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Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.
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Pueblo Maorí , Pueblos Isleños del Pacífico , Humanos , LDL-Colesterol , HDL-Colesterol/genética , Polimorfismo Genético , Proteínas de Transferencia de Ésteres de Colesterol/genéticaRESUMEN
Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.
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Variaciones en el Número de Copia de ADN , Gota , Antígenos de Histocompatibilidad Clase I , Nativos de Hawái y Otras Islas del Pacífico , Humanos , Genotipo , Gota/etnología , Gota/genética , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA , Nativos de Hawái y Otras Islas del Pacífico/genéticaRESUMEN
BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Genoma , Genoma Humano , Genómica , Genotipo , Humanos , Secuenciación Completa del GenomaRESUMEN
OBJECTIVE: The Maori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations. METHODS: A list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry. RESULTS: We identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (rs1635712 [KIAA0319], ORmeta = 1.28, Pmeta = 0.03; rs16869924 [CLNK], ORmeta = 1.37, Pmeta = 0.002; rs2070025 [fibrinogen A alpha chain (FGA)], ORmeta = 1.34, Pmeta = 0.02). The CLNK variant, within the established SLC2A9 gout locus, was genetically independent of the association signal at SLC2A9. CONCLUSION: We provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.
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Gota , Nativos de Hawái y Otras Islas del Pacífico , Frecuencia de los Genes , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Gota/genética , Humanos , Nativos de Hawái y Otras Islas del Pacífico/genética , Nueva Zelanda , Polimorfismo de Nucleótido SimpleAsunto(s)
Efecto Fundador , Enfermedad de Parkinson , Proteínas Quinasas , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/genética , Polinesia , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Background: Risk behaviors for young adults such as alcohol use are associated with increased risk of morbidity and mortality. Patterns of risk behavior may be genetically determined and vary between genders. Previous studies in both young adults and heavy drinking adult samples have demonstrated that some genotypes, such as OPRM1 A118G, COMT Val158Met and DRD2 Taq1A and DRD4 C52IT, may predict addictive behaviors including alcohol consumption and impulsivity, although results have been mixed. Methods: This study aimed to investigate the predictive relationship of these four single nucleotide polymorphisms (SNPs) prospectively on student patterns of drinking using a micro-longitudinal daily diary design in a sample of 628 young adults ages 18-25 of predominantly of European ethnicity. Linear mixed models were used to examine the effect of SNPs on the number of drinks per drinking session with gender as a moderating variable. Results: There were no main effects for genotype on alcohol consumption, nor for gender × genotype for any of the SNPs. There was a trend for an effect of the DRD2 Taq1A on the number of drinks per drinking day and for the interaction of gender and DRD2 Taq1A on the number of drinks per drinking day. Conclusion: These findings suggest that the DRD2 Taq1A, OPRM1 A118G, DRD4 C521T, or COMT Val158Met polymorphisms, are not associated with alcohol consumption in young adults, although there may be a relationship between DRD2 Taq1A and alcohol consumption in young adult males.
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Background: To understand the genetic underpinnings of emotion, researchers have studied genetic variants in the oxytocin system, a hormone and neurotransmitter important to socio-emotional functioning. The oxytocin receptor gene (OXTR) variant rs53576 has been associated with emotional traits such as positive affect and related constructs such as optimism and self-esteem. Individuals carrying the A allele (AG and AA genotypes) of rs53576 have been found to score lower in these traits when compared to GG homozygotes, although not always. Given recent mixed evidence regarding this polymorphism, replication of these associations is critical. Methods: Using a cross-sectional design, the present study tested the association between rs53576 and a wide variety of emotional traits and states in a sample of 611 young adults ages 18 - 25 of various ethnicities (European, Asian, Maori/Pacific Islander, other). Participants completed standard trait measures of positive and negative affect, depressive symptoms, life engagement, psychological well-being, optimism, and self-esteem. They also completed state measures of positive and negative affect and life engagement for 13-days using Internet daily diaries. Results: Controlling for ethnicity and gender, variation at the OXTR variant rs53576 obtained from blood samples was not related to any of the emotional traits or states. This null finding occurred despite measuring emotions in "near to real time" using daily diaries and having sufficient power to detect a medium effect size difference between homozygous genotype groups. Conclusion: These findings suggest that variation at the rs53576 locus may not be as involved in emotional differences as initial studies suggested.
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OBJECTIVE: The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients. METHODS: We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin-8 (IL-8)/CXCL8, IL-1ß, IL-6, IL-10, IL-12, and tumor necrosis factor, after which we performed proteome-wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities. Replication analysis was performed specifically for myeloid-related protein 8 (MRP-8)/MRP-14 complex. RESULTS: Compared to healthy controls and disease control patients, patients with gouty arthritis (n = 48) had significantly higher mean levels of CXCL8 (P < 0.001), while other cytokines were almost undetectable. Similarly, patients with intercritical gout showed high levels of CXCL8. CXCL8 was independently associated with diabetes mellitus in patients with intercritical gout (P < 0.0001). Proteome-wide analysis in gouty arthritis (n = 18) and intercritical gout (n = 39) revealed MRP-8 and MRP-14 as the proteins with the greatest differential expression between low and high levels of CXCL8 and also showed a positive correlation of MRP8/MRP14 complex with CXCL8 levels (R(2) = 0.49, P < 0.001). These findings were replicated in an independent cohort. The proteome of gout patients with high levels of CXCL8 was associated with diabetes mellitus (odds ratio 16.5 [95% confidence interval 2.8-96.6]) and CVD (odds ratio 3.9 [95% confidence interval 1.0-15.3]). CONCLUSION: Circulating levels of CXCL8 are increased during both the acute and intercritical phases of gout, and they coincide with a specific circulating proteome that is associated with risk of diabetes mellitus and CVD. Further research focused on the roles of CXCL8 and MRP8/MRP14 complex in patients with gout is warranted.
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Calgranulina A/inmunología , Calgranulina B/inmunología , Enfermedades Cardiovasculares/inmunología , Diabetes Mellitus/inmunología , Gota/inmunología , Interleucina-8/inmunología , Proteoma/inmunología , Adulto , Anciano , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Femenino , Gota/metabolismo , Humanos , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-12/inmunología , Interleucina-12/metabolismo , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Proteoma/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
INTRODUCTION: Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading. METHODS: Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele. RESULTS: The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m². CONCLUSIONS: In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk. CLINICAL TRIALS REGISTRATION: The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).
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Transportadoras de Casetes de Unión a ATP/genética , Fructosa/farmacología , Proteínas de Neoplasias/genética , Ácido Úrico/análisis , Ácido Úrico/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Adulto , Alelos , Glucemia , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Gota/genética , Gota/metabolismo , Humanos , Hiperuricemia/genética , Masculino , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Sistema de Registros , Factores de RiesgoAsunto(s)
Fructosa/farmacocinética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo I/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo I/metabolismo , Ácido Úrico/sangre , Ácido Úrico/orina , Genotipo , Voluntarios Sanos , Humanos , Hiperuricemia/genética , Hiperuricemia/metabolismoRESUMEN
OBJECTIVE: Consumption of high fructose corn syrup (HFCS)-sweetened beverages increases serum urate and risk of incident gout. Genetic variants in SLC2A9, that exchanges uric acid for glucose and fructose, associate with gout. We tested association between sugar (sucrose)-sweetened beverage (SSB) consumption and prevalent gout. We also tested the hypothesis that SLC2A9 genotype and SSB consumption interact to determine gout risk. METHODS: Participants were 1634 New Zealand (NZ) European Caucasian, Ma¯ori and Pacific Island people and 7075 European Caucasians from the Atherosclerosis Risk in Communities (ARIC) study. NZ samples were genotyped for rs11942223 and ARIC for rs6449173. Effect estimates were multivariate adjusted. RESULTS: SSB consumption increased gout risk. The OR for four drinks/day relative to zero was 6.89 (p=0.045), 5.19 (p=0.010) and 2.84 (p=0.043) for European Caucasian, Ma¯ori and Pacific Islanders, respectively. With each extra daily SSB serving, carriage of the gout-protective allele of SLC2A9 associated with a 15% increase in risk (p=0.078), compared with a 12% increase in non-carriers (p=0.002). The interaction term was significant in pooled (pInteraction=0.01) but not meta-analysed (pInteraction=0.99) data. In ARIC, with each extra daily serving, a greater increase in serum urate protective allele carriers (0.005 (p=8.7×10(-5)) compared with 0.002 (p=0.016) mmol/L) supported the gout data (pInteraction=0.062). CONCLUSIONS: Association of SSB consumption with prevalent gout supports reduction of SSB in management. The interaction data suggest that SLC2A9-mediated renal uric acid excretion is physiologically influenced by intake of simple sugars derived from SSB, with SSB exposure negating the gout risk discrimination of SLC2A9.
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Bebidas , Sacarosa en la Dieta/efectos adversos , Interacción Gen-Ambiente , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Gota/genética , Hiperuricemia/genética , Ácido Úrico/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Genotipo , Gota/epidemiología , Humanos , Hiperuricemia/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Maori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets. METHODS: A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata. RESULTS: A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039). CONCLUSIONS: Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.
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Predisposición Genética a la Enfermedad/genética , Gota/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Adulto , Estudios de Casos y Controles , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: SLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is associated with development of hyperuricaemia and gout. OBJECTIVE: To determine whether genetic variation in SLC2A9 influences the acute serum urate response to a fructose load. METHODS: Following an overnight fast, 76 healthy volunteers (25 Maori, 26 Pacific, 25 European Caucasian) drank a solution containing 64 g fructose. Serum and urine were obtained immediately before and then 30, 60, 120 and 180 min after ingestion. The SLC2A9 single nucleotide polymorphism (SNP) rs11942223 was genotyped and data were analysed based on the presence or absence of the gout protective minor allele (C). RESULTS: The rs11942223 C allele was present in 17 participants (22%). In the entire group, fructose intake led to an increase in serum urate, which peaked 60 min following fructose ingestion (analysis of variance p=0.006). The presence of the C allele was associated with an attenuated hyperuricaemic response (p(SNP)<0.0001) and increased fractional excretion of uric acid (FEUA) (p(SNP)<0.0001) following the fructose load. The effects of rs11942223 variants on serum urate and FEUA in response to fructose were present only in Caucasian ancestral subgroups but not in the Maori and Pacific ancestral subgroup. CONCLUSIONS: Variation in SLC2A9 influences acute serum urate and FEUA responses to a fructose load. SLC2A9 genotype may influence the development of gout on exposure to fructose-containing beverages, particularly in European Caucasian populations.
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Fructosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Gota/genética , Hiperuricemia/genética , Edulcorantes Nutritivos/metabolismo , Ácido Úrico/metabolismo , Adolescente , Adulto , Femenino , Fructosa/farmacología , Genotipo , Gota/metabolismo , Humanos , Hiperuricemia/metabolismo , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/genética , Edulcorantes Nutritivos/farmacología , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto JovenRESUMEN
OBJECTIVES: The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility. METHODS: A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used. RESULTS: The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; ORâ=â0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85). CONCLUSIONS: We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.
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Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Secuencia de Bases , Haplotipos , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Genetic variation in ABCG2 (rs2231142, Q141K), encoding a uric acid transporter, is associated with gout in diverse populations. The aim of this study was to examine a role for ABCG2 in gout susceptibility in New Zealand Maori, Pacific Island and Caucasian samples. Patients (n = 185, 173 and 214, for Maori, Pacific Island and Caucasian, respectively) satisfied the American College of Rheumatology gout classification criteria. The comparison samples comprised 284, 129 and 562 individuals, respectively, without gout. rs2231142 was genotyped and stratification accounted for using genomic control markers. Association of the minor allele of rs2231142 with gout was observed in the Pacific Island samples (OR = 2.80, P(STRAT) < 0.001 after accounting for effects of population structure), but not in the Maori samples (OR = 1.08, P(STRAT)= 0.70), with heterogeneity in association evident between the Maori and Pacific Island datasets (P(HET) = 0.001). A similar dichotomy in association was observed when samples were stratified into Western (Tonga, Samoa, Niue, Tokelau) versus Eastern Polynesian (Maori, Cook Island) origin (OR = 2.59, P(STRAT) < 0.001; OR = 1.12, P(STRAT)= 0.48, respectively; P(HET) = 0.005). Association with gout was observed in the Caucasian samples (OR = 2.20, P = 3.2 × 10(-8)). Unlike SLC2A9, which is a strong risk factor for gout in both Maori and Pacific Island people, ABCG2 rs2231142 has a strong effect only in people of Western Polynesian ancestry. Our results emphasize the need to account for sub-population differences when undertaking biomedical genetic research in a group defined by a geographical region and shared ancestry but characterized by migratory events that create bottlenecks and altered genetic structure in the founder populations.
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Transportadoras de Casetes de Unión a ATP/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Gota/etnología , Gota/genética , Proteínas de Neoplasias/genética , Población Blanca/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Emigración e Inmigración , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda , Filogenia , Polimorfismo de Nucleótido Simple/genética , Polinesia , Adulto JovenRESUMEN
BACKGROUND: The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation. METHODS AND FINDINGS: We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: pâ=â0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESRâ=â50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1-50.0) for haplotype 1 and 14.2 mg/l (9.5-23.2) for haplotype 4. CONCLUSIONS: Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
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Artritis Reumatoide/genética , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Sedimentación Sanguínea , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA. METHODS: FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry. RESULTS: Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4). CONCLUSIONS: One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.
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Artritis Reumatoide/genética , Receptores de IgG/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Proteínas Ligadas a GPI , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: Angiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin alphanubeta 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples. METHODS: We compared genotype frequencies in 740 NZ Caucasian RA patients and 553 controls genotyped for rs3738919, using a polymerase chain reaction-restriction fragment length polymorphism assay. A TaqMan genotyping SNP assay was used to type 713 Caucasian RA patients and 515 control samples from Oxford for the rs3738919 variant. Association of rs3738919 with RA was tested in these two sample sets using the chi-square goodness-of-fit test. The Mantel-Haenszel test was used to perform a meta-analysis, combining the genetic results from four independent Caucasian case control cohorts, consisting of 3,527 cases and 4,126 controls. Haplotype analysis was also performed using SNPs rs3911238, rs10174098 and rs3738919 in the Wellcome Trust Case Control Consortium, NZ and Oxford case control samples. RESULTS: We found no evidence for association between ITGAV and RA in either the NZ or Oxford sample set (odds ratio [OR] = 0.88, P(allelic) = 0.11 and OR = 1.18, P(allelic) = 0.07, respectively). Inclusion of these data in a meta-analysis (random effects) of four independent cohorts (3,527 cases and 4,126 controls) weakens support for the hypothesis that rs3738919 plays a role in the development of RA (OR(combined) = 0.92, 95% confidence interval 0.80 to 1.07; P = 0.29). No consistent haplotype associations were evident. CONCLUSIONS: Association of ITGAV SNP rs7378919 with RA was not replicated in NZ or Oxford case control sample sets. Meta-analysis of these and previously published data lends limited support for a role for the ITGAV in RA in Caucasians of European ancestry.