scholarly journals 300Association between rs2231142 of ABCG2 and gout, hyperuricemia and uric acid: Systematic review and meta-analysis

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Thitiya Lukkunaprasit ◽  
Sasivimol Rattanasiri ◽  
Saowalak Turongkaravee ◽  
Atiporn Ingsathit ◽  
John Attia ◽  
...  

Abstract Background Genome-wide association studies showed that rs2231142 (C421A) of ABCG2 gene has strong effects on gout and uric acid (UA). However, replication studies showed conflicting results. We aimed to pool effects of rs2231142 on gout, hyperuricemia, and UA across studies. Methods Studies were located from MEDLINE and Scopus until 17th June 2018. Data extractions were performed by two independent reviewers. Hardy-Weinberg equilibrium was checked. Genotype effects were pooled by ethnicity using mixed-effect logistic model for gout and hyperuricemia and multivariate meta-analysis for UA. Publication bias was assessed using funnel plots and Egger’s tests. Results Thirty studies were eligible; 21, 5, and 8 studies assessed association between rs2231142 and gout, hyperuricemia, and UA, respectively. Carrying AA and CA genotypes were 3.2 (2.4, 4.4) and 1.6 (1.5, 1.8) higher odds to develop gout in Caucasians. Likewise, in Asians, the ORs for corresponding genotypes were 4.5 (4.1, 5.0) and 2.1 (2.0, 2.3) for gout; 2.3 (1.8, 2.8) and 1.6 (1.4, 1.8) for hyperuricemia. Mean differences of UA in Caucasians carrying AA and CA were 50.4 (32.7, 68.2) and 19.5 (14.2, 24.7) µmol/l compared with those carrying CC genotype while in Asians, they were 18.4 (8.7, 28.1) and 11.5 (4.1, 18.9) µmol/l, respectively. Additive gene effects were suggested. Conclusions Significant effects of rs2231142 on gout, hyperuricemia, and elevated UA were confirmed. Our findings should be useful in personalized risk scores for prediction of gout and diseases related to high UA. Key messages rs2231142 increased the risk of gout and UA in Asians and Caucasians

Diabetes Care ◽  
2022 ◽  
Author(s):  
Tinashe Chikowore ◽  
Kenneth Ekoru ◽  
Marijana Vujkovi ◽  
Dipender Gill ◽  
Fraser Pirie ◽  
...  

OBJECTIVE Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American–, European-, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American–derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European- and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19–4.03; P = 2.79 × 10−17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS African American–derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.


2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Thitiya Lukkunaprasit ◽  
Sasivimol Rattanasiri ◽  
Saowalak Turongkaravee ◽  
Naravut Suvannang ◽  
Atiporn Ingsathit ◽  
...  

Abstract Background Replication studies showed conflicting effects of ABCG2 and SLC2A9 polymorphisms on gout and serum urate. This meta-analysis therefore aimed to pool their effects across studies. Methods Studies were located from MEDLINE and Scopus from inception to 17th June 2018. Observational studies in adults with any polymorphism in ABCG2 or SLC2A9, and outcome including gout, hyperuricemia, and serum urate were included for pooling. Data extractions were performed by two independent reviewers. Genotype effects were pooled stratified by ethnicity using a mixed-effect logistic model and a multivariate meta-analysis for dichotomous and continuous outcomes. Results Fifty-two studies were included in the analysis. For ABCG2 polymorphisms, mainly studied in Asians, carrying 1–2 minor-allele-genotypes of rs2231142 and rs72552713 were respectively about 2.1–4.5 and 2.5–3.9 times higher odds of gout than non-minor-allele-genotypes. The two rs2231142-risk-genotypes also had higher serum urate about 11–18 μmol/l. Conversely, carrying 1–2 minor alleles of rs2231137 was about 36–57% significantly lower odds of gout. For SLC2A9 polymorphisms, mainly studied in Caucasians, carrying 1–2 minor alleles of rs1014290, rs6449213, rs6855911, and rs7442295 were about 25–43%, 31–62%, 33–64%, and 35–65% significantly lower odds of gout than non-minor-allele-genotypes. In addition, 1–2 minor-allele-genotypes of the latter three polymorphisms had significantly lower serum urate about 20–49, 21–51, and 18–54 μmol/l than non-minor-allele-genotypes. Conclusions Our findings should be useful in identifying patients at risk for gout and high serum urate and these polymorphisms may be useful in personalized risk scores. Trial registration PROSPERO registration number: CRD42018105275.


Human Cell ◽  
2021 ◽  
Vol 34 (2) ◽  
pp. 293-299
Author(s):  
Makoto Kawaguchi ◽  
Akiyoshi Nakayama ◽  
Yuka Aoyagi ◽  
Takahiro Nakamura ◽  
Seiko Shimizu ◽  
...  

AbstractGout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02–1.68] for rs10821905 of A1CF, P = 6.49 × 10–3, OR with 95% CI: 1.29 [1.07–1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10–4, OR with 95% CI: 1.39 [1.17–1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10–5, OR with 95% CI 1.32 [1.15–1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.


2021 ◽  
pp. 1-9
Author(s):  
Annabell Coors ◽  
Mohammed-Aslam Imtiaz ◽  
Meta M. Boenniger ◽  
N. Ahmad Aziz ◽  
Monique M. B. Breteler ◽  
...  

Abstract Background Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. Methods Analyses were based on the data of 2956 participants (aged 30–95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. Results Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. Conclusions There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.


2022 ◽  
Author(s):  
Tinashe Chikowore ◽  
Kenneth Ekoru ◽  
Marijana Vujkovic ◽  
Dipender Gill ◽  
Fraser Pirie ◽  
...  

<b>Objective. </b>Polygenic prediction of type 2 diabetes in<b> </b>continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American, European or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. <p><b>Research Design and Methods</b>. Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls. The South African Zulu study (1602 cases and 981 controls) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (2148 cases and 2161 controls).</p> <p> <b>Results. </b>The discriminatory ability of the African American and Multi-ethnic PRS were similar. However<b>, </b>the African American derived PRS was more transferable in all the countries represented in the AADM cohort, and predictive of type 2 diabetes in the country combined analysis compared to the European and multi-ethnic derived scores. Notably, participants in the 10<sup>th</sup> decile of this PRS had a 3.63-fold greater risk (OR 3.63; 95%CI (2.19 - 4.03), p = 2.79 x 10<sup>-17</sup>) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. </p> <p><b>Conclusions </b>African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in type 2 diabetes.</p>


2021 ◽  
Author(s):  
Marta R Moksnes ◽  
Ailin Falkmo Hansen ◽  
Sarah E Graham ◽  
Sarah A Gagliano Taliun ◽  
Kuan-Han Wu ◽  
...  

AbstractIron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI) and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257 953 individuals. We identify 127 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate the latest genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.


2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Xueyan Zhou ◽  
Fei Liao ◽  
Junlong Zhang ◽  
Yun Qin ◽  
Heng Xu ◽  
...  

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and alterations in CDKN2A were considered to play an important role on leukemogenesis. Two single nucleotide polymorphisms (SNPs) at CDKN2A locus were identified to impact on ALL susceptibility via genome wide association studies, and followed by multiple subsequent replication studies at the specific hits. Here, we conducted a systematic review and meta-analysis to re-evaluate the association of both SNPs (rs3731217 and rs3731249) with ALL susceptibility by gathering the data from 24 independent studies, totally containing 7922 cases/21503 controls for rs3731217 and 6295 cases/24191 controls for rs3731249. Both SNPs were significantly associated with ALL risk (odds ratio [OR] = 0.72 and 2.26 respectively), however, exhibit race-specific pattern. In summary, our meta-analysis indicated that two SNPs at CDKN2A locus are associated with ALL susceptibility independently mainly in Caucasians. Future large-scale studies are required to validate the associations in other ethnicities.


2020 ◽  
Vol 9 (2) ◽  
pp. 341 ◽  
Author(s):  
Jasmina Mallet ◽  
Yann Le Strat ◽  
Caroline Dubertret ◽  
Philip Gorwood

Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.


2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S103-S103
Author(s):  
Tim Bigdeli ◽  
Ayman Fanous ◽  
Nallakkandi Rajeevan ◽  
Frederick Sayward ◽  
Yuli Li ◽  
...  

Abstract Background Schizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array. Methods Primary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date. Results Polygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P&lt;10–30) and AA (P&lt;0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P&lt;0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378. Discussion We newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.


2020 ◽  
Author(s):  
Clara Albiñana ◽  
Jakob Grove ◽  
John J. McGrath ◽  
Esben Agerbo ◽  
Naomi R. Wray ◽  
...  

AbstractThe accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWAS). However, it is now common for researchers to have access to large individual-level data as well, such as the UK biobank data. To the best of our knowledge, it has not yet been explored how to best combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (Meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using twelve real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare Meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and Meta-PRS. We find that, when large individual-level data is available, the linear combination of PRSs (Meta-PRS) is both a simple alternative to Meta-GWAS and often more accurate.


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