Ancestrally unbiased polygenic breast cancer (BC) risk assessment.

10502 Background: BC risk is influenced by single-nucleotide polymorphisms (SNPs) with small effects that can be aggregated into polygenic risk scores (PRSs). PRSs have primarily been developed and validated for populations of European descent. To make a PRS available for all women, we developed and validated a novel global PRS (gPRS) that utilizes individual ancestral genetic composition. Methods: Ancestry-specific PRSs corresponding to 3 continental ancestries were developed from 149 SNPs (93 BC and 56 ancestry-informative): an African PRS was developed using a cohort of 31,126 self-reported African American patients referred for hereditary cancer testing; an East Asian PRS was developed based on published data from the Asia Breast Cancer Consortium; and a European PRS was developed using data from the Breast Cancer Association Consortium and 24,259 European hereditary cancer testing patients. For each patient, ancestry-informative SNPs were used to calculate the fractional ancestry attributable to each of the 3 continents. The gPRS was the sum of ancestry specific PRSs weighted according to genetic ancestral composition. In an independent validation cohort (N = 62,707), we evaluated discrimination and calibration of gPRS, and compared performance against a previously described 86-SNP PRS for women of European ancestry. Associations of SNPs and PRSs with BC were analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Odds ratios (ORs) are reported per standard deviation within the corresponding patient population. P-values are reported as two-sided. Results: The gPRS was strongly associated with BC in the full validation cohort and in sub-cohorts defined by self-reported ancestry (Table). 95% (88/93) of BC SNPs had ≥1% frequency of risk alleles within each of the self-reported populations. Compared to the aforementioned 86-SNP PRS, the gPRS showed improved discrimination overall, and within each sub-cohort, with the exception of the Asian population where the sample size was too small to show superiority of either score. The 86-SNP PRS was calibrated for white non-Hispanic women but mis-calibrated for non-European ancestries. The gPRS was properly calibrated for all women. Conclusions: The 149-SNP gPRS is validated and calibrated for women of all ancestries. Combined with clinical and biological risk factors, this approach may offer improved risk stratification for all women, regardless of ancestry.[Table: see text]

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Applicability of Obesity-Related SNPs and Their Effect Size Measures Defined on Populations with European Ancestry for Genetic Risk Estimation among Roma

Genes ◽

10.3390/genes11050516 ◽

2020 ◽

Vol 11 (5) ◽

pp. 516 ◽

Cited By ~ 1

Author(s):

Erand Llanaj ◽

Péter Pikó ◽

Károly Nagy ◽

Gábor Rácz ◽

Sándor János ◽

...

Keyword(s):

Effect Size ◽

Genetic Risk ◽

Association Studies ◽

Strong Association ◽

European Ancestry ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Continuous Variables ◽

Roma Population ◽

The Impact

Investigations on the impact of genetic factors on the development of obesity have been limited regarding the Roma population—the largest and most vulnerable ethnic minority in Europe of Asian origin. Genetic variants identified from genetic association studies are primarily from European populations. With that in mind, we investigated the applicability of data on selected obesity-related single nucleotide polymorphisms (SNPs), obtained from the Hungarian general (HG) population of European origin, on the Hungarian Roma (HR) population. Twenty preselected SNPs in susceptible alleles, known to be significantly associated with obesity-related phenotypes, were used to estimate the effect of these SNPs on body mass index (BMI) and waist circumference (WC) in HG (N = 1783) and HR (N = 1225) populations. Single SNP associations were tested using linear and logistic regression models, adjusted for known covariates. Out of 20 SNPs, four located in FTO (rs1121980, rs1558902, rs9939609, and rs9941349) showed strong association with BMI and WC as continuous variables in both samples. Computations based on Adult Treatment Panel III (ATPIII) and the International Diabetes Federation’s (IDF) European and Asian criteria showed rs9941349 in FTO to be associated only with WC among both populations, and two SNPs (rs2867125, rs6548238) in TMEM18 associated with WC only in HG population. A substantial difference (both in direction and effect size) was observed only in the case of rs1801282 in PPARγ on WC as a continuous outcome. Findings suggest that genetic risk scores based on counting SNPs with relatively high effect sizes, defined based on populations with European ancestry, can sufficiently allow estimation of genetic susceptibility for Roma. Further studies are needed to clarify the role of SNP(s) with protective effect(s).

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An 8-lncRNA Signature Predicts Survival of Triple-Negative Breast Cancer Patients Without Germline BRCA1/2 Mutation

10.21203/rs.3.rs-60544/v1 ◽

2020 ◽

Author(s):

Minling Liu ◽

Wei Dai ◽

Mengyuan Zhu ◽

Xueying Li ◽

Shan Huang ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Validation Cohort ◽

Functional Enrichment ◽

Biological Behavior ◽

Risk Scores ◽

Training Cohort

Abstract Background: Triple-negative breast cancer (TNBC) is a particular breast cancer subtype with poor prognosis due to its aggressive biological behavior and strong heterogeneity. TNBC with germline BRCA1/2 mutation (gBRCAm) have higher sensitivity to DNA damaging agents including platinum-based chemotherapy and PARP inhibitors. But the treatment of TNBC without gBRCAm remains challenging. This study aimed to develop a long non-coding RNA (lncRNA) signature of TNBC patients without gBRCAm to improve risk stratification and optimize individualized treatment.Methods: 98 TNBC patients without gBRCAm were acquired from The Cancer Genome Atlas (TCGA) database. The univariable Cox regression analysis and LASSO Cox regression model were applied to establish an lncRNA signature in the training cohort (N = 59). Then Kaplan–Meier survival curve and time-dependent ROC curve were used to validate the prognostic ability of the signature. The signature related mRNAs were identified using the Pearson correlation. Functional enrichment analysis of related mRNA was performed using the Metascape. The qPCR assay was performed to confirm the expressions and clinicopathological correlationsof two potential lncRNAs HAGLROS and TONSL-AS1 in 30 paired clinical triple-negative breast cancer samples without gBRCAm.Results:We developed an 8-lncRNA signature in the training cohort including HAGLROS, AL139002.1, AL391244.2, AP000696.1, AL391056.1, AL513304.1, TONSL-AS1 and AL031008.1. In both the training and validation cohort, patients with higher risk scores showed significantly worse overall survival compared to those with lower risk scores(P=0.00018 and P =0.0068 respectively). 1, 5, 8-year AUC in the training cohort were 1.000, 1.000 and 0.908 respectively, in the validation cohort were 0.785, 0.790 and 0.892 respectively indicating that our signature has a good prognostic capacity. Signature related mRNA mainly enriched in terms include RNA metabolic process, DNA repair pathways, and so on. Two potential lncRNAs HAGLROS and TONSL-AS1 were found frequently overexpressed in TNBC without gBRCAm, and significantly associated with tumor grade and invasion.Conclusions: We constructed a novel 8-lncRNA signaturewhich significantly associated with the overall survival of TNBC patients without gBRCAm. Among those 8lncRNAs, HAGLROS and TONSL-AS1 may be potential therapeutic targetswhich function needed further exploration.

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Investigation of Triple-Negative Breast Cancer Risk Alleles in An International African-Enriched Cohort

10.21203/rs.3.rs-109841/v1 ◽

2020 ◽

Author(s):

Rachel Martini ◽

Yalei Chen ◽

Brittany Jenkins ◽

Isra Elhussin ◽

Esther Cheng ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Potential ◽

African Ancestry ◽

Case Series ◽

European Ancestry ◽

Risk Alleles

Abstract Large-scale efforts to identify breast cancer risk alleles have historically taken place among women on European ancestry, with recent efforts to validate these alleles or identify risk alleles applicable to women of African descent. We investigated the effect of previously reported breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case-control and nested case-series approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.4204, p = 0.005). We have shown that differential prevalence of the protective allele may reflect a polymorphic function of ANKLE1 in TNBC breast cancer outcomes. These AA specific risk alleles present opportunities for future studies of therapeutic potential that address race-specific differences in BC and TNBC risk and disease outcome.

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Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population

Genes ◽

10.3390/genes9090427 ◽

2018 ◽

Vol 9 (9) ◽

pp. 427 ◽

Cited By ~ 14

Author(s):

Sebastián Morales ◽

Tomas De Mayo ◽

Felipe Gulppi ◽

Patricio Gonzalez-Hormazabal ◽

Valentina Carrasco ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

South American ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

American Population ◽

South American Population ◽

Risk Alleles ◽

Increased Risk

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

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Single Nucleotide Polymorphisms and Thromboembolism in Acute Lymphoblastic Leukemia — a NOPHO ALL2008 Study

Blood ◽

10.1182/blood-2018-99-109902 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 143-143 ◽

Cited By ~ 1

Author(s):

Kirsten Brunsvig Jarvis ◽

Marissa Le Blanc ◽

Morten Tulstrup ◽

Ellen Ruud ◽

Ruta Tuckuviene ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Single Nucleotide Polymorphisms ◽

Risk Score ◽

Genetic Risk ◽

Lymphoblastic Leukemia ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Risk Alleles ◽

All Treatment

Abstract Introduction: Thromboembolism (TE) is a major toxicity of acute lymphoblastic leukemia (ALL) treatment and contributes to substantial morbidity and mortality. Several germline DNA variants have been associated with TE in adults without cancer. A meta-analysis of genome-wide association studies on TE by Germain et al. (Am J Hum Genet 2015) identified single nucleotide polymorphisms (SNPs) in 8 genes that contribute to increased risk of TE in adults (ABO,F2, F5,F11, FGG,PROCR,TSPAN15, and SLC44A2). De Haan et al. (Blood 2012) found that SNPs in 5 of these (F5, F2, F11, FGG, and ABO) predicted TE almost as well as a 31 SNP-based risk score. However, the impact of these SNPs in patients with cancer, particularly in children, remains uncertain. Materials and methods: The Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol for children and adults (1-45 years) included a 3-drug induction (vincristine, doxorubicin, glucocorticosteroid) followed by exposure to asparaginase (1,000 IU/m.sq. i.m.) from week 5 until week 33 (details of therapy in Toft, Leukemia 2018). We collected germline DNA and prospectively registered TE events on 1482 children and adults diagnosed with ALL and treated according to the ALL2008 protocol in seven Nordic and Baltic countries (7/2008-7/2016) (Rank, Blood 2018). Inclusion criteria for TE were i) symptomatic venous or arterial TE confirmed by imaging or by autopsy for TE diagnosed post mortem or ii) asymptomatic TE confirmed by imaging due to other non-TE symptoms and treated with systemic anticoagulation. Based on previously published data and a priori power calculations, we selected and genotyped 5 SNPs: F5 rs6025 (risk allele frequency (RAF) 0.05), F11 rs2036914 (RAF 0.52), FGG rs2066865 (RAF 0.22), and ABO SNPs rs8176719 (RAF 0.39) and rs2519093 (RAF 0.24). Three SNPs (F5 and the two ABO SNPs) were found by imputation, which was done on a subset of patients with European ancestry and included in the NOPHO ALL2008 protocol (N = 1229). We constructed genetic risk scores using a combination of the SNPs. Results: During the ALL treatment period 107 of 1482 patients developed TE (2.5-year cumulative incidence 7.3%, 95% confidence interval (CI) 5.9-8.5). In multivariate Cox regression analysis controlling for age, gender, presence of mediastinal mass and enlarged lymph nodes (N = 1192, whereof TE events 84), we found statistically significant associations with TE development for SNPs F5 rs6025 (hazard ratio (HR) 2.96, 95% CI 1.59-5.48), F11 rs2036914 (HR 1.62, 95% CI 1.18-2.24), and FGG rs2066865 (HR 1.40 95% CI 1.01-1.95), whereas there were no significant associations with ABO SNPs rs8176719 (HR 0.98, 95% CI 0.64-1.51) or rs2519093 (HR 1.06, 95% CI 0.65-1.73). An unweighted 3 SNP risk score based on SNPs F5, F11, and FGG was associated with TE development (HR 1.59, 95% CI 1.27-1.98) (Figure 1). Twenty-six of 217 patients with ≥3 risk alleles developed TE (12.0%, 95% CI 8.1-17.2), compared to 62 of 1007 patients with <3 risk alleles (6.2%, 95% CI 4.8-7.9). The association was strongest in the adolescent age group (10-18 years; HR 1.88, 95% CI 1.35-2.63). Thirteen of 43 adolescents with ≥3 risk alleles developed TE (30.2%, 95% CI 17.8-46.3), compared to 20 of 182 adolescents with <3 risk alleles (11.0%, 95% CI 7.0-16.7) (Figure 2). In adults (>18 years) the proportion who developed TE was quite high in both the group with ≥3 risk alleles (23.5%, 95% CI 7.8-50.2) and with <3 risk alleles (17.6% 95%CI 11.1-26.3). In children (1-10 years) the proportion who developed TE was low in both the group with ≥3 risk alleles (5.7%, 95% CI 2.8-10.9) and with <3 risk alleles (3.2%, 95% CI 2.1-4.8). A weighted 3 SNP genetic risk score based on estimated odds ratios from literature for SNPs F5, F11 and FGG was also associated with TE development (HR 2.84, 95% CI 1.85-4.36). Again, the association was strongest in adolescents (HR 4.20, 95% CI 2.22-7.94). Conclusion: Based on the strong association between F5 rs6025, F11 rs2036914, and FGG rs2066865 and TE development, not least for adolescents, future preventive measures for TE should target adolescents with ≥3 risk alleles as well as any adults ≥18 years. Disclosures No relevant conflicts of interest to declare.

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On cross-ancestry cancer polygenic risk scores

PLoS Genetics ◽

10.1371/journal.pgen.1009670 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009670

Author(s):

Lars G. Fritsche ◽

Ying Ma ◽

Daiwei Zhang ◽

Maxwell Salvatore ◽

Seunggeun Lee ◽

...

Keyword(s):

Breast Cancer ◽

South Asian ◽

Disease Risk ◽

Association Studies ◽

East Asian ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Target Sample

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

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Variants of estrogen-related genes and breast cancer risk in European and African American women

Endocrine Related Cancer ◽

10.1530/erc-14-0250 ◽

2014 ◽

Vol 21 (6) ◽

pp. 853-864 ◽

Cited By ~ 7

Author(s):

Lei Quan ◽

Chi-Chen Hong ◽

Gary Zirpoli ◽

Michelle R Roberts ◽

Thaer Khoury ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

African American Women ◽

African Ancestry ◽

European Ancestry ◽

Health Study ◽

Nucleotide Polymorphisms ◽

Estrogen Exposure ◽

Estrogen Synthesis

It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene–environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women’s Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in theESR1gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20–1.80,P=0.0002; rs2046210, OR=1.24, 95% CI=1.04–1.47,P=0.02; and rs3020314, OR=1.43, 95% CI=1.19–1.70,P=0.00009), but not in AA women. The only other gene associated with breast cancer risk wasCYP1A2in AA women (rs2470893, OR=1.42, 95% CI=1.00–2.02,P=0.05), but not in EA women. When stratified by ER status,ESR1rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with theESR1SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer.

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Association of polymorphisms in ZFHX1B, KCNQ5 and GJD2 with myopia progression and polygenic risk prediction in children

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-318708 ◽

2021 ◽

pp. bjophthalmol-2020-318708

Author(s):

Li Jia Chen ◽

Fen Fen Li ◽

Shi Yao Lu ◽

Xiu Juan Zhang ◽

Ka Wai Kam ◽

...

Keyword(s):

Risk Prediction ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Myopia Progression ◽

Polygenic Risk ◽

Axial Elongation ◽

Risk Alleles ◽

Increased Risk ◽

Fast Progression

AimsTo assess the association of single-nucleotide polymorphisms (SNPs) with myopia progression for polygenic risk prediction in children.MethodsSix SNPs (ZC3H11B rs4373767, ZFHX1B rs13382811, KCNQ5 rs7744813, MET rs2073560, SNTB1 rs7839488 and GJD2 rs524952) were analysed in 1043 school children, who completed 3-year follow-up, using TaqMan genotyping assays. SNP associations with progression in spherical equivalent (SE) were analysed by logistic regression. Polygenic risk scores (PRS) were applied for computing the sum of the risk alleles of multiple SNPs corresponding to myopia progression, weighted by the effect sizes of corresponding SNPs.ResultsGJD2 rs524952 showed significant association with fast progression (OR=1.32, 95% CI 1.10 to 1.59; p=0.003) and KCNQ5 rs7744813 had nominal association (OR=1.32, 95% CI 1.04 to 1.67; p=0.02). In quantitative traits locus analysis, GJD2 rs524952 and KCNQ5 rs7744813 were associated with progression in SE (β=−0.038 D/year, p=0.008 and β=−0.042 D/year, p=0.02) and axial elongation (β=0.016 mm/year, p=0.01 and β=0.017 mm/year, p=0.027). ZFHX1B rs13382811 also showed nominal association with faster progression in SE (β=−0.041 D/year, p=0.02). PRS analysis showed that children with the highest PRS defined by rs13382811, rs7744813 and rs524952 had a 2.26-fold of increased risk of fast myopia progression (p=4.61×10−5). PRS was also significantly associated with SE progression (R2=1.6%, p=3.15×10−5) and axial elongation (R2=1.2%, p=2.6×10−4).ConclusionsIn this study, multi-tiered evidence suggested SNPs in ZFHX1B, KCNQ5 and GJD2 as risk factors for myopia progression in children. Additional attention and appropriate interventions should be given for myopic children with high-risk PRS as defined by GJD2 rs524952, KCNQ5 rs7744813 and ZFHX1B rs13382811.

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From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

Breast Care ◽

10.1159/000515319 ◽

2021 ◽

pp. 1-12

Author(s):

Emma R. Woodward ◽

Elke M. van Veen ◽

D. Gareth Evans

Keyword(s):

Breast Cancer ◽

High Risk ◽

Reproductive Factors ◽

Risk Scores ◽

Clinical Indication ◽

Nucleotide Polymorphisms ◽

Moderate Risk ◽

Risk Genes ◽

Increased Risk ◽

Gene Panels

Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

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Causal Relationship between Adiponectin and Diabetic Retinopathy: A Mendelian Randomization Study in an Asian Population

Genes ◽

10.3390/genes12010017 ◽

2020 ◽

Vol 12 (1) ◽

pp. 17

Author(s):

Yu-Chuen Huang ◽

Ya-Wen Chang ◽

Chun-Wen Cheng ◽

Chia-Ming Wu ◽

Wen-Ling Liao ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Asian Population ◽

Risk Scores ◽

Diabetic Patients ◽

Nucleotide Polymorphisms ◽

Significance Level ◽

A Genome ◽

Potential Biomarker

Adiponectin (APN) is suggested to be a potential biomarker for predicting diabetic retinopathy (DR) risk, but the association between APN and DR has been inconsistent in observational studies. We used a Mendelian randomization (MR) analysis to evaluate if circulating APN levels result in DR. We applied three different genetic risk scores (GRS): GRSAll combined all 47 single nucleotide polymorphisms (SNPs), which from a genome-wide association study (GWAS) database-catalog reach significance level; GRSLimited comprised 16 GRSAll-SNPs with a rigorous threshold (p < 5.0 × 10−8 for GWAS), and GRSAPN combined 5 SNPs significantly associated with APN level. The MR-inverse-variance weighted method analysis showed that for each 1-SD increase in genetically induced increase in plasma APN, the OR of having DR was β = 0.20 (95% CI: −0.46–0.85, p = 0.553) for GRSAPN, 0.61 (95% CI: 0.10–1.13, p = 0.020) for GRSAll, and 0.57 (95% CI: −0.06 to 1.20, p = 0.078) for GRSLimited. Sensitivity analysis, including MR-egger regression and the weighted-median approach, did not provide evidence of the pleiotropic effect of IVs. Limited evidence for the causal role of APN in DR risk among Taiwanese diabetic patients was shown based on MR analysis in the present study.

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