrium where genetic instruments influence the outcome via correlated rather than direct effects, overestimated genetic associations, and selection and survival biases. In addition, many genetic databases and MR studies primarily include populations genetically similar to European reference populations; improved diversity of participants in these databases and studies is critically needed.Conclusions and RelevanceThis review provides an overview of MR methodology, including assumptions, strengths, and limitations. Several important applications of MR in cardiovascular disease research are highlighted, including the identification of drug targets, evaluation of potential cardiovascular risk factors, as well as emerging methodology. Overall, while MR alone can never prove a causal relationship beyond reasonable doubt, MR offers a rigorous approach for investigating possible causal relationships in observational data and has the potential to transform our understanding of the etiology and treatment of cardiovascular disease.

Vitamin A - a scoping review for Nordic nutrition Recommendations 2023.

Vitamin A refers to a group of fat-soluble compounds with retinol activity, including all-trans retinol and pro-vitamin A carotenoids. Bioactive compounds include retinal and all-trans retinoic acid with important functions in vision, immune function, growth, and development. The literature search that was performed for the current scoping review yielded a total of seven publications relevant to setting the recommended daily intake for vitamin A. In total, six publications assessed the relationship of serum retinol and/or dietary vitamin A intake with fracture risk (n = 2), cancer (n = 3), and deficiency after bariatric surgery (n = 1). One additional report by the European Food Safety Administration (EFSA) with updated average requirements was included. The outcomes-based systematic reviews and meta-analyses showed positive associations for vitamin A intake and serum retinol with risk of hip fracture. Weak or inconclusive associations were observed for cancer or obesity. One publication by EFSA with updated estimated average requirements and population reference intakes for dietary vitamin A intakes was published in 2015. The EFSA recommendations and estimated average requirements are based on a European reference population, with body weights derived from an assumed body mass index of 22, which might be too low and not representative of the Nordic and Baltic populations, and consequently resulting in lower estimated average requirements and recommendations. In conclusion, there were limited new outcomes-based data for vitamin A and health outcomes.

Abstract 13979: Titin-Truncating Variants Predispose to Dilated Cardiomyopathy in Patients Genetically Similar to African Reference Populations

Introduction: Heterozygous mutations within the TTN gene can cause the translation of shortened forms of the titin protein known as titin-truncating variants (TTNtvs) leading to dilated cardiomyopathy (DCM) among certain individuals. We previously reported an odds ratio (OR) of 18.7 for DCM among individuals genetically similar to the European reference population (EUR) with high percentage spliced in (hiPSI) TTNtvs, however we were unable to show a similar relationship among individuals genetically similar to the African reference population (AFR). Methods: Penn Medicine Biobank volunteers with whole exome sequencing were screened for TTNtvs with minor allele frequency <0.001 and percent spliced in >0.9. Participants were also screened for a DCM diagnosis defined using International Classification of Diseases, ninth and tenth revision diagnoses codes. Left ventricular ejection fraction (LVEF) values were extracted from structured transthoracic echocardiography reports. Logistic and linear regression were employed to evaluate the association between hiPSI TTNtvs and DCM or LVEF adjusting for age, sex, and first five genetic principal components. Results: Of the 43,731 participants with sequencing data, 11,136 (27.1%) were genetically similar to the AFR reference population, 50.3% were male, and the median age was 57.8 years (IQR: 44.9-69.5 years). One percent (418 individuals) had a hiPSI TTNtv. The age- and sex-adjusted OR of having DCM was similar among AFR and EUR participants carrying hiPSI TTNtvs (AFR OR: 4.37, 95% CI 2.68 to 7.13, P < 0.001; EUR OR: 5.86, 95% CI 4.58 to 7.49, P < 0.001; meta OR: 5.48, 95% CI 4.31 to 6.97, P < 0.001). Among those individuals with echocardiography data available, hiPSI TTNtvs were associated with significantly decreased minimum LVEF independent of genetic reference population similarity (EUR β: -10.08, 95% CI -12.71 to -7.44, P < 0.001; AFR β: -12.83, 95% CI -18.39 to -7.27, P < 0.001; Meta β: -10.58, 95% CI -12.96 to -8.20, P < 0.001). Conclusions: Our analysis demonstrates a strong association between hiPSI TTNtv and both DCM and minimum LVEF in diverse populations suggesting that genetic testing and counseling recommendations should not differ between these populations.

Quality of life in men with Klinefelter syndrome: a multicentre study.

Klinefelter syndrome (KS) is associated with an increased risk of lower socioeconomic status and a higher risk for morbidity and mortality, which may have a significant impact on quality of life (QOL). The objective of this study is to investigate QOL in a large European cohort of men with KS. Cross-sectional multicentre study. Two-hundred-eighteen men with KS were recruited from 14 clinical study centres in 6 European countries which participated in the European dsd-LIFE study. Male normative data from a healthy and a psychiatric reference population were used for comparison. The validated World Health Organization (WHO) QOL (WHOQOL)-BREF questionnaire was used to investigate five main domains of quality of life (WHOQOL): global, physical, psychological, environment, and social. The QOL physical domain score was lower for men with KS compared to the healthy reference population (KS: 66.9; s.d. 19.4, n = 193; healthy reference population: 76.5; s.d. 16.2, n = 1324, P < 0.001) but higher compared to the psychiatric reference population (54.6; s.d. 20.6; n = 77, P < 0.001). The WHOQOL-psychological domain score was lower for men with KS compared to the healthy reference population (KS: 63.6; s.d. 17.8, n = 193; healthy reference population: 67.8; s.d. 15.6, n = 1324, P < 0.05) but higher compared to the psychiatric reference population (45.9; s.d. 26.0), n = 77, P < 0.001). The social domain score on the WHOQOL questionnaire was found to be lower in men with Klinefelter syndrome (KS) compared to the healthy reference population (KS: 60.0; s.d. 21.6, n = 193; healthy reference population: 68.2; s.d. 13.8, n = 1324, P < 0.001). However, this score was similar to that of the psychiatric reference population (61.0; s.d. 17.0, n = 77, P = 0.5). The WHO environment domain score of men with KS (70.0; s.d. 15.0, n = 193) was similar to the healthy reference population (70.5; s.d. 20.7, n = 1324) but higher compared to the psychiatric reference population (61.9; s.d. 20.8, n = 77, P = 0.002). Experienced discrimination, less social activities, and the presence of chronic health problems were associated with significantly decreased QOL in men with KS. Overall QOL in European men with KS is significantly worse compared to a healthy European reference population. Especially, the presence of discrimination, less social activities, and chronic health problems is associated with lower physical, psychological, and social QOL. Further studies are necessary to investigate if a multidisciplinary approach may help to provide adequate counselling and psychosocial support to improve QOL.

Historical genomes elucidate European settlement and the African diaspora in Delaware

The 17th-century colonization of North America brought thousands of Europeans to Indigenous lands in the Delaware region, which comprises the eastern boundary of the Chesapeake Bay in what is now the Mid-Atlantic region of the United States.1 The demographic features of these initial colonial migrations are not uniformly characterized, with Europeans and European-Americans migrating to the Delaware area from other countries and neighboring colonies as single persons or in family units of free persons, indentured servants, or tenant farmers.2 European colonizers also instituted a system of racialized slavery through which they forciblytransported thousands of Africans to the Chesapeake region. Historical information about African-descended individuals in the Delaware region is limited, with a population estimate of less than 500 persons by 1700 CE.3,4 To shed light on the population histories of this period, we analyzed low-coverage genomes of 11 individuals from the Avery's Rest archaeological site (circa 1675-1725 CE), located in Delaware. Previous osteological and mitochondrial DNA (mtDNA) sequence analyses showed a southern group of eight individuals of European maternal descent, buried 15-20 feet from a northern group of three individuals of African maternal descent.5 Autosomal results further illuminate genomic similarities to Northwestern European reference populations or West and West-Central African reference populations, respectively. We also identify three generations of maternal kin of European ancestry and a paternal parent-offspring relationship between an adult and child of African ancestry. These findings expand our understanding of the origins and familial relationships in late 17th and early 18th century North America.

IMPLICATIONS OF CYP2D6 POLYMORPHISMS FOR THERAPEUTIC DRUG MONITORING IN PATIENTS WITH HYPERTENSION

When using therapeutic drug monitoring for evaluating non-adherence, serum concentrations of drugs are related to the actual intake, but also to pharmacokinetic variability. We aimed to map CYP2D6 polymorphisms in treated hypertensive patients and assess implications for a previous classification of adherence.Metoprolol is predominantly metabolized by CYP2D6, and is the most commonly prescribed beta-blocker in our population. Reduced metabolism can lead to increased concentrations of this drug, potentially causing more side effects and erroneous evaluation of adherence.In a multicenter study we mapped CYP2D6 polymorphisms retrospectively in 331 patients being prescribed at least 2 antihypertensive agents, already reported as adherent or non-adherent based on serum concentrations of antihypertensive drugs by mass-spectrometry (UPLC-MS/MS).The CYP2D6 panel included the non-functional variants (null) 2D6*3, 2D6*4, 2D6*5, 2D6*6, 2D6*13 and 2D6*68, and the reduced-functional variants (red) 2D6*9, 2D6*10 and 2D6*41. 2D6*2 or absence of the assayed variant alleles was interpreted as 2D6*1 (wild-type).Patients with *null/*null and absent enzyme activity were classified as poor metabolizers, and patients with *null/*wild-type or *null/*red and varied degree of reduced enzyme activity as intermediate metabolizers. Normal metabolizers included homozygote wildtype and *wildtype/*red. Patients with duplications of functional alleles, leading to increased enzyme activity, were classified as ultra-rapid metabolizers.Based on genotype, 117 patients (35.3%) were intermediate-, 21 (6.3%) were poor- and 3 (0.9%) were ultra-rapid metabolizers, comparable to the European reference population. The low frequency of ultra-rapid metabolizers did not affect the classification of non-adherence. Serum concentrations of metoprolol were related to the CYP2D6 genotype. Some (perhaps 5-10%) non-adherent patients with absent or severely reduced enzyme activity may have been misclassified as adherent; with a higher serum concentration of metoprolol due to poor metabolism rather than excellent adherence.Conclusions: In 331 hypertensive patients with a normal distribution of CYP2D6 polymorphisms, the genotype seemed to influence the serum concentration of metoprolol, but did not affect the classification of non-adherence. However, perhaps 5-10% of the non-adherent patients with reduced metabolism may have been misclassified as adherent.

Omeprazole Treatment Failure in Gastroesophageal Reflux Disease and Genetic Variation at the CYP2C Locus.

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19–82) and GerdQ score of 11 (5–17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

Polymorphism rs7214723 in CAMKK1: a new genetic variant associated with cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. CVDs have a complex etiology due to the several factors underlying its development including environment, lifestyle, and genetics. Given the role of calcium signal transduction in several CVDs, we investigated via PCR-restriction fragment length polymorphism (RFLP) the single nucleotide polymorphism (SNP) rs7214723 within the calcium/calmodulin-dependent kinase kinase 1 (CAMKK1) gene coding for the Ca2+/calmodulin-dependent protein kinase kinase I. The variant rs7214723 causes E375G substitution within the kinase domain of CAMKK1. A cross-sectional study was conducted on 300 cardiac patients. RFLP-PCR technique was applied, and statistical analysis was performed to evaluate genotypic and allelic frequencies and to identify an association between SNP and risk of developing specific CVD. Genotype and allele frequencies for rs7214723 were statistically different between cardiopathic and several European reference populations. A logistic regression analysis adjusted for gender, age, diabetes, hypertension, BMI and previous history of malignancy was applied on cardiopathic genotypic data and no association was found between rs7214723 polymorphism and risk of developing specific coronary artery disease (CAD) and aortic stenosis (AS). These results suggest the potential role of rs7214723 in CVD susceptibility as a possible genetic biomarker.

Health-related quality of life in refugee minors from Syria, Iraq and Afghanistan resettled in Sweden: a nation-wide, cross-sectional study

PurposeTo examine health-related quality of life (HRQoL) in refugee minors resettled in Sweden and compare results to a European reference population, while exploring associations between sociodemographic factors and HRQoL dimensions.MethodsA cross-sectional, nation-wide study was conducted with a stratified sample of refugee minors ages 12–15 and 16–18 from Afghanistan, Iraq and Syria, resettled in Sweden between 2014 and 2018. HRQoL was measured using KIDSCREEN-27. HRQoL dimension scores of the sample were compared to mean scores of European age and gender-matched reference population. Associations between sociodemographic factors and HRQoL dimensions were investigated with independent t tests and ANOVA. A multivariable regression analysis was performed to identify the sociodemographic factors associated with HRQoL.ResultsThe questionnaire was sent to 10,000 potential respondents. The response rate was 26%, yielding n = 2559 refugee minors (boys 55%, girls 45%) in the study sample. Compared to European references, minors in the present study had significantly lower scores of HRQoL within psychological wellbeing and peers and social support, whereas levels for autonomy and parent/guardian relations and school environment were higher. Several sociodemographic factors were significantly associated with all HRQoL dimensions, with those 16–18 years old, having average or poor family economy, and living with an unrelated adult or family reporting lower levels of HRQoL. Minors from Afghanistan had significantly lower scores of HRQoL for all dimensions compared to those from Iraq and Syria.ConclusionRefugee minors had significantly lower levels of HRQoL for psychological wellbeing and peers and social support compared to European references. Future research should further investigate this potential HRQoL gap further.

Clinical target achievement is associated with better quality of life among dialysis patients: results from a continuous quality improvement program in a Portuguese healthcare network.

Patients with kidney failure have multifaced clinical needs. Continuous quality improvement (CQI) programs initiated by large healthcare provider networks bear the promise of improving guideline adherence and improving patient-centered outcome, including health-related quality of life (HRQOL). We aimed at evaluating the association between key performance indicators (KPI) adopted for our CQI and HRQOL in a large network of dialysis providers. We conducted a survey study in 39 centers belonging to the Portuguese Fresenius Medical Care (FME) network, in September 2017. For each participant, we retrospectively extracted clinical information during the 6-month period preceding survey administration. We used this information to calculate KPI as defined by the FME-CQI policy. Those KPI were selected in the FME-CQI policy as modifiable intermediate endpoints for which previous evidence suggested a causal relationship with patients' morbidity and mortality. HRQOL was assessed by the Kidney Disease Quality of Life Short Form 36 (KDQOL-36) questionnaire. Among 4691 eligible patients who were invited to participate in the survey, 2263 (48.2%) answered the self-administered survey. Based on KPI standards, patients had 1.5 (± 1.2) off-target clinical parameters on average. KDQOL-36 score were generally higher than those observed in European reference population. We found a significant linear association between KPI parameters and HRQOL. This pattern was robust to adjustment for satisfaction scores. Our data demonstrated a graded, monotonic, dose-response relationship between the number of off-target KPIs and HRQOL. Such relationship was not mediated by patients' satisfaction and may be attributed to amelioration of disease-specific symptoms and functional capacity.

ABCG5 and ABCG8 genetic variants in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a common inherited disease characterized by elevated low-density lipoprotein cholesterol (LDL-C) plasma levels and increased cardiovascular disease risk. Most patients carry a mutation in the low-density lipoprotein receptor gene (LDLR). Common and rare variants in the genes encoding adenosine triphosphate-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) have been shown to affect LDL-C levels. The objective of this study was to investigate whether and to which extent heterozygous variants in ABCG5 and ABCG8 are associated with the hypercholesterolemic phenotype. We sequenced ABCG5 and ABCG8 in a cohort of 3031 clinical FH patients and compared the prevalence of variants with a European reference population (gnomAD). Clinical characteristics of carriers of putative pathogenic variants in ABCG5 and/or ABCG8 were compared with heterozygous carriers of mutations in LDLR. Furthermore, we assessed the segregation of one ABCG5 and two ABCG8 variants with plasma lipid and sterol levels in three kindreds. The frequencies of (likely) pathogenic LDLR, APOB, PCSK9, ABCG5, and ABCG8 variants in our FH cohort were 11.42%, 2.84%, 0.69%, 1.48%, and 0.96%, respectively. We identified 191 ABCG5 and ABCG8 variants of which 53 were classified as pathogenic or likely pathogenic. Of these 53 variants, 51 were either absent from a reference population or more prevalent in our FH cohort than in the reference population. LDL-C levels were significantly lower in heterozygous carriers of a (likely) pathogenic ABCG5 or ABCG8 variant compared to LDLR mutation carriers (6.2±1.7 vs 7.2±1.7mmol/L, P<.001). The combination of both an ABCG5 or ABCG8 variant and a LDLR variant was found not to be associated with significant higher LDL-C levels (7.8±2.3 vs 7.2±1.7mmol/L, P=.259). Segregation analysis in three families (nine carriers, in addition to the index cases, and 16 noncarriers) did not show complete segregation of the ABCG5/G8 variants with high LDL-C levels, and LDL-C levels were not different (3.9±1.3 vs 3.5±0.6mmol/L in carriers and noncarriers, respectively, P=.295), while plasma plant sterol levels were higher in carriers compared to noncarriers (cholestanol: 10.2±1.7 vs 8.4±1.6μmol/L, P=.007; campesterol: 22.5±10.1 vs 13.4±3.5μmol/L, P=.008; sitosterol: 17.0±11.6 vs 8.2±2.6μmol/L, P=.024). 2.4% of subjects in our FH cohort carried putative pathogenic ABCG5 and ABCG8 variants but had lower LDL-C levels compared to FH patients who were heterozygous carriers of an LDLR variant. These results suggest a role for these genes in hypercholesterolemia in FH patients with less severely elevated LDL-C levels. We did not find evidence that these variants cause autosomal dominant FH.

Prenatal vitamin D and cord blood insulin-like growth factors in Dhaka, Bangladesh.

Fetal growth restriction is linked to adverse health outcomes and is prevalent in low- and middle-income countries; however, determinants of fetal growth are still poorly understood. The objectives were to determine the effect of prenatal vitamin D supplementation on the insulin-like growth factor (IGF) axis at birth, to compare the concentrations of IGF-I in newborns in Bangladesh to a European reference population and to estimate the associations between IGF protein concentrations and birth size. In a randomized controlled trial in Dhaka, Bangladesh, pregnant women enrolled at 17–24 weeks of gestation were assigned to weekly oral vitamin D3 supplementation from enrolment to delivery at doses of 4200 IU/week, 16,800 IU/week, 28,000 IU/week or placebo. In this sub-study, 559 woman–infant pairs were included for analysis and cord blood IGF protein concentrations were quantified at birth. There were no significant effects of vitamin D supplementation on cord blood concentrations of IGF-I (P = 0.398), IGF-II (P = 0.525), binding proteins (BPs) IGFBP-1 (P = 0.170), IGFBP-3 (P = 0.203) or the molar ratio of IGF-I/IGFBP-3 (P = 0.941). In comparison to a European reference population, 6% of girls and 23% of boys had IGF-I concentrations below the 2.5th percentile of the reference population. IGF-I, IGF-II, IGFBP-3 and the IGF-I/IGFBP-3 ratio were positively associated with at least one anthropometric parameter, whereas IGFBP-1 was negatively associated with birth anthropometry. In conclusion, prenatal vitamin D supplementation does not alter or enhance fetal IGF pathways.

Sexuality in Males With Congenital Adrenal Hyperplasia Resulting From 21-Hydroxylase Deficiency.

PurposeAlthough sexuality has been reported to be impaired in females with congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency, sexuality in males with CAH so far has remained largely unconsidered.PatientsOne of the largest European male cohorts of patients with CAH in which sexuality in male patients with CAH was assessed.MethodsSexuality was evaluated in 91 sexually active male patients with CAH using questionnaires investigating sexual orientation, age at sexual initiation, sexual activity, satisfaction with sex life, and sexual problems, such as fears or dislike of sexual activity, lack or excessive sexual desire, difficulties getting aroused or reaching an orgasm, premature ejaculation, and no or incomplete erection.ResultsSexuality in male patients with CAH was similar to European reference populations. If sexuality problems were present, they were less frequently reported by the most severely affected CAH males. Adducing a holistic perspective, sexual problems showed substantial association to psychological problems, such as anxiety and depression.ConclusionsSexuality in male patients with CAH in general was unaffected and sexuality problems seemed to be associated in particular with psychological problems. Because sexual health is a key factor of general health, we recommend that sexuality as well as psychological issues explicitly should be addressed in health care of patients with a CAH diagnosis, independent of sex.

Assessment of Access hsTnI 99th percentiles upper reference limits following IFCC recommendations

BackgroundThe detection of an increase and/or decrease of cardiac troponin (cTnI) values, with at least one value above the 99th percentile of the upper reference limit (URL) have a central role in acute myocardial infarction (AMI) diagnosis. The employment of sex specific 99th percentile URLs and High-sensitivity (Hs) assays are recommended. We assessed sex specific 99th percentile URL for Access Hs-cTnI and AccuTnI3+ (Beckman Coulter) using European donor reference population following recent International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendations. Methods300 males and 300 females plasma samples were collected. Both chemiluminescent immunoenzymatic assays were performed on UniCel DxI 800 platform (Beckman Coulter). ResultsFor Access hsTnI, the observed sex-specific 99th percentile URLs were 5.5 (90% CI: 4.4–7.6) for females and 13.9 ng/L (90% CI: 7.4–17.4) for males. For AccuTnI+3 we could not establish them because the assay couldn't report detectable values of troponin for most of the analyzed samples. ConclusionThe sex-specific 99th percentile URLs established for Access hsTnI assay were significantly lower than those declared by the manufacturer caused by the different choice of population selection, age groups and sample types: for those reasons, we maintain the 99th URLs provided by manufacturer.

Abstract A37: Genome-wide association study of colorectal tumors in Latin American individuals from Colombia

Abstract Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide, with higher incidence among more developed countries. However, mortality rates are higher and increasing in less-developed regions, including Colombia. Incidence and mortality rates of CRC vary across the country, with the lowest rates among populations with increased concentration of Native Americans. Our group previously reported that increased European and African ancestry was associated with higher adenomatous polyps (AP) and CRC risk in Colombians. Based on this observation we hypothesize that genetic contribution to the observed regional variation on CRC development in Colombia might be partly explained by the influence of genetic variants with different frequency distribution in the European, Amerindian, and African ancestral components. Objective: To test our hypothesis we performed a genome-wide association study (GWAS) of colorectal tumors in Colombian CRC and AP cases and controls. Materials and Methods: We conducted a GWAS of Colombians from different regions of the country that included 162 CRC cases, 122 AP cases, and 131 controls. Only SNPs with MAF ≥ 0.05 were included. The role of these common variants was assessed by logistic regression models adjusted for age, sex, and the first 10 principal components (PCs) of the genetic variation. Analyses were performed for a total of 606410 SNPs. The P value threshold for genome-wide significant SNPs was set at the traditional value of ≤ 5 × 10−8. Results: We replicated some of the previously reported associations (8 out of 44 SNPs, P ≤ 0.05) of which 7 had directionally concordant ORs. Regarding the remaining 36 published risk variants, 25 had directionally concordant ORs, even though neither of them was significant at nominal P ≤ 0.05. None of the SNPs analyzed passed the threshold for genome-wide significance. However, we found multiple suggestive associations. One novel SNP within the region 2q11.2-q12 near the gene MAP4K4 was associated with the risk of AP (rs4280476-G; OR 0.36; 95% CI 0.23-0.56; P = 8.7 x 10-6). We also found four novel SNPs across three regions with suggestive CRC risk associations: rs10514122-A located in the locus 5q14 near the TBCA gene (OR 0.30; 95% CI 0.18-0.49; P = 3.6 x 10-6), rs10746883-G (OR 0.37; 95% CI 0.25-0.56; P = 3.2 x 10-6) and the rs10781032-A (OR 0.35; 95% CI 0.22-0.53; P = 1.7 x 10-6), in high LD with each other (R2 = 0.81), located in the locus 9q21.1-q21.2 near the genes TRPM3 and TMEM2 and the SNP rs2800641-G located in the region 6q25.2 near the MYCT1 gene (OR 2.96; 95% CI 1.83-4.77; P = 8.9 x 10-6). The inflation factors (λ), when comparing AP or CRC cases vs controls, were 1.05 and 1.04, respectively, indicating appropriate control for population stratification. Finally, it is of note that the MAF reported for the 5 novel SNPs identified in our study shows important differences between European, Asian, and African reference populations from the public database 1,000 genomes. Conclusions: In this GWAS of AP and CRC in individuals from Colombia, we replicated some of the previously reported associations and identified suggestive signals for 5 novel risk alleles located at four loci (2q11.2-q12, 5q14, 9q21.1-q21.2, and 6q25.2). Further work is needed to replicate our findings in other Latin American populations. Citation Format: Maria Carolina Sanabria-Salas, Laura Fejerman, Konrad Rawlik, Albert Tenesa, Martha L. Serrano-Lopez, Jovanny Zabaleta, Gustavo A. Hernandez-Suarez. Genome-wide association study of colorectal tumors in Latin American individuals from Colombia [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A37.

Abstract P101: MEGA Analysis of Alcohol Consumption: The PAGE Study

Harmful use of alcohol results in 3.3 million deaths annually and 139 million disability-adjusted life years, and is a risk factor for obesity, hypertension, cardiomyopathy, and stroke. According to the NIAAA, while some minority groups (African Americans and Hispanics) are more likely to abstain from alcohol, those who do drink have higher rates of alcohol consumption and binge drinking. In addition, most genetic studies of alcohol have focused on dependence phenotypes. In populations of European and East Asian ancestry, genes related to alcohol metabolism, including ADH and ALDH , have been identified, and AUTS2 and SLC6A1 have been associated with alcohol consumption. Studies focused on diverse populations are necessary to provide insight into population-specific genetic variability and guide precision screening and intervention efforts. We aim to further efforts in precision medicine using The Multi-Ethnic Genotyping Array (MEGA), a custom array designed to capture genetic variants in minority populations to allow for imputation to low minor allele frequencies (MAF) across ancestries, as well as clinically relevant variants and deep genotyping of previously identified GWAS regions associated with complex diseases. We performed the first discovery study for alcohol traits using MEGA genotype data in African American, Hispanic, Asian, Native Hawaiian, and Native American PAGE participants to discover novel genetic variants influencing alcohol consumption. Our preliminary results focus on non-pregnant women over 21 (N=21,641), with phenotype data on drinks/week in study-specific single variant additive regression models controlling for age, PCs, and study center. Study-specific results were then meta-analyzed in METAL. Four variants on chromosome 8 (R 2 =0.33-0.81) passed our chip-wide significance threshold of p=2.8E-8. Of these, rs115165977 showed the strongest association with drinks/week (beta=1.93, se=0.32, p=1.70E-09). This variant is monomorphic in European and East Asian reference populations, but has a MAF between 0.01-0.03 in non-Asian PAGE populations. Rs115165977 is near ZFPM2 , a gene previously associated with cardiomyopathy that codes for a transcription factor regulating GATA proteins important for heart morphogenesis. This mouse ortholog of ZFPM2 has also been associated with alcohol acceptance and alcohol-induced loss of the righting reflex. Future work will focus on analysis of alcohol consumption using PAGE imputed data in the full sample, as well as fine-mapping known alcohol-related loci typed on the MEGA chip.

Evaluation of the iPLEX® ADME PGx Pro Panel and allele frequencies of pharmacogenetic markers in Danes

ObjectivesThe iPlex® ADME PGx Pro Panel was developed to investigate 191 polymorphisms including single nucleotide polymorphisms (SNPs), insertion-deletions (INDELS), and copy number variations (CNV) relevant for absorption, distribution, metabolism, and excretion (ADME) of drugs. The purpose of this study was to perform a technical evaluation of the iPlex® ADME PGx Pro Panel by genotyping 50 unrelated Danes and estimate preliminary genotype frequencies among Danes. Design and methodsThe investigations were performed by the use of PCR, single base extension (SBE) and Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS). ResultsThe typing quality of 161 SNP assays was categorized as well performing or acceptable, whereas 22 SNP assays were categorized as either questionable or unacceptable. The frequencies of the genotypes observed in the Danish population were compared to those of the European reference population from the 1000 Genome Project. Three SNPs (rs737865, rs35167514, and rs34305973) showed statistically significantly differences between the frequencies of the 1000 Genomes Europeans and the Danes. The CNV assays could only be used as a guideline. ConclusionIn conclusion, the iPlex® ADME PGx Pro Panel is a cost-effective way of genotyping genes relevant for ADME.