No association between genetic variants in angiogenesis and inflammation pathway genes and breast cancer survival among Chinese women

Background: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown. Methods: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS). Results: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study. Conclusions: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer. Impact: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.     

Genetic variants in telomere-maintaining genes and skin cancer risk

Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes (TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT-CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case–control study of Caucasians nested within the Nurses’ Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT-CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) [95% confidence interval (95% CI)] of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14–1.81), 1.50 (1.14–1.98), 1.87 (1.19–2.91), and 0.73 (0.59–0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length (P for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility.     

Genetic variants in telomere-maintenance genes and bladder cancer risk

Telomeres are critical in maintaining genomic stability. Genetic variants in telomere pathway genes may affect telomere and telomerase function, and subsequently cancer risk. We evaluated 126 SNPs from 10 genes related to telomere regulation in relation to bladder cancer risk. Five SNPs, 4 from TEP1 gene and 1 from PINX1 gene, were found to be highly significant (P<0.01). Out of these, the most significant association was found in rs2228041 of TEP1 (OR 1.66, 95% CI 1.19–2.31) while rs1469557 of PINX1 had a protective effect (OR 0.75, 95% CI 0.61–0.93). Haplotype analysis showed that a TEP1 haplotype consisting of the variant alleles of 7 SNPs exhibited a 2.28 fold increased risk (95% CI 1.13–4.60). We then performed cumulative analysis of multiple risk variants, as well as Classification and Regression Tree (CART) to look for gene-gene interactions. In cumulative effect analysis, the group with 4–5 risk variants had an OR of 2.57 (95% CI = 1.62–4.09) versus the reference group with 0 risk variants. The CART analysis categorized individuals into five subgroups with different bladder cancer risk profiles based on their distinct genotype background. To our knowledge, this is one of the largest, most comprehensive studies on bladder cancer risk concerning telomere-regulating pathway gene SNPs and our results support that genetic variations of telomere maintenance modulate bladder cancer risk individually and jointly.     

Genetic variation in microRNA genes and prostate cancer risk in North Indian population

Recent evidence indicates the involvement of microRNAs (miRNAs), in cell growth control, differentiation, and apoptosis, thus playing a role in tumorigenesis. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA-binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We genotyped SNPs hsa-mir196a2 (rs11614913), hsa-mir146a (rs2910164), and hsa-mir499 (rs3746444) in a case–control study including 159 prostate cancer patients and 230 matched controls. Patients with heterozygous genotype in hsa-mir196a2 and hsa-mir499, showed significant risk for developing prostate cancer (P = 0.01; OR = 1.70 and P ≤ 0.001; OR = 2.27, respectively). Similarly, the variant allele carrier was also associated with prostate cancer, (P = 0.01; OR = 1.66 and P ≤ 0.001; OR = 1.97, respectively) whereas, hsa-mir146a revealed no association in prostate cancer. None of the miRNA polymorphisms were associated with Gleason grade and bone metastasis. This is the first study on Indian population substantially presenting that individual as well as combined genotypes of miRNA-related variants may be used to predict the risk of prostate cancer and may be useful for identifying patients at high risk.     

Genetic variants at 1p11.2 and breast cancer risk: a two-stage study in Chinese women

Background

Genome-wide association studies (GWAS) have identified several breast cancer susceptibility loci, and one genetic variant, rs11249433, at 1p11.2 was reported to be associated with breast cancer in European populations. To explore the genetic variants in this region associated with breast cancer in Chinese women, we conducted a two-stage fine-mapping study with a total of 1792 breast cancer cases and 1867 controls.

Methodology/Principal Findings

Seven single nucleotide polymorphisms (SNPs) including rs11249433 in a 277 kb region at 1p11.2 were selected and genotyping was performed by using TaqMan® OpenArray™ Genotyping System for stage 1 samples (878 cases and 900 controls). In stage 2 (914 cases and 967 controls), three SNPs (rs2580520, rs4844616 and rs11249433) were further selected and genotyped for validation. The results showed that one SNP (rs2580520) located at a predicted enhancer region of SRGAP2 was consistently associated with a significantly increased risk of breast cancer in a recessive genetic model [Odds Ratio (OR)  =  1.66, 95% confidence interval (CI)  =  1.16–2.36 for stage 2 samples; OR  =  1.51, 95% CI  =  1.16–1.97 for combined samples, respectively]. However, no significant association was observed between rs11249433 and breast cancer risk in this Chinese population (dominant genetic model in combined samples: OR  =  1.20, 95% CI  =  0.92–1.57).

Conclusions/Significance

Genotypes of rs2580520 at 1p11.2 suggest that Chinese women may have different breast cancer susceptibility loci, which may contribute to the development of breast cancer in this population.     

Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.     

Dysregulation of microRNA biogenesis machinery in cancer

MicroRNAs (miRNAs) are integral to the gene regulatory network. A single miRNA is capable of controlling the expression of hundreds of protein coding genes and modulate a wide spectrum of biological functions, such as proliferation, differentiation, stress responses, DNA repair, cell adhesion, motility, inflammation, cell survival, senescence and apoptosis, all of which are fundamental to tumorigenesis. Overexpression, genetic amplification, and gain-of-function mutation of oncogenic miRNAs (“onco-miRs”) as well as genetic deletion and loss-of-function mutation of tumor suppressor miRNAs (“suppressor-miRs”) are linked to human cancer. In addition to the dysregulation of a specific onco-miR or suppressor-miRs, changes in global miRNA levels resulting from a defective miRNA biogenesis pathway play a role in tumorigenesis. The function of individual onco-miRs and suppressor-miRs and their target genes in cancer has been described in many different articles elsewhere. In this review, we primarily focus on the recent development regarding the dysregulation of the miRNA biogenesis pathway and its contribution to cancer.     

Physical activity and the risk of breast cancer among Nigerian women

BackgroundAlthough physical activity has been associated with a reduced risk of breast cancer risk in high income countries (HIC), its role has not been widely studied in sub-Saharan Africa. Our aim was to investigate the association between physical activity (PA) and the risk of breast cancer in Nigeria.MethodsWe conducted a hospital-based case-control study involving participants from five hospitals in Lagos and Abuja. Women were interviewed in-person between October 2016 and May 2017 using a semi-structured questionnaire. Total PA was estimated by summing occupational, household, transport and leisure PA scores. PA was summarised as metabolic equivalents (MET) hours per week (MET-hr/wk). The putative association between breast cancer incidence and PA was analysed using multivariable logistic regression.Results379 histologically confirmed breast cancer cases and 403 controls took part. Compared to women in the lowest categories, women in the upper middle category of total PA(adjusted OR-AOR 0.44, 95% CI: 0.27, 0.78),uppermost categories of total non-vigorous PA (AOR 0.26, 95%CI:0.09,0.75), household PA(AOR 0.0.38, 95% CI: 0.20, 0.71) and occupational PA (AOR 0.64, 95% 0.40, 1.02) had a reduced risk of breast cancer following adjustment for relevant confounders. Transport and leisure PA were not significantly associated with a reduced risk of breast cancer.ConclusionThe total effect of various PA related to regular activities of Nigerian women was associated with a reduced risk of breast cancer. PA especially at household and occupational environments should be promoted as part of breast cancer prevention strategy in Nigeria.     

African ancestry is associated with asthma risk in African Americans

Background

Asthma is a common complex condition with clear racial and ethnic differences in both prevalence and severity. Asthma consultation rates, mortality, and severe symptoms are greatly increased in African descent populations of developed countries. African ancestry has been associated with asthma, total serum IgE and lower pulmonary function in African-admixed populations. To replicate previous findings, here we aimed to examine whether African ancestry was associated with asthma susceptibility in African Americans. In addition, we examined for the first time whether African ancestry was associated with asthma exacerbations.

Methodology/Principal Findings

After filtering for self-reported ancestry and genotype data quality, samples from 1,117 self-reported African-American individuals from New York and Baltimore (394 cases, 481 controls), and Chicago (321 cases followed for asthma exacerbations) were analyzed. Genetic ancestry was estimated based on ancestry informative markers (AIMs) selected for being highly divergent among European and West African populations (95 AIMs for New York and Baltimore, and 66 independent AIMs for Chicago). Among case-control samples, the mean African ancestry was significantly higher in asthmatics than in non-asthmatics (82.0±14.0% vs. 77.8±18.1%, mean difference 4.2% [95% confidence interval (CI):2.0–6.4], p<0.0001). This association remained significant after adjusting for potential confounders (odds ratio: 4.55, 95% CI: 1.69–12.29, p = 0.003). African ancestry failed to show an association with asthma exacerbations (p = 0.965) using a model based on longitudinal data of the number of exacerbations followed over 1.5 years.

Conclusions/Significance

These data replicate previous findings indicating that African ancestry constitutes a risk factor for asthma and suggest that elevated asthma rates in African Americans can be partially attributed to African genetic ancestry.     

Genetic variation in telomere maintenance genes, telomere length and breast cancer risk

Background

Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.

Methods

We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.

Results

We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use <5yrs and 0.59 (SD = 0.24) for HRT use ≥5yrs after adjusting for age of blood donation and race and ethnicity.

Conclusions

We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.     

New germline mutations in non-BRCA genes among breast cancer women of Mongoloid origin

Molecular Biology Reports - In accordance with the Asian BRCA Consortium data, there is a significant difference in incidence rate of breast cancer depending on age, as well as spectrum and...     

Genetic variants in telomere‐maintenance genes are associated with ovarian cancer risk and outcome

Most ovarian cancer patients present at an advanced stage with poor prognosis. Telomeres play a critical role in protecting chromosomes stability. The associations of genetic variants in telomere maintenance genes and ovarian cancer risk and outcome are unclear. We genotyped 137 single nucleotide polymorphisms (SNPs) in telomere‐maintenance genes in 417 ovarian cancer cases and 417 matched healthy controls to evaluate their associations with cancer risk, survival and therapeutic response. False discovery rate Q‐value was calculated to account for multiple testing. Eleven SNPs from two genes showed nominally significant associations with the risks of ovarian cancer. The most significant SNP was TEP1: rs2228026 with participants carrying at least one variant allele exhibiting a 3.28‐fold (95% CI: 1.72‐6.29; P < 0.001, Q = 0.028) increased ovarian cancer risk, which remained significant after multiple testing adjusting. There was also suggested evidence for the associations of SNPs with outcome, although none of the associations had a Q < 0.05. Seven SNPs from two genes showed associations with ovarian cancer survival (P < 0.05). The strongest association was found in TNKS gene (rs10093972, hazard ratio = 1.88; 95% CI: 1.20‐2.92; P = 0.006, Q = 0.076). Five SNPs from four genes showed suggestive associations with therapeutic response (P < 0.05). In a survival tree analysis, TEP1:rs10143407 was the primary factor contributing to overall survival. Unfavourable genotype analysis showed a cumulative effect of significant SNPs on ovarian cancer risk, survival and therapeutic response. Genetic variations in telomere‐maintenance genes may be associated with ovarian cancer risk and outcome.     

Chronotype and postmenopausal breast cancer risk among women in the California Teachers Study

ABSTRACT

Chronotype is the behavioral manifestation of an individual’s underlying circadian rhythm, generally characterized by one’s propensity to sleep at a particular time during the 24 hour cycle. Evening chronotypes (“night owls”) generally suffer from worse physical and mental health compared to morning chronotypes (“morning larks”) – for reasons that have yet to be explained. One hypothesis is that evening chronotypes may be more susceptible to circadian disruption, a condition where the coordinated timing of biologic processes breaks down. The role of chronotype as an independent or modifying risk factor for cancer has not been widely explored. The objective of the current study was to evaluate the risk of breast cancer associated with chronotype in a case-control study nested within the California Teachers Study (CTS) cohort. The study population consisted of 39686 post-menopausal CTS participants who provided information on chronotype by completing a questionnaire in 2012–2013. 2719 cases of primary invasive breast cancer diagnosed from 1995/1996 through completion of the chronotype questionnaire were identified by linkage of the CTS to the California Cancer Registry. 36967 CTS participants who had remained cancer-free during this same time period served as controls. Chronotype was ascertained by responses to an abbreviated version of the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) and was characterized into five categories: definite morning, more morning than evening, neither morning or evening, more evening than morning, definite evening. Multivariable unconditional logistic regression analyses were performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for each of the chronotypes, adjusted for established breast cancer risk factors. Compared to definite morning types, definite evening types had an increased risk of breast cancer with elevated ORs that were statistically significant in both the crude (OR = 1.24, 95% CI: 1.10–1.40) and fully-adjusted models (OR = 1.20, 95% CI: 1.06–1.35). The risk estimates in the fully-adjusted model for all other chronotypes did not significantly differ from one. These results suggest that evening chronotype may be an independent risk factor for breast cancer among a population of women who are not known to have engaged in any substantial night shift work. Further research in other populations of non-shift workers is warranted.     

Genetic variants at 14q24.1 and breast cancer susceptibility: a fine-mapping study in Chinese women

A single nucleotide polymorphism (SNP) rs999737 at 14q24.1 was identified as a susceptibility marker of breast cancer in a genome-wide association study of the European population, which was also confirmed by some of the following studies in populations of European descent. However, rs999737 is very rare or nonpolymorphic in non-Europeans including Chinese, and the role of other genetic variants at 14q24.1 has not been evaluated in populations of non-European descent. In this study, we first selected 21 common tagging SNPs (minor allele frequency [MAF] >0.05 in the Chinese population) by searching the Hapmap database, covering a linage disequilibrium region of more than 70?Kb at 14q24.1, and then conducted a two-stage study (stage I: 878 cases and 900 controls; stage II: 914 cases and 967 controls) to investigate the associations between these tagging SNPs and risk of breast cancer in a Chinese population. In stage I, two SNPs (rs2842346 and rs17828907) were identified to be significantly associated with breast cancer risk (p=0.030 and 0.027 for genotype distributions, respectively). However, no significant associations were found between these two SNPs and breast cancer risk in either stage II or the combined dataset. These findings suggest that common variants at 14q24.1 might not be associated with the risk of breast cancer in the Chinese population, which will need the replication in additional larger studies.     

Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women

Breast cancer is the most prevalent cancer among women in Western countries, and its prevalence is also increasing in Asia. The major risk factor for breast cancer can be traced to reproductive events that influence the lifetime levels of hormones. However, a large percentage of breast cancer cases cannot, be explained by these risk factors. The identification of susceptibility factors that predispose individuals to breast cancer (for instance, if they are exposed to particular environmental agents) could possibly give further insight into the etiology of this malignancy and provide targets for the future development of therapeutics. The most interesting candidate genes include those that mediate a range of functions. These include carcinogen metabolism, DNA repair, steroid hormone metabolism, signal transduction, and cell cycle control. we conducted a hospital-based case-control study on South Korea to evaluate the potential modifying role of the genetic pollymprphisms of selected low penetrance gens that are involved carcinogen metabolisms (i.e., CYP1A1, CYP2E1, GSTM1/T1/P1, NAT1/2, etc.), estrogen synthesis and metabolism (i.e., CYP19, CYP17, CYP1B1, COMT, ER-alpha, etc.), DNA repair (i.e., XRCC1/3, ERCC2/4, ATM, AGT, etc.), and signal transduction as well as others (i.e., TGF- beta, IGF-1, TNF- beta, IL-1B, IL-1RN, etc.). We also took into account the potential interaction between these and the known risk factors of breast cancer. The results of selected genes will be presented in this mini-review.     

Common variants of xeroderma pigmentosum genes and prostate cancer risk

The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA–XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR = 2.60; p < 0.001) and with the AA genotype (OR = 531; p < 0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer.     

CAG repeat variants in the POLG1 gene encoding mtDNA polymerase-gamma and risk of breast cancer in African-American women

The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mitochondrial DNA replication in humans, contains a polyglutamine tract encoded by CAG repeats of varying length. The length of the CAG repeat has been associated with the risk of testicular cancer, and other genomic variants that impact mitochondrial function have been linked to breast cancer risk in African-American (AA) women. We evaluated the potential role of germline POLG-CAG repeat variants in breast cancer risk in a sample of AA women (100 cases and 100 age-matched controls) who participated in the Women's Circle of Health Study, an ongoing multi-institutional, case-control study of breast cancer. Genotyping was done by fragment analysis in a blinded manner. Results from this small study suggest the possibility of an increased risk of breast cancer in women with minor CAG repeat variants of POLG, but no statistically significant differences in CAG repeat length were observed between cases and controls (multivariate-adjusted odds ratio 1.74; 95% CI, 0.49-6.21). Our study suggests that POLG-CAG repeat length is a potential risk factor for breast cancer that needs to be explored in larger population-based studies.     

Genetic association for renal traits among participants of African ancestry reveals new loci for renal function

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m²), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10⁻⁷) and FNDC1 (p-value = 3.0×10⁻⁷) for UACR, and KCNQ1 with eGFR (p = 3.6×10⁻⁶). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.