Genetic analysis localizes a novel locus on chromosome 4q for the glaucoma endophenotype, cup-to-disc ratio: The Jiri Eye Study

Purpose: Glaucoma is a heterogeneous disease influenced by genetic risk factors. However, not all genetic risk factors have been identified. The aim of this project is to localize genetic factors influencing known glaucoma endophenotypes: intraocular pressure (IOP), central corneal thickness (CCT), and vertical cup-to-disc ratio (VCDR). Methods: This family-based study design utilizes phenotypic and genomic data from a single well-characterized pedigree residing in the Jiri region of Nepal. Measures of IOP, CCT and VCDR were obtained by Goldmann applanation tonometry, OCT, and slit lamp biomicroscopy, respectively. Using a genome-wide genotype data set (~550,000 SNPs), we performed a genome-wide linkage scan for IOP, CCT, and VCDR adopting a quantitative approach in SOLAR. For localized quantitative trait locus (QTL) signals, we screened all SNPs within the 1-LOD (95% confidence) interval using the classical measured genotype approach to association analysis and allowing for non-independence amongst the pedigree members. Results: For this study, phenotypic and genotype data from 1,163 (55% female) members of the Jirel population were available. The mean age of the sample is 43.8 (SD=15.7) years. IOP (h2=19%, p=6.1×10-5), CCT (h2=57%, p=1.6×10-26), and VCDR (h2=48%, p=9.7×10-22) were significantly heritable. We localized a significant QTL for VCDR on chromosome 4 (LOD=3.05 at 86.83 Mb). The top association signal within this QTL was for an intronic SNP (rs4148155; p=2.01×10-6, b=0.24) in the ABCG2 (ATP binding cassette subfamily G member 2) gene, which satisfied our QTL-specific Bonferroni-corrected significance criterion (p\u3c6.59×10-5). ABCG2 is a known stem cell marker, which is positively expressed in clonal human trabecular meshwork stem cells. Another positional candidate gene of note is SCD5 (Stearoyl-CoA desaturase 5), which is shown to suppress neurite outgrowth, a marker of neuronal differentiation. SCD5 is of significant interest given that expression of myocilin (MYOC) also inhibits neurite outgrowth. Conclusions: To our knowledge, the VCDR QTL on chromosome 4 is a novel locus and does not overlap with other glaucoma endophenotypes or glaucoma disease status. These results highlight the importance of continued evaluation of genetic factors influencing glaucoma endophenotypes in under-studied populations, such as the Jirels, as new information may be elucidated

Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project

The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p \u3c 1.58 × 10-7) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p \u3c 1.58 × 10-6) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions

Fatty acids linked to cardiovascular mortality are associated with risk factors

Background. Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors. Objective. We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors. Methods. In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ]35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin). Results. The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors. Conclusions. The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD,MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs

Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study

Abstract Background Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study. Methods We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members. Results All renal urate excretion measures were significantly heritable (p <2 × 10−6) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 × 10−7. We observed a strong association (p < 8 × 10−8) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 × 10−6, MAFs: 0.28–0.31). Conclusion For the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations

Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study

Previous studies have demonstrated that low density lipoprotein cholesterol (LDL-C) concentration is influenced by both genes and environment. Although rare genetic variants associated with Mendelian causes of increased LDL-C are known, only one common genetic variant has been identified, the apolipoprotein E gene

Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study

Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P &lt; 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p &lt; 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p &lt;6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p &lt; 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation

Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study

Recent studies have identified chromosomal regions linked to variation in high density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (Apo A-1) and triglyceride (TG), although results have been inconsistent and previous studies of American Indian populations are limite

Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project

The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10-7) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10-6) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions