Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ∼4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10−8 for rs7775228 and 6.73×10−8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.
The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.
The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent.
None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.
Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.
Osteoarthritis (OA), the most common form of arthritis, is a highly debilitating disease of the joints and can lead to severe pain and disability. There is no cure for OA. Current treatments often fail to alleviate its symptoms leading to an increased demand for joint replacement surgery. Previous epidemiological and genetic research has established that OA is a multifactorial disease with both environmental and genetic components. Over the past 6 years, a candidate gene study and several genome-wide association scans (GWAS) in populations of Asian and European descent have collectively established 15 loci associated with knee or hip OA that have been replicated with genome-wide significance, shedding some light on the aetiogenesis of the disease. All OA associated variants to date are common in frequency and appear to confer moderate to small effect sizes. Some of the associated variants are found within or near genes with clear roles in OA pathogenesis, whereas others point to unsuspected, less characterised pathways. These studies have also provided further evidence in support of the existence of ethnic, sex, and joint specific effects in OA and have highlighted the importance of expanded and more homogeneous phenotype definitions in genetic studies of OA.
Conflicting findings on the association of single nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with susceptibility to knee osteoarthritis (OA) have been reported in European Caucasians. To examine the associations of these SNPs with OA in East Asian populations and to evaluate their global significance, we conducted two case-control studies in 955 Chinese and 750 Japanese patients.
We genotyped the previously implicated SNPs rs585017 (in RHOB) and rs4720262 (in TXNDC3) in patients with primary symptomatic knee OA with radiographic confirmation and in matched control individuals, and analyzed their associations. We further conducted a meta-analysis of the study findings together with those of previously reported European studies using the DerSimonian-Laird procedure.
A significant association of RHOB with knee OA was observed in male Chinese patients (P = 0.02). No significant associations were found for RHOB in any other comparisons in the East Asian populations. The association of TXNDC3 was replicated in Chinese female (P = 0.04) and Japanese (P = 0.03) patients, although none of these associations persisted after Bonferroni correction. Significant association (P = 0.02 for the allelic frequency) with nonsignificant heterogeneity was found in the East Asian replication study. No significant association was found in any comparison in the meta-analysis for all studies.
Our study replicates the association, previously reported in European Caucasians, of TXNDC3 with knee OA susceptibility in an East Asian population.
A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10−34), HLA-DQB1 on 6p21 (P=4.7 × 10−7), and CDKN2A/B on 9p21 (P=6.1 × 10−16). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10−40). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects – population specific and common – on susceptibility to CAD.
coronary artery disease; gene; association study; Japanese
Changes in knee mechanics following anterior cruciate ligament reconstruction (ACLR) have been implicated as a contributor to the development of premature osteoarthritis (OA). However, changes in ambulatory loading in this population have not been well documented. While the magnitude of the external knee moment vector is a major factor in loading at the knee, there is not a comprehensive understanding of the changes in the individual components of the vector following ACL reconstruction. The purpose of this study was to test for differences in the three components of the external knee moment during walking and stair locomotion between ACLR, contralateral and healthy control knees. Forty-five ACLR and 45 healthy control subjects were tested during walking, stair ascent and descent. ACLR knees had a lower first peak adduction moment than contralateral knees during all three activities. Similarly, additional cases of significant differences between ACLR and contralateral knees consisted of lower peak moments for the ACLR than the contralateral knees. These differences were due to both ACLR and contralateral knees as the ACLR knees indicated lower and the contralateral knees greater peak moments compared to healthy control knees. The results suggest a compensatory change involving greater loading in the contralateral knee, perhaps due to lower loading of the ACLR knee. Further, lower knee moments of the ACLR knee suggest that increased joint loading may not be the initiating factor in the development of OA following ACL reconstruction; but rather previous described kinematic or biological changes might initiate the pathway to knee OA.
ACL; reconstruction; moments; knee; control
In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD).
We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1×10−30 in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls.
Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci–APOB, APOE-C1, CETP, and APOA5–and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3×10−41), CETP rs3764261 for HDL-C (p = 5.2×10−24), and APOA5 rs662799 for triglycerides (p = 5.8×10−54). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7×10−8), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1×10−7), and APOE rs7412 (p = 6.1×10−13).
Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.
Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4− (AQP4−) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4 + against AQP4− patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4− MS, which excluded DRB1*15:01. This study is the largest study of the HLA’s contribution to MS in Japanese individuals.
multiple sclerosis; HLA; Japanese; MHC; AQP4
An association between osteoarthritis (OA) and functional polymorphisms in the aspartic acid (D) repeat of the asporin (ASPN) gene was reported in Japanese and Han Chinese populations. The aim of this study was to assess the association of variants in the ASPN gene with the presence of radiographic hand and/or knee OA in a US Caucasian population.
Ten SNPs within the ASPN gene were genotyped in 775 affected siblings with radiographically confirmed hand or knee OA, and the allelic, genotypic and haplotypic association results were examined.
One variant (SNP RS7033979) showed nominal evidence of association with both hand OA (P=0.042) and knee OA (P=0.032). Four additional SNPs showed nominal evidence of association with knee OA only. These associations were only observed with genotypic tests; the corresponding allelic and haplotype tests did not corroborate the single-point association results.
These data suggest that polymorphisms within ASPN are not a major influence in susceptibility to hand or knee OA in US Caucasians.
Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.
We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.
We identified five genome-wide significant loci (binomial test p≤5·0×10−8) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.
Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.
arcOGEN was funded by a special purpose grant from Arthritis Research UK.
Genetic variants associated with fasting glucose in European ancestry populations are increasingly well understood. However, the nature of the associations between these SNPs and fasting glucose in other racial and ethnic groups is unclear. We sought to examine regions previously identified to be associated with fasting glucose in Caucasian GWAS across multiple ethnicities in the Multi-Ethnic Study of Atherosclerosis (MESA). Non-diabetic MESA participants with fasting glucose measured at the baseline exam and with GWAS genotyping were included; 2349 Caucasians, 664 individuals of Chinese descent, 1366 African Americans, and 1171 Hispanics. Genotype data was generated from the Affymetrix 6.0 array and imputation in IMPUTE. Fasting glucose was regressed on SNP dosage data in each ethnic group adjusting for age, gender, MESA study center, and ethnic-specific principal components. SNPs from the three gene regions with the strongest associations to fasting glucose in previous Caucasian GWAS (MTNR1B / GCK / G6PC2) were examined in depth. There was limited power to replicate associations in other ethnic groups due to smaller allele frequencies and limited sample size; SNP associations may also have differed across ethnic groups due to differing LD patterns with causal variants. rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude and direction of association with fasting glucose across ethnic groups, although the associations were often not nominally significant. In conclusion, certain SNPs in MTNR1B and GCK demonstrate consistent effects across four racial and ethnic groups, narrowing the putative region for these causal variants.
GWAS; fasting glucose; SNP
The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
We performed a meta-analysis of 2 genome-wide association studies of
coronary artery disease comprising 1,515 cases with coronary artery disease and
5,019 controls, followed by de novo replication studies in
15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully
identified four new loci for coronary artery disease reaching genome-wide
significance (P < 5 × 10−8),
which mapped in or near TTC32-WDR35, GUCY1A3,
C6orf10-BTNL2 and ATP2B1. We also
replicated four loci previously identified in European populations
(PHACTR1, TCF21, CDKN2A/B
and C12orf51). These findings provide new insights into
biological pathways for the susceptibility of coronary artery disease in Chinese
We aimed to explore the involvement of a multiallelic functional polymorphism in knee osteoarthritis (OA) susceptibility as a prototype of possible genetic factors escaping GWAS detection.
OA patients and controls from three European populations (Greece, Spain and the UK) adding up to 1003 patients (716 women, 287 men) that had undergone total knee joint replacement (TKR) due to severe primary OA and 1543 controls (758 women, 785 men) lacking clinical signs or symptoms of OA were genotyped for the D6S1276 microsatellite in intron 1 of BMP5. Genotype and mutiallelic trend tests were used to compare cases and controls.
Significant association was found between the microsatellite and knee OA in women (P from 3.1 x10-4 to 4.1 x10-4 depending on the test), but not in men. Three of the alleles showed significant differences between patients and controls, one of them of increased risk and two of protection. The gender association and the allele direction of change were very concordant with those previously reported for hip OA.
We have found association of knee OA in women with the D6S1276 functional microsatellite that modifies in cis the expression of BMP5 making this a sounder OA genetic factor and extending its involvement to other joints. This result also shows the interest of analysing other multiallelic polymorphisms.
The pleiotropic cytokine, interleukin-6 (IL-6), has emerged as a key factor in the biology of aging and the physiology of inflammation. Yet much of what we know about the normal functioning of IL-6 has been generated primarily from research on European populations and Americans of European descent. Our analyses compared IL-6 levels in 382 middle-aged and older Japanese to the values found in 1209 Caucasian- and African-Americans from the Midlife in the United States survey (MIDUS). Across the life span from 30–80 years of age, mean IL-6 levels were strikingly lower in Japanese individuals. Significantly lower levels of C-reactive protein (CRP) and fibrinogen (FBG) provided confirmatory evidence for a population difference in proinflammatory activity. Because IL-6 release has been associated with obesity, differences in body mass index (BMI) were taken into consideration. Japanese had the lowest, and African-Americans had the highest overall BMIs, but significant group differences in IL-6 persisted even after BMI was included as a covariate in the analyses. Additional support for distinct variation in IL-6 biology was generated when systemic levels of the soluble receptor for IL-6 (sIL-6r) were evaluated. Serum sIL-6r was higher in Japanese than Americans, but was most notably low in African-Americans. Our cytokine data concur with national differences in the prevalence of age-related illnesses linked to inflammatory physiology, including cardiovascular disease. The findings also highlight the importance of broadening the diversity of people included in population studies of health and aging, especially given the relative paucity of information for some Asian countries and on individuals of Asian heritage living in the US.
interleukin-6; soluble interleukin-6 receptor; aging; inflammation; Japanese; African-American; race; C-reactive protein; fibrinogen; body mass index; obesity
Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population.
We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32×10−4; odds ratio = 0.48 [95% CI = 0.31–0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway.
Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.
Neural tube defects (NTDs) constitute a major group of congenital malformations with an overall incidence of approximately 1 to 2 in 1000 live births in the United States. Hispanic Americans have a 2.5 times higher risk than the Caucasian population. Spina bifida meningomyelocele (SBMM) is a major clinical presentation of NTDs resulting from lack of closure of the spinal cord caudal to the head. In a previous study of spina bifida (SB) patients of European Caucasian descent, it was suggested that specific haplotypes of the platelet-derived growth factor receptor-α (PDGFRA) gene P1 promoter strongly affected the rate of NTD genesis. In our study, we evaluated the association of PDGFRA P1 in a group of 407 parent-child triads (167 Caucasian, 240 Hispanics) and 164 unrelated controls (89 Caucasian, 75 Hispanic). To fully evaluate the association of PDGFRA P1, we performed both transmission-disequilibrium test (TDT) and association analyses to test the hypotheses that PDGFRA P1 was (1) transmitted preferentially in SBMM affected children and (2) associated with the condition of SBMM comparing affected children to unaffected controls. We did find that there was a different allelic and genotypic distribution of PDGFRA P1 when comparing Hispanics and Caucasians. However, neither ethnic group showed strong association between SBMM and the PDGFRA P1 region. These findings suggest that PDGFRA P1 does not have a major role in the development of SBMM.
spina bifida meningomyelocele (SBMM); population stratification; platelet-derived growth factor receptor-α (PDGFRA) gene P1 promotor; association study; transmission disequilibrium testing (TDT)
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354–1.657; P = 4.74×10−31). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.
The prevalence of knee osteoarthritis(OA) in East Asia is as common for men and even higher for women than that reported in the Caucasian population. Since both population aging and economic growth have taken place at a much faster pace in Asian countries, such as South Korea, one would expect knee OA to become a major public health problem. However, few studies have examined the influence of knee OA on the quality of life (QoL) and physical function in Asia. The aim of this cross-sectional study is to investigate the influence of knee osteoarthritis (OA) on the quality of life (QoL), function and lower extremity physical performance and the gender difference in its influence in elderly community residents in Korea.
Participants were from the population-based Hallym Aging Study (HAS). The mean age of the 504 study subjects was 70.2 years and 274 (54%) were women. Demographic information was obtained by questionnaire, and radiographic evaluations consisted of weight-bearing semi-flexed knee radiographs. Self-reported QoL and function were assessed using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Short Form 12-item (SF-12). Performance-based lower extremity function was assessed using the tests consisting of standing balance, usual walk and chair stands. The odds ratios(ORs) for belonging to the worst quartile of WOMAC and physical performance test were calculated by logistic regression analysis in radiographic knee OA compared to non-OA after adjustment of confounders. Scores for SF-12 items were analyzed using general linear models and means adjusted for age, BMI and OA severity were compared.
Subjects with radiographic knee OA had significantly increased OR for belonging to the worst WOMAC quartile(for pain, 2.13,95% confidence interval[CI], 1.33-3.40, for stiffness, 2.94,95% CI,1.78-4.86, and for function, 2.97, 95% CI,1.83-4.81) and significantly worse SF-12 scores compared to non-OA after adjustment of age, BMI and sex. Women had worse WOMAC and SF-12 scores compared to men, regardless of the presence of radiographic knee OA after adjustment of age, BMI and OA severity. OA subjects had significantly worse performance score for usual walk and chair stands compared to non-OA subjects, but the ORs were no more significant after adjustment of sex.
Knee OA negatively affects the QoL and physical function in both genders, but women are more adversely affected than men.
A recent meta-analysis of published genome-wide association studies (GWAS) in populations of European descent reported novel associations of markers mapping to the CD40, CCL21 and CDK6 genes with rheumatoid arthritis (RA) susceptibility while a large-scale, case-control association study in a Japanese population identified association with multiple single nucleotide polymorphisms (SNPs) in the CD244 gene. The aim of the current study was to validate these potential RA susceptibility markers in a UK population.
A total of 4 SNPs (rs4810485 in CD40, rs2812378 in CCL21, rs42041 in CDK6 and rs6682654 in CD244) were genotyped in a UK cohort comprising 3962 UK patients with RA and 3531 healthy controls using the Sequenom iPlex platform. Genotype counts in patients and controls were analysed with the χ2 test using Stata.
Association to the CD40 gene was robustly replicated (p=2×10−4, OR 0.86, 95% CI 0.79 to 0.93) and modest evidence was found for association with the CCL21 locus (p=0.04, OR 1.08, 95% CI 1.01 to 1.16). However, there was no evidence for association of rs42041 (CDK6) and rs6682654 (CD244) with RA susceptibility in this UK population. Following a meta-analysis including the original data, association to CD40 was confirmed (p=7.8×10−8, OR 0.87 (95% CI 0.83 to 0.92).
In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus.
Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.
We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.
Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).
Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
It has been reported that there is an inverse association between osteoarthritis (OA) and osteoporosis. However, the relationship of bone mass to OA in a Japanese population whose rates of OA are different from Caucasians remains uncertain.
We studied the association of appendicular bone mineral density (second metacarpal; mBMD) and quantitative bone ultrasound (calcaneus; stiffness index) with knee and hand OA among 567 Japanese community-dwelling women. Knee and hand radiographs were scored for OA using Kellgren-Lawrence (K/L) scales. In addition, we evaluated the presence of osteophytes and of joint space narrowing. The hand joints were examined at the distal and proximal interphalangeal (DIP, PIP) and first metacarpophalangeal/carpometacarpal (MCP/CMC) joints.
After adjusting for age and body mass index (BMI), stiffness index was significantly higher in women with K/L scale, grade 3 at CMC/MCP joint compared with those with no OA. Adjusted means of stiffness index and mBMD were significantly higher in women with definite osteophytes at the CMC/MCP joint compared to those without osteophytes, whereas there were no significant differences for knee, DIP and PIP joints. Stiffness index, but not mBMD, was higher in women with definite joint space narrowing at the CMC/MCP joint compared with those with no joint space narrowing.
Appendicular bone mass was increased with OA at the CMC/MCP joint, especially among women with osteophytes. Our findings suggest that the association of peripheral bone mass with OA for knee, DIP or PIP may be less clearcut in Japanese women than in other populations.
Genome-wide association studies (GWAS) have identified more than 30 single nucleotide polymorphisms (SNPs) that were reproducibly associated with prostate cancer (PCa) risk in populations of European descent. In aggregate, these variants have shown potential to predict risk for PCa in European men. However, their utility for PCa risk prediction in Chinese men is unknown.
We selected 33 PCa risk-related SNPs that were originally identified in populations of European descent. Genetic scores were estimated for subjects in a Chinese case-control study (1,108 cases and 1,525 controls) based on these SNPs. To assess the performance of the genetic score on its ability to predict risk for PCa, we calculated Area under the curve (AUC) of the receiver operating characteristic (ROC) in combination with 10-fold cross-validation.
The genetic score was significantly higher for cases than controls (P = 5.91×10-20), and was significantly associated with risk of PCa in a dose-dependent manner (P for trend: 4.78×10-18). The AUC of the genetic score was 0.604 for risk prediction of PCa in Chinese men. When ORs derived from this Chinese study population were used to calculate genetic score, the AUCs were 0.631 for all 33 SNPs and 0.617 when using only the 11 significant SNPs.
Our results indicate that genetic variants related to PCa risk may be useful for risk prediction in Chinese men. Prospective studies are warranted to further evaluate these findings.
Genetic score; Cumulative risk; Prostate cancer; AUC; Risk prediction; Susceptibility; Chinese