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We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h 2 = 26.3%, 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10 -8 ) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10 -9 ) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure., Competing Interests: HS, VN, TY, JG, TP, PD, MM, EH, AM, AH No competing interests declared, (© 2024, Schurz et al.)

The prevalence and severity of SLE have been found to vary across populations of different ancestries. This review explores whether these differences can be explained by the genetic aetiology of the condition. Large genetic studies suggest that populations of different ancestry share the same risk loci but individual risk alleles are more common in some, leading to a higher prevalence and severity and an earlier onset of the condition. Despite many of the loci being shared across populations, some have been found to be ancestry specific and these are hypothesized to have undergone differential selective pressure in recent human history. Additionally, the effectiveness of some of the drugs used in SLE has been found to vary across ancestries, which might affect progression of the disease, but it is unclear whether these differences are pharmacogenetic. We concluded that to understand the full role of genetics in the risk, presentation and response to treatment of SLE, larger studies including individuals from a wider representation of ancestries will be required., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background and Purpose: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid)., Methods: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis., Results: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance ( P <5.00×10 -9 ) and 4 novel loci at genome-wide significance ( P <5.00×10 -8 ), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke ( P <3.11×10 -6 ). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2 , HDAC9 , ZFHX3 , and LRCH1 ., Conclusions: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3-7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease., (© 2021. The Author(s).)

Purpose: This study systematically reviews the distribution of racial/ancestral features and their inclusion as covariates in genetic-toxicity association studies following radiation therapy., Materials and Methods: Original research studies associating genetic features and normal tissue complications following radiation therapy were identified from PubMed. The distribution of radiogenomic studies was determined by mining the statement of country of origin and racial/ancestrial distribution and the inclusion in analyses. Descriptive analyses were performed to determine the distribution of studies across races/ancestries, countries, and continents and the inclusion in analyses., Results: Among 174 studies, only 23 with a population of more one race/ancestry which were predominantly conducted in the United States. Across the continents, most studies were performed in Europe (77 studies averaging at 30.6 patients/million population [pt/mil]), North America (46 studies, 20.8 pt/mil), Asia (46 studies, 2.4 pt/mil), South America (3 studies, 0.4 pt/mil), Oceania (2 studies, 2.1 pt/mil), and none from Africa. All 23 studies with more than one race/ancestry considered race/ancestry as a covariate, and three studies showed race/ancestry to be significantly associated with endpoints., Conclusion: Most toxicity-related radiogenomic studies involved a single race/ancestry. Individual Participant Data meta-analyses or multinational studies need to be encouraged., Competing Interests: None

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Violence and drug abuse are highly destructive phenomena found world-wide, especially in Brazil. They seem to rise proportionally to one another and possibly related. Additionally, genetics may also play a role in drug abuse. This study has focused on identifying the use of cocaine within postmortem cases arriving at the Institute of Legal Medicine of Sao Paulo as well as the presence of certain single nucleotide polymorphisms (SNPs) to better understand one's susceptibility to abuse the drug. Both hair and blood samples have been extracted through a simple methanol overnight incubation or a rapid dilute-and-shoot method, respectively. The samples were then analyzed using an UPLC-ESI-MS/MS and genotyped through RT-PCR. Statistical analyses were performed via SPSS software. From 105 postmortem cases, 53% and 51% of the cases shown to be positive for cocaine in hair and blood, respectively. Genetic wise, a significant difference has been observed for SNP rs4263329 from the BCHE gene with higher frequencies of the genotypes A/G and G/G seen in cocaine users (OR=8.91; 95%CI=1.58-50.21; p=0.01). Likewise, also SNP rs6280 from the DRD3 gene presented a significant association, with both genotypes T/C and C/C being more frequent in users (OR=4.96; 95% CI=1.07-23.02; p=0.04). To conclude, a rather high proportion of cocaine has been found, which may suggest a connotation between the use of the drug and risky/violent behaviors. Additionally, significant associations were also found within two SNPs related to cocaine use, however, due to several inherent limitations, these must be confirmed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Previous studies have evaluated the association between the phospholipase A2 m-type receptor (PLA2R1) rs4664308 polymorphism and the risk of idiopathic membranous nephropathy (IMN), but the results need to be integrated. We hypothesized that the PLA2R1 rs4664308 polymorphism is associated with IMN risk in different ethnicities and assessed this hypothesis by using meta-analysis and case-control studies.A literature searches on PLA2R1 rs4664308 and IMN risk was conducted using the EMBASE, PubMed, Cochrane Library, and Chinese Medical Databases. The relationship between PLA2R1 rs4664308 and IMN risk was evaluated in 5 genetic models, namely, allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) models. Subgroup analysis was conducted by ethnicity on Asian and non-Asian populations.Eight sets of data from 6 articles met study objectives were selected and 6797 subjects (IMN: 2324 Controls: 4,473) were included. Heterogeneity was found in the DG, HMG, and HTG models but not in the AG or RG models. The minor allele(G) of PLA2R1 rs4664308 showed a significant negative correlation with IMN risk in all genetic random models: odds ratio of AG: 0.44(0.37-0.51), RG: 0.35(0.29-0.42), DG: 0.38(0.31-0.48), HMG: 0.26(0.19-0.37), and HTG: 0.61(0.48-0.77; P < .00001), and Asians and non-Asians showed the same effect of PLA2R1 rs4664308 on IMN risk. Analysis of Asians and non-Asians revealed no publication bias in any of the 5 genetic models.The minor allele of PLA2R1 rs4664308 has a protective activity against IMN in Asians and non-Asians. It provided new insights into potential curative and preventative treatments for IMN.

Genome-wide association studies have uncovered thousands of genetic variants that are associated with a wide variety of human traits. Knowledge of how trait-associated variants are distributed within and between populations can provide insight into the genetic basis of group-specific phenotypic differences, particularly for health-related traits. We analyzed the genetic divergence levels for 1) individual trait-associated variants and 2) collections of variants that function together to encode polygenic traits, between two neighboring populations in Colombia that have distinct demographic profiles: Antioquia (Mestizo) and Chocó (Afro-Colombian). Genetic ancestry analysis showed 62% European, 32% Native American, and 6% African ancestry for Antioquia compared with 76% African, 10% European, and 14% Native American ancestry for Chocó, consistent with demography and previous results. Ancestry differences can confound cross-population comparison of polygenic risk scores (PRS); however, we did not find any systematic bias in PRS distributions for the two populations studied here, and population-specific differences in PRS were, for the most part, small and symmetrically distributed around zero. Both genetic differentiation at individual trait-associated single nucleotide polymorphisms and population-specific PRS differences between Antioquia and Chocó largely reflected anthropometric phenotypic differences that can be readily observed between the populations along with reported disease prevalence differences. Cases where population-specific differences in genetic risk did not align with observed trait (disease) prevalence point to the importance of environmental contributions to phenotypic variance, for both infectious and complex, common disease. The results reported here are distributed via a web-based platform for searching trait-associated variants and PRS divergence levels at http://map.chocogen.com (last accessed August 12, 2020)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors., Objective: We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial-ethnic populations (Whites, Blacks, Hispanics, and Asians)., Methods: We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRS TChol ), low-density lipoprotein cholesterol (GRS LDLc ), and triglycerides (GRS TG ) and lower high-density lipoprotein cholesterol (GRS HDLc )., Results: At 40 weeks' gestation, a unit increase in GRS TG was associated with 11.4 g higher fetal weight (95% confidence interval [CI] 2.8-20.0 g) among normal-weight Whites, 26.3 g (95% CI 6.0-46.6 g) among obese Blacks, and 30.8 g (95% CI 6.3-55.3 g) among obese Hispanics. Higher GRS HDLc was associated with increased fetal weight across 36 to 40 weeks among normal-weight Whites and across 13 to 20 weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40 weeks among normal-weight Hispanics. Higher GRS TChol was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids., Conclusion: Associations between fetal weight and maternal lipid GRS appear to vary by maternal race-ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth., (Published by Elsevier Inc.)

Background: To determine whether vitamin D receptor ( VDR ) gene polymorphisms are correlated with susceptibility to diabetic vascular complications. Methods: We included all eligible studies, and used Stata12.0 to calculate the pooled results. Results: Eight thousand eleven diabetic patients and 1635 normal controls from 27 studies were included. Our results showed that there was no correlation between VDR gene Taq I variants and diabetic nephropathy (DN) or diabetic retinopathy (DR) susceptibility. In comparison with diabetic patients without DN, there was a link between the VDR gene Apa I variant and DN susceptibility under allelic model ( p  = 0.029) in all populations. In addition, the VDR gene Bsm I variant correlated with DN under both dominant ( p  = 0.005) and allelic ( p  = 0.003) models in Asian populations. The VDR gene Fok I variant was also correlated with DN susceptibility under the recessive model ( p  = 0.027) in the Asian subgroup. In comparison with diabetic patients without DR, we identified a link between the VDR gene Apa I variant and DR susceptibility under the dominant model ( p  = 0.034) in all populations. Also, the VDR gene Fok I variant was correlated with DR under the recessive ( p  = 0.016), the allelic ( p  = 0.001), and the dominant ( p  < 0.001) models in all populations. When compared with healthy controls, the VDR gene Bsm I variant was associated with DR under the additive ( p  = 0.014), the allelic ( p  = 0.033), and the dominant ( p  < 0.001) models in Indian populations. Conclusions: The VDR gene Bsm I, Apa I, and Fok I gene variants are associated with DN and DR susceptibility. No association was found between the VDR gene Taq I gene variants and diabetic vascular complications.

Background: African Americans (AAs) and Hispanic/Latinos (HLs) have higher risk of obesity than European Americans, possibly due to differences in environment and lifestyle, but also reflecting differences in genetic background., Objective: To gain insight into factors contributing to BMI (in kg/m2) and obesity risk (BMI ≥ 30) among ancestry groups, we investigate the role of self-reported ancestry, proportion of genetic African ancestry, and country of birth in 6368 self-identified AA and 7569 HL participants of the New York-based BioMe Biobank., Methods: AAs and HLs are admixed populations that trace their genetic ancestry to the Americas, Africa, and Europe. The proportion of African ancestry (PAA), quantified using ADMIXTURE, was higher among self-reported AA (median: 87%; IQR: 79-92%) than among HL (26%; 15-41%) participants. Approximately 18% of AA and 59% of HL participants were non-US-born., Results: Because of significant differences between sexes (PPAA*sex interaction = 4.8 × 10-22), we considered women and men separately. Among women, country of birth and genetic ancestry contributed independently to BMI. US-born women had a BMI 1.99 higher than those born abroad (P = 7.7 × 10-25). Every 10% increase in PAA was associated with a BMI 0.29 higher (P = 7.1 × 10-10). After accounting for PAA and country of birth, the contribution of self-reported ancestry was small (P = 0.046). The contribution of PAA to higher BMI was significantly more pronounced among US-born (0.35/10%PAA, P = 0.003) than among non-US-born (0.26/10%PAA, P = 0.01) women (PPAA*sex interaction = 0.004). In contrast, among men, only US-born status influenced BMI. US-born men had a BMI 1.33 higher than non-US-born men, whereas PAA and self-reported ancestry were not associated with BMI. Associations with obesity risk were similar to those observed for BMI., Conclusions: Being US-born is associated with a substantially higher BMI and risk of obesity in both men and women. Genetic ancestry, but not self-reported ancestry, is associated with obesity susceptibility, but only among US-born women in this New York-based population., (Copyright © American Society for Nutrition 2019.)

The endoplasmic reticulum aminopeptidases (ERAPs), ERAP1 and ERAP2, makes a role in shaping the HLA class I peptidome by trimming peptides to the optimal size in MHC-class I-mediated antigen presentation and educating the immune system to differentiate between self-derived and foreign antigens. Association studies have shown that genetic variations in ERAP1 and ERAP2 genes increase susceptibility to autoimmune diseases, infectious diseases, and cancers. Both ERAP1 and ERAP2 genes exhibit diverse polymorphisms in different populations, which may influence their susceptibly to the aforementioned diseases. In this article, we review the distribution of ERAP1 and ERAP2 gene polymorphisms in various populations; discuss the risk or protective influence of these gene polymorphisms in autoimmune diseases, infectious diseases, and cancers; and highlight how ERAP genetic variations can influence disease associations., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To examine associations of HLA class I and class II alleles with ankylosing spondylitis (AS) in three cohorts of patients of European, Asian and African ancestry., Methods: HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 alleles were genotyped in 1948 unrelated white and 67 African-American patients with AS from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, the North American Spondylitis Consortium and Australo-Anglo-American Spondyloarthritis Consortium, 990 white and 245 African-American Controls and HLA-B alleles in 442 Han Chinese patients with AS and 346 controls from Shanghai and Gansu, China. In addition to the case:control analyses, HLA-B*27 -negative patients with AS were analysed separately, and logistic regression and 'relative predispositional effects' (RPE) analyses were carried out to control for the major effect of HLA-B*27 on disease susceptibility., Results: Although numerous associations were seen between HLA alleles and AS in whites, among HLA-B*27-negative patients with AS , positive associations were seen with HLA-A*29, B*38, B*49, B*52, DRB1*11 and DPB1*03:01 and negative associations with HLA-B*07, HLA-B*57, HLA-DRB1*15:01, HLA-DQB1*02:01 and HLA -DQB1*06:02 . Additional associations with HLA-B*14 and B*40 (B60) were observed via RPE analysis, which excludes the HLA-B*27 alleles. The increased frequency of HLA-B*40:01 and decreased frequency of HLA-B*07 was also seen in Han Chinese and African-Americans with AS. HLA-B*08 was decreased in whites with acute anterior uveitis., Conclusions: These data, analysing the largest number of patients with AS examined to date in three ethnic groups, confirm that other HLA class I and II alleles other than HLA-B*27 to be operative in AS predisposition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Previous research has provided evidence of a hereditary predisposition for anterior cruciate ligament (ACL) injury. The purpose of this study was to evaluate the association between ancestral population genetics and risk of non-contact ACL injuries., Methods: Blood samples were collected from 177 individuals with a history of non-contact ACL injury and 556 non-injured control individuals for analysis of the genetic material through the use of a panel of 48 INDELs ancestry genetic markers from three ancestral origins., Results: Among patients with non-contact ACL injury, 82% were male and 18% were female. In the control group, 78% were male, and 22% were female. The mean age of the non-contact ACL injury group was 31.7 years (± 10.2), and the control group was 33.8 years (± 13.2). The individual genetic contribution from INDELs of each ancestral origin varied considerably: ranging between 1.5-94.8% contribution for INDELs of African origin (mean of 21.4% of INDELs); between 2 and 96.1% contribution for INDELs of European origin (mean of 66.7% of INDELs); and between 1.3-96.4% contribution for INDELs of Amerindian origin (mean of 11.7% of INDELs). When comparing paired subjects from the non-contact ACL and control groups, the genetic analysis showed that the European ancestry score was higher in the non-contact ACL group than control group (0.70 ± 0.21 vs 0.63 ± 0.22 respectively, p < 0.001), whereas African ancestry scores (ACL group 0.18 ± 0.18 vs control group 0.24 ± 0.21, p < 0.001) and Amerindian ancestry scores (ACL group 0.11 ± 0.09 vs control group 0.12 ± 0.10, n.s.) were lower among the non-contact ACL group than in controls., Conclusion: European INDELs markers were found to represent a potential genetic predisposition for non-contact ACL injuries when compared to African and Amerindian INDELs. This study has the potential to correlate a measurable and distinct genetic marker with risk of a non-contact ACL injury. Thus, it increases knowledge base and volume of molecular and genetical factors associated with this pathology. Furthermore, this study provides guidance and evidence for the development of genetic risk-screening panels for non-contact ACL injury., Level of Evidence: Level III Diagnostic Study.

PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

Background: Pathogens exert selective pressure which may lead to substantial changes in host immune responses. The human complement receptor type 1 (CR1) is an innate immune recognition glycoprotein that regulates the activation of the complement pathway and removes opsonized immune complexes. CR1 genetic variants in exon 29 have been associated with expression levels, C1q or C3b binding and increased susceptibility to several infectious diseases. Five distinct CR1 nucleotide substitutions determine the Knops blood group phenotypes, namely Kna/b, McCa/b, Sl1/Sl2, Sl4/Sl5 and KCAM+/-., Methods: CR1 variants were genotyped by direct sequencing in a cohort of 441 healthy individuals from Brazil, Vietnam, India, Republic of Congo and Ghana., Results: The distribution of the CR1 alleles, genotypes and haplotypes differed significantly among geographical settings (p≤0.001). CR1 variants rs17047660A/G (McCa/b) and rs17047661A/G (Sl1/Sl2) were exclusively observed to be polymorphic in African populations compared to the groups from Asia and South-America, strongly suggesting that these two SNPs may be subjected to selection. This is further substantiated by a high linkage disequilibrium between the two variants in the Congolese and Ghanaian populations. A total of nine CR1 haplotypes were observed. The CR1*AGAATA haplotype was found more frequently among the Brazilian and Vietnamese study groups; the CR1*AGAATG haplotype was frequent in the Indian and Vietnamese populations, while the CR1*AGAGTG haplotype was frequent among Congolese and Ghanaian individuals., Conclusion: The African populations included in this study might have a selective advantage conferred to immune genes involved in pathogen recognition and signaling, possibly contributing to disease susceptibility or resistance.

The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing 'black versus white'), individuals of African ancestry have a globally increased risk of malignancies compared with Caucasians and Asian Americans. Differences in socioeconomic status and health-care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable lifestyles and socioeconomic status as African Americans (Hispanic paradox) points to the concomitant importance of genetic determinants. Here, we overview the molecular basis of racial disparity in cancer susceptibility ranging from genetic polymorphisms and cancer-driver gene mutations to obesity, chronic inflammation, and immune responses. We discuss implications for race-adapted cancer screening programs and clinical trials to reduce disparities in cancer burden., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed., Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer., Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05-2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03-3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21-0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data., Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression., (©2015 American Association for Cancer Research.)

In the past ten years, there has been an expansion of scientific interest in population genetics linked to both understanding histories of human migration and the way that population difference and diversity may account for and/or be implicated in health and disease. In this article, I examine how particular aspects of a globalizing research agenda related to population differences and genetic ancestry are taken up in locally variant ways in the nascent field of Brazilian cancer genetics. Drawing on a broad range of ethnographic data from clinical and nonclinical contexts in the south of Brazil, I examine the ambiguities that attention to genetic ancestry generates, so revealing the disjunctured and diverse ways a global research agenda increasingly orientated to questions of population difference and genetic ancestry is being used and reused.

A 56-bp variable number of tandem repeat polymorphism is confirmed in intron 4 of the human deoxyribonuclease I (DNase I) gene (HumDN1). The purpose of the present study was to document global ethnic variations of allelic frequencies in HumDN1 VNTR polymorphisms. In this study, HumDN1 VNTR polymorphisms in 11 worldwide populations were examined by polymerase chain reaction and compared with those reported previously. Fifteen genotypes were identified in these 11 populations. Novel genotypes were found: 1/2 was observed in Ghanaians and mestizos, 3/6 was in Tamangs, 4/6 was in Tibetans and Nahuas, 6/6 was in Sinhalese. The African population showed the highest frequency for the HumDN1(∗)3 allele. Among Asian populations, the different genotype distribution was observed. The predominant allele in Mongolian, Korean, Japanese, and Chinese populations was HumDN1(∗)3, followed by HumDN1(∗)4, and then HumDN1(∗)5. In Chinese from South China, Tamangs, and Sinhalese, HumDN1(∗)4 and HumDN1(∗)5 were predominant. The allele frequency for HumDN1(∗)4 was high in three Mexican populations, but a significant difference was observed between Nahuas and Huicoles. Germans and Turks showed a similar distribution. This study is the first to show the existence of a certain genetic heterogeneity in the worldwide distribution of HumDN1 VNTR polymorphism., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: In Qataris, a population characterized by a small size and a high rate of consanguinity, between two-thirds to three-quarters of adults are overweight or obese. We investigated the relevance of 23 obesity-related loci in the Qatari population., Methods: Eight-hundred-four individuals assessed to be third generation Qataris were included in the study and assigned to 3 groups according to their body mass index (BMI): 190 lean (BMI < 25 kg/m(2)); 131 overweight (25 kg/m(2) ≤ BMI < 30 kg/m(2)) and 483 obese (BMI ≥ 30 kg/m(2)). Genomic DNA was isolated from peripheral blood and genotyped by TaqMan., Results: Two loci significantly associated with obesity in Qataris: the TFAP2B variation (rs987237) (A allele versus G allele: chi-square = 10.3; P = 0.0013) and GNPDA2 variation (rs10938397) (A allele versus G allele: chi-square = 6.15; P = 0.013). The TFAP2B GG genotype negatively associated with obesity (OR = 0.21; P = 0.0031). Conversely, the GNDPA2 GG homozygous genotype associated with higher risk of obesity in subjects of age < 32 years (P = 0.0358)., Conclusion: We showed a different genetic profile associated with obesity in the Qatari population compared to Western populations. Studying the genetic background of Qataris is of primary importance as the etiology of a given disease might be population-specific.

Background: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest., Objective: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children., Methods: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry., Results: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively)., Conclusion: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The interleukin (IL)-1β-511 C/T polymorphism has been shown to be functional and to contribute to the risk of gastric cancer. However, the relationship between the IL-1β-511 C/T polymorphism and gastric carcinogenesis remains inconclusive. A systematical electronic search was conducted of the MEDLINE, EMBASE, and CENTRAL databases. A random and a fixed effects model were exploited to estimate summary odds ratios and 95 % confidence intervals. Subgroup and sensitivity analyses were carried out with respect to ethnicity, quality assessment scores, control sources, genotyping methods, cancer histopathology and location, and Helicobacter pylori (H. pylori) infection. A total of 45 studies containing 9,066 cases of gastric cancer and 11,192 control subjects satisfied the inclusion criteria. The IL-1β-511 C/T polymorphism was found to enhance the risk of stomach cancer for overall and HWE-satisfying studies. Asians showed a positive relationship in both the overall and HWE-satisfying groups, whereas Caucasians did not. Based on subgroup analysis, H. pylori infection and genotype analysis using PCR-RFLP methods increase the association between IL-1β-511 T allele carrier and risk of stomach cancer. A positive relationship was found between the IL-1β-511 C/T SNP and stomach carcinoma susceptibility, and the results suggest that Asian ethnicity, H. pylori infection and methodologically, PCR-RFLP genotyping strengthen this relationship. Reflecting on prevalence of H. pylori in Asian countries, additional studies on the IL-1β-511 C/T SNP in the context of ethnicity and H. pylori infection may provide key insights into the mechanism underlying gastric cancer carcinogenesis. It was found PCR-RFLP is the most reliable genotyping method, and thus, it is recommendable to adopt it to determine the presence of the IL-1β-511 C/T SNP.

The aim of the present study was to integrate all the eligible studies and investigate whether the transforming growth factor-β1 (TGF-β1) gene polymorphisms (TGF-β1 T869C and TGF-β1 T29C) are correlated with postmenopausal osteoporosis (PMOP) risk. PMOP is a common skeletal disease and several genetic factors play an important role in the development and progression of PMOP. Significant associations between TGF-β1 gene polymorphisms (TGF-β1 T869C and TGF-β1 T29C) and PMOP risk have been reported; however, some of these results are controversial. A systematic online search was performed using PubMed, EMBASE, Web of Science, and the Cochrane Library to identify case-control studies investigating the relationship between TGF-β1 T869C and TGF-β1 T29C polymorphisms and the susceptibility of PMOP. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study populations. Eight studies involving 1851 cases and 2247 controls met the inclusion criteria after assessment by 2 reviewers. Overall, there were significant associations between TGF-β1 T869C and TGF-β1 T29C polymorphisms and PMOP (TGF-β1 T869C—C vs T: OR = 1.18, 95% CI = 1.02-1.36, P = 0.030; CC vs TT: OR = 1.38, 95% CI = 1.01-1.88, P = 0.042; CC vs, Ct/tt: OR = 1.39, 95% CI = 1.09-1.76, P = 0.008; TGF-β1 T29C—CT vs TT: OR = 1.25, 95% CI = 1.02-1.53, P = 0.032; CT/CC vs TT: OR = 1.37, 95% CI = 1.02-1.84, P = 0.035). In the subgroup analysis of ethnicity, significant association was observed between TGF-β1 T869C polymorphism and PMOP risk in Asian population (C vs T: OR = 1.18, 95% CI = 1.01-1.38, P = 0.043; CC vs TT: OR = 1.41, 95% CI = 1.01-1.97, P = 0.047; CT/CC vs TT: OR = 1.31, 95% CI = 1.03-1.66, P = 0.026; CC vs, Ct/tt: OR = 1.35, 95% CI = 1.03-1.75, P = 0.028); however, there was no significant association between TGF-β1 T869C polymorphism and PMOP risk in Caucasian population. With regard to TGF-β1 T29C polymorphism, significant association was also observed in Asian population (CT vs TT: OR = 1.37, 95% CI = 1.07-1.75, P = 0.013; CT/CC vs TT: OR = 1.54, 95% CI = 1.16-2.05, P = 0.003), while there was no significant association in Caucasian population. The TGF-β1 T869C and TGF-β1 T29C polymorphisms may be involved in susceptibility to PMOP, particular in Asian patients.

Endothelial nitric oxide synthase (eNOS) is the catalyst of endothelial nitric oxide (NO) synthesis. Polymorphisms in the eNOS gene may influence the risk of intracranial aneurysm (IA), but the results of existing researches are still inconsistent. Thus, we performed the present meta-analysis to derive a more precise estimation between eNOS polymorphisms (T786C, G894T, 27-bp-variable number of tandem repeat [VNTR]) and IA risk. Case-control studies evaluating the association between the eNOS polymorphisms and IA risk were searched in PubMed, Ovid & Embase, Web of Science, and Chinese Wanfang datasets with the last search up to July 15, 2014. The pooled odds ratios (ORs) for the association between eNOS polymorphisms and IA and their corresponding 95% confidence intervals (CIs) were estimated using the random or fixed-effects model. Finally, 10 studies for T786C polymorphism (1819 cases and 1893 controls), 9 studies for G894T polymorphism (1393 cases and 1508 controls), and 7 studies for 27-bp-VNTR polymorphism (1281 cases and 1406 controls) were included in the meta-analyses. In the overall analysis, no evidence of association between eNOS polymorphisms and susceptibility of IA was found. When subgrouped by race descent, significantly increased risk was detected among Asians for T786C polymorphism (heterozygous comparison of codominant model: OR = 1.294, 95% CI = 1.025-1.634; dominant model: OR = 1.277, 95% CI = 1.019-1.600), but not in Caucasians or the other 2 polymorphisms. Our meta-analysis suggested that T786C polymorphism was associated with increased risk of IA among Asians, whereas G894T and 27-bp-VNTR polymorphisms might have no influence on the susceptibility of IA.

The multifunctional cytokine tumor necrosis factor alpha (TNF-α) plays an important role in cell proliferation, differentiation, apoptosis, lipid metabolism, and endothelial function. To date, many studies have evaluated the association between the TNF-α -308G> A polymorphism and breast cancer risk; however, the results remain ambiguous and inconclusive. To derive a more precise estimation of the association and assess its strength, we carried out a meta-analysis of 20 published case-control studies with 12,360 cases and 15,110 controls using crude odd ratios (ORs) with 95 % confidence intervals (CIs). Overall, no significant associations were found for all genetic models (allele model OR = 1.06, 95 % CI 0.90-1.24, P heterogeneity < 0.001; homozygous model OR = 1.25, 95 % CI 0.85-1.82, P heterogeneity < 0.001; recessive model OR = 1.26, 95 % CI 0.88-1.82, P heterogeneity = 0.001; dominant model OR = 1.00, 95 % CI 0.85-1.18, P heterogeneity < 0.001). Moreover, no significant associations were observed when stratified by ethnicity, control source, genotyping method, or Hardy-Weinberg equilibrium status. However, in the menopausal status subgroup, significantly decreased breast cancer risks were found among postmenopausal women (allele model OR = 0.90, 95 % CI 0.83-0.98; dominant model OR = 0.89, 95 % CI 0.81-0.98), while the TNF-α -308 AA genotype was a breast cancer risk factor in premenopausal women (homozygous model OR = 4.38, 95 % CI 1.44-13.36; recessive model OR = 4.43, 95 % CI 1.47-13.42). This meta-analysis indicated that the TNF-α -308G> A polymorphism is not associated with breast cancer risk in the overall population but that the A allele may be a protective factor for breast cancer in postmenopausal women, and the AA genotype may be a breast cancer risk factor in premenopausal women.

Recently, several molecular epidemiological studies have focused on the association between pri-miR-34b/c rs4938723 SNP and the susceptibility to different cancers. Due to the controversial rather than conclusive results, we performed this meta-analysis to assess more precise and comprehensive conclusion about the association. Data published until July 2014 were collected from PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Data, Chinese BioMedical Literature Database, and VIP database of Chinese Journal. Ultimately, 13 articles with a total of 7,753 cases and 8,014 controls were considered eligible for inclusion. The odds ratio (OR) and its 95 % confidence interval (95%CI) were used to assess the strength of association. In the overall analysis, a significant association between pri-miR-34b/c rs4938723 polymorphism and increased cancer susceptibility was found in heterozygous model (TC vs. TT: OR = 1.148, 95%CI 1.034-1.275, P = 0.010) and dominant model (CC + TC vs. TT: OR =1.166, 95%CI 1.028-1.322, P = 0.017). In subgroup analysis of ethnicity, pri-miR-34b/c rs4938723 polymorphism was significantly associated with an increased cancer susceptibility for Asian population in heterozygous model (TC vs. TT: OR = 1.169, 95%CI 1.031-1.326, P = 0.015) and dominant model (CC + TC vs. TT: OR = 1.185, 95%CI 1.017-1.382, P = 0.030), whereas no significant association for Caucasian population was observed in any genetic models. Intriguingly, stratified analysis revealed opposite results that pri-miR-34b/c polymorphism contributed to susceptibility to hepatocellular carcinoma while reduced susceptibility to colorectal cancer and esophageal squamous cell cancer in Asians. Considering some limitation of our meta-analysis, future well-designed case-control studies with larger sample sizes are required to confirm our findings.

This article examines how race and ancestry are taken up in gene-environment interaction (GEI) research on complex diseases such as heart disease, diabetes, and cancer. Using 54 in-depth interviews of 33 scientists and over 200 hours of observation at scientific conferences, we explore how GEI researchers use and interpret race, ethnicity, and ancestry in their work. We find that the use of self-identified race and ethnicity (SIRE) exists alongside ancestry informative markers (AIMs) to ascertain genetic ancestry. Our participants assess the utility of these two techniques in relative terms, downplaying the accuracy and value of SIRE compared to the precision and necessity of AIMs. In doing so, we argue that post-genomic scientists seeking to understand the interactions of genetic and environmental disease determinants actually undermine their ability to do so by valorizing precise characterizations of individuals' genetic ancestry over measurement of the social processes and relations that differentiate social groups., (© American Sociological Association 2014.)

It has been suggested that hOGG1 Ser326Cys polymorphism may be a risk factor for colorectal cancer. Published data on its association with colorectal cancer generated contradictory results; thus, we performed an updated meta-analysis of eligible published studies to estimate the effect of hOGG1 Ser326Cys polymorphism on colorectal cancer susceptibility. We reviewed many abstracts and finally included 18 eligible case-control studies comprising 5235 cases and 8438 controls. We pooled data with a fixed or random-effect model. Subgroup analysis by ethnicity was also performed. The overall data indicated a significant association of hOGG1 Ser326Cys polymorphism on colorectal cancer risk (allele model OR = 1.14, 95 %CI 1.02-1.27; homozygote model OR = 1.32, 95 %CI 0.92-1.92; recessive model OR = 1.12, 95 %CI 1.00-1.26; dominant model OR = 1.15, 95 %CI 1.00-1.32). Furthermore, in the subgroup analysis by ethnicity, increased cancer risk was observed among Caucasians under the allele, heterogeneity, recessive, and dominant models (allele model OR = 1.23, 95 %CI = 1.05-1.44; homozygote model OR = 1.49, 95%CI 1.05-2.12; recessive model OR = 1.40, 95 %CI 1.16-1.69; dominant model OR = 1.21, 95 %CI = 1.12-1.45). In summary, the present meta-analysis suggested that hOGG1 Ser326Cys polymorphism might modify the susceptibility to colorectal cancer among the total population, especially among Caucasians.

The purpose of this study was to examine whether the insertion (I) or deletion (D) polymorphism of the angiotensin-converting enzyme gene (ACE) is associated with susceptibility to systemic sclerosis (SSc). A meta-analysis examining the associations between the ACE I/D polymorphism and SSc was conducted in overall and European populations using 1) allelic contrast (D vs I); 2) recessive (DD vs ID + II); 3) dominant (DD + ID vs II); and 4) additive (DD vs ID vs II) models. A total of 7 studies consisting of 837 cases and 754 controls were available for meta-analysis. The meta-analysis revealed no association between the D allele and SSc in any study subjects [odds ratio (OR) = 0.956, 95% confidence interval (CI) = 0.733-1.246, P = 0.737]. Stratification by ethnicity indicated no association between the D allele of the ACE I/D polymorphism and SSc in Europeans (OR = 1.117, 95%CI = 0.776-1.607, P = 0.551). Meta-analysis using all other genetic models showed the same D allele pattern in the overall and European groups. This meta-analysis showed that the ACE I/D polymorphism was not associated with susceptibility to SSc in the study subjects and in Europeans.

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, is highly involved in the activation and coordination of the anti-mycobacterial immune response. We performed a meta-analysis to assess the association between TIRAP C539T polymorphism and tuberculosis (TB) risk., Methods: A systematic literature search for relevant studies up to February 27, 2014 was conducted in PUBMED, EMBASE, Web of science, CNKI, VIP, and Wanfang database. The association between gene and disease was assessed using odds ratios (ORs) with 95% confidence intervals (95%CIs) based on five genetic models., Results: A total of 16 qualified studies were enrolled in this meta-analysis. The results of pooling all studies detected statistically resistance of TIRAP C539T mutants to TB risk (T vs. C: OR 0.80, 95%CI 0.65-0.97; TC vs. CC: OR 0.71, 95%CI 0.55-0.92; TT+TC vs. CC: OR 0.74, 95% CI 0.58-0.94). Further subgroup analyses by ethnicity also demonstrated reduced risk of TB in European population (T vs. C: OR 0.71, 95%CI 0.52-0.95; TC vs. CC: OR 0.56, 95%CI 0.35-0.91; TT+TC vs. CC: OR 0.61, 95%CI 0.40-0.92), whereas no such effects were observed in other ethnicities., Conclusion: This present meta-analysis suggests TIRAP C539T polymorphism is significantly correlated with reduced risk of TB infection, with stronger effect in European. Additional well-designed, larger-scale epidemiological studies among different ethnicities are needed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Fitzpatrick skin phototype (FSPT) is the most common method used to assess sunburn risk and is an independent predictor of skin cancer risk. Because of a conventional assumption that FSPT is predictable based on pigmentary phenotypes, physicians frequently estimate FSPT based on patient appearance., Objective: We sought to determine the degree to which self-reported race and pigmentary phenotypes are predictive of FSPT in a large, ethnically diverse population., Methods: A cross-sectional survey collected responses from 3386 individuals regarding self-reported FSPT, pigmentary phenotypes, race, age, and sex. Univariate and multivariate logistic regression analyses were performed to determine variables that significantly predict FSPT., Results: Race, sex, skin color, eye color, and hair color are significant but weak independent predictors of FSPT (P<.0001). A multivariate model constructed using all independent predictors of FSPT only accurately predicted FSPT to within 1 point on the Fitzpatrick scale with 92% accuracy (weighted kappa statistic 0.53)., Limitations: Our study enriched for responses from ethnic minorities and does not fully represent the demographics of the US population., Conclusions: Patient self-reported race and pigmentary phenotypes are inaccurate predictors of sun sensitivity as defined by FSPT. There are limitations to using patient-reported race and appearance in predicting individual sunburn risk., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

This article discusses the clinical utility of genomic information for personalized preventive care of a healthy adult. Family health history is currently the most applicable genomic predictor for common, multifactorial diseases, and can also show patterns that suggest an inherited high susceptibility to a particular form of cancer or other disease. Both bloodline ancestry and shared environmental factors are important predictors for many disease states. DNA and family history analyses give information that is probabilistic, not deterministic. Therefore, family history can highlight behavioral, social, or cultural risk factors that can be modified to prevent diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The aim of our meta-analyses is to test the association between six genetic polymorphisms and gastric cancer., Methods: A systematic search was performed for all the available candidate genes and gastric cancer among several online databases including PubMed, Embase, Web of Science, the Cochrane Library, CNKI and Wanfang online libraries. After a comprehensive screening, a total of six genes were harvested for the current meta-analyses. These genes include TLR2 (-196 to -174 ins>del), MTR (rs1805087), MTRR (rs1801394), XPC (rs2228001), TP73 (G4C14-A4T14), and TP53 (rs1042522)., Results: Altogether 49 comparative studies among 11 776 cases and 18 633 controls were involved in our meta-analyses. TP53 rs1042522 polymorphism was shown to be associated with gastric cancer risk under the dominant model (P=0.02, OR=1.03, 95% CI=1.00-1.05). A subgroup meta-analysis indicated a significant association under dominant model between TP53 rs1042522 and gastric cancer in the Eastern Asians (P=0.03, OR=1.17, 95%=1.02-1.34)., Conclusions: These results suggest that TP53 rs1042522 polymorphism might contribute to the susceptibility of gastric cancer under the dominant model, especially in Eastern Asians., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10(-7) for BMI, 1.80×10(-6) for FM, and 5.29×10(-4) for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10(-3) to 4.94×10(-2)). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.

We conducted a meta-analysis of case-control studies to determine whether SELP genetic polymorphisms contribute to the pathogenesis of coronary heart disease (CHD) and myocardial infarction (MI). A range of electronic databases were searched: MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and the Chinese biomedical database (1982-2013) without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. Nine case-control studies with a total of 3,154 CHD patients, 1,608 MI patients and 17,304 healthy controls were involved in this meta-analysis. Six common polymorphisms in the SELE gene were assessed, including -1969G/A (rs1800805 G>A), -1817T/C (rs1800808 T>C), -2123C/G (rs1800807 C>G), Thr715Pro (rs6136 A>C), Leu599Val (rs6133 G>T), and Ser290Asn (rs6131 C>T). Our findings illustrated significantly positive associations of SELE genetic polymorphisms with the development of CHD and MI. The results of subgroup analysis by SNP type indicated that -1969G/A, -1817T/C, -2123C/G, Thr715Pro and Ser290Asn in the SELP gene might be strongly correlated with CHD and MI risk, but no similar results were found in SELP Leu599Val polymorphism. In the subgroup analysis by ethnicity, our results indicated significant relationships between SELE genetic polymorphisms and the pathogenesis of CHD and MI among Asians and Caucasians. However, we observed no significant associations between SELP genetic polymorphisms and the risk of CHD and MI among Africans. Our findings provide empirical evidence that SELE genetic polymorphisms may contribute to the pathogenesis of CHD and MI, especially among Asians and Caucasians. Thus, SELP genetic polymorphisms could be potential and practical biomarkers for early diagnosis of CHD and MI.

Background and Objective: X-ray repair cross-complementing group 3 (XRCC3) is responsible for maintaining the integrity of the genome, playing a critical role in protecting it against mutations which lead to cancer. Polymorphisms at exons 7 of the XRCC3 gene may alter the XRCC3 repair efficiency. The aim of this study is to derive a precise estimation of the relationship between XRCC3 Thr241Met polymorphism and gastric cancer (GC) risk., Methods: Two investigators independently searched the databases of Pubmed, EMBASE and China National Knowledge Infrastructure (CNKI) up to May 15, 2013. Odds ratio (OR) and 95% confidence intervals (CI) for XRCC3 Thr241Met polymorphism and GC were calculated in a fixed- or random- effects model depending on statistical heterogeneity., Results: This meta-analysis included 9 case-control studies, which included 2209 cases and 3269 controls. Overall, the combined results based on all studies indicated that there was no association between XRCC3 Thr241Met polymorphism and GC susceptibility for all genetic models. When stratifying for race, we found the 241Met/Met genotype carriers might be at high risk of GC among Asians, but not among Caucasians. When stratifying by the location of gastric cancer, the combined results showed that Met/Met genotype carriers might have an increased risk of GC in non-cardiac gastric cancer, but not in cardiac cancer., Conclusion: This meta-analysis confirmed that the XRCC3 Thr241Met gene polymorphism might be a risk factor for GC among Asians, and that differences in genotype distribution may be related to the location of gastric cancer. More well-designed studies based on larger population are needed to confirm our results., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: The Combined Analysis of Psychiatric Studies (CAPS) project conducted extensive review and regularization across studies of all schizophrenia linkage data available as of 2011 from the National Institute of Mental Health-funded Center for Collaborative Genomic Studies on Mental Disorders, also known as the Human Genetics Initiative (HGI). The authors reanalyzed the data using statistical methods tailored to accumulation of evidence across multiple, potentially highly heterogeneous, sets of data., Method: Data were subdivided based on contributing study, major population group, and presence or absence within families of schizophrenia with a substantial affective component. The posterior probability of linkage (PPL) statistical framework was used to sequentially update linkage evidence across these data subsets (omnibus results)., Results: While some loci previously implicated using the HGI data were also identified in the present omnibus analysis (2q36.1, 15q23), others were not. Several loci were found that had not previously been reported in the HGI samples but are supported by independent linkage or association studies (3q28, 12q23.1, 11p11.2, Xq26.1). Not surprisingly, differences were seen across population groups. Of particular interest are signals on 11p15.3, 11p11.2, and Xq26.1, for which data from families with a substantial affective component support linkage while data from the remaining families provide evidence against linkage. All three of these loci overlap with loci reported in independent studies of bipolar disorder or mixed bipolar-schizophrenia samples., Conclusions: Public data repositories provide the opportunity to leverage large multisite data sets for studying complex disorders. Analysis with a statistical method specifically designed for such data enables us to extract new information from an existing data resource.

The macrophage migration inhibitory factor (MIF) is related to the progression of atherosclerosis, which, in turn, is a key factor in the development of acute coronary syndrome (ACS). MIF has a CATT short tandem repeat (STR) at position -794 that might be involved in its expression rate. The aim of this study was to investigate the association between the -794 (CATT)5-8  MIF gene polymorphism and susceptibility to ACS in a western Mexican population. This research included 200 ACS patients classified according to the criteria of the American College of Cardiology (ACC) and 200 healthy subjects (HS). The -794 (CATT)5-8  MIF gene polymorphism was analyzed using a conventional polymerase chain reaction (PCR) technique. The 6 allele was the most frequent in both groups (ACS: 54% and HS: 57%). The most common genotypes in ACS patients and HS were 6/7 and 6/6, respectively, and a significant association was found between the 6/7 genotype and susceptibility to ACS (68% versus 47% in ACS and HS, resp., P = 0.03). We conclude that the 6/7 genotype of the MIF -794 (CATT)5-8 polymorphism is associated with susceptibility to ACS in a western Mexican population.

Background and Objective: The association between glutathione S-transferase T1 (GSTT1) gene polymorphisms and colorectal cancer (CRC) susceptibility is still controversial. In order to clarify the effect of GSTT1 genotype on the CRC risk, we carried out an updated meta-analysis of published case-control studies to provide more precise evidence., Methods: Two investigators independently searched the databases of Pubmed, EMBASE and China National Knowledge Infrastructure (CNKI) up to October 15, 2012. Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated to investigate the strength of the association in a fixed- or random-effects model depending on statistical heterogeneity., Results: Forty-six case-control studies with 15,373 colorectal cancer cases and 21,238 controls were included. Overall, the pooled results indicated that GSTT1 null genotype was significantly associated with increased CRC risk (OR=1.21, 95% CI=1.10-1.33). When stratifying for ethnicity and control sources, we also observed positive association between GSTT1 null genotype and increased risk of CRC. When stratifying by the location, we found there was a statistically significant association in the rectal cancer (OR=1.28, 95% CI=1.01-1.64), but not in colon cancer (OR=1.27, 95% CI=0.94-1.73). Subgroup analyses for Dukes stage, histological differentiation of CRC and smoking habit did not reveal any significant differences in genotype distribution. In addition, we observed a strong correlation between increased CRC risk and the combined GSTM1 and GSTT1 null genotype., Conclusions: This meta-analysis suggests that the GSTT1 null genotype may contribute to increased risk of colorectal cancer. More well-designed studies based on larger population are needed to confirm our results., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Most Crohn's disease (CD) genes discovered in recent years are associated with biological systems critical to the development of this disease. TGFB1 and IL10 are cytokines with important roles in CD. The aim of this study was to evaluate the association between CD, its clinical features and TGFB1 and IL10 gene polymorphisms., Methods: This case-control study enrolled 91 patients and 91 controls from the state of Bahia, Brazil. Five single nucleotide polymorphisms (SNPs) were studied in the TGFB1 gene (codon 10 T > C--rs1800470; codon 25 G > C--rs1800471) and IL10 gene (-1082 A > G--rs1800896; -819 T > C--rs1800871; -592 A > C--rs1800872). An analysis of the genetic polymorphisms was performed using a commercial kit. A comparison of allele frequencies and genotypes was estimated by calculating the odds ratio (OR) with a confidence interval adjusted via the Bonferroni test for a local alpha of 1%. A stratified analysis was applied for gender, race and smoking history. Patients with CD were characterized according to the Montreal classification., Results: The C allele and CC genotype of the TGFB1 gene rs1800470 were both significantly associated with CD. The stratified analysis showed no confounding factors for the co-variables of gender, race and smoking history. The IL10 gene rs1800896 G allele was significantly associated with age at diagnosis of CD, while the T allele of the IL10 gene rs1800871 was significantly associated with perianal disease. The SNPs rs1800871 and rs1800872 were in 100% linkage disequilibrium., Conclusions: TGFB1 gene polymorphisms may be associated with susceptibility to the development of CD, and IL10 gene polymorphisms appear to influence the CD phenotype in this admixed population.

Background and Objective: Emerging evidence indicates that common functional polymorphisms in the estrogen receptor 1 (ESR1) gene may have an impact on an individual's susceptibility to endometrial cancer, but individually published results are inconclusive. The aim of this meta-analysis is to derive a more precise estimation of the associations between eight polymorphisms in the ESR1 gene and endometrial cancer risk., Methods: A literature search of PubMed, Embase, Web of Science and China Biology Medicine (CBM) databases was conducted on publications published before November 1(st), 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using the STATA 12.0 software., Results: Thirteen case-control studies were included with a total of 7,649 endometrial cancer cases and 16,855 healthy controls. When all the eligible studies were pooled into the meta-analysis, the results indicated that PvuII (C>T) polymorphism was associated with an increased risk of endometrial cancer, especially among Caucasian populations. There were also significant associations between rs3020314 (C>T) polymorphism and an increased risk of endometrial cancer. Furthermore, rs2234670 (S/L) polymorphism may decrease the risk of endometrial cancer. However, no statistically significant associations were found in XbaI (A>G), Codon 325 (C>G), Codon 243 (C>T), VNTR (S/L) and rs2046210 (G>A) polymorphisms., Conclusion: The current meta-analysis suggests that PvuII (C>T) and rs3020314 (C>T) polymorphisms may be risk factors for endometrial cancer, especially among Caucasian populations.

The Val762Ala polymorphism poly [ADP-ribose] polymerase 1 (PARP1) gene [ADPRT (adenosine diphosphate ribosyltransferase) gene] affects enzymatic activity, which modulates cancer susceptibility among human populations. Individual data on 13,745 cases and 16,947 controls from 28 published case-control studies were re-evaluated. Odds ratios (OR) were estimated for ethnic group, cancer type, smoking joint effects and studies confined to the Hardy-Weinberg equilibrium. We applied subgroup, sensitivity and outlier analyses as well as the Bonferroni correction for multiple testing. The results show strong evidence that the variant (C) allele confers significant increased risk in the Chinese (OR 1.20-1.44, P < 0.0001-0.002), exacerbated by smoking (OR 1.66-2.53, P < 0.0001) and joint interaction with XRCC1 Arg399Gln (OR 1.39, P < 0.0001) as well as adjustment for tumor type (gastric carcinoma ORs 1.39-2.01, P < 0.0001). These significant effects were unaltered following conservative correction for multiple tests. By contrast, this procedure erased the protective significance in Caucasians, but not in two American subgroups, (i) those in the brain tumor category (0.77-0.79, P < 0.0001) and (ii) smokers in the dominant model (OR 0.86, P < 0.0001). These differential findings between the two ethnicities maybe correlated with significantly (P < 0.0001) greater allele frequency of the variant allele (C) among the Chinese compared to Caucasians. Our racial and tissue-specific summary estimates imply consideration of the Val762Ala polymorphism as candidate gene marker for screening cancer patients' best suited for PARP inhibitor therapy.