Biomedical subjects

Christopher J Groves

Publications and source records attributed to Christopher J Groves.

13 recordsLinked to original sources

PubMed2006

Cell-surface and cytokine biomarkers in autoimmune and inflammatory diseases.

Increasing emphasis is being placed on biomarkers as indicators of disease states in patients with autoimmune and inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. Careful description of the expression of cell-surface markers and cytokines produced by T and B lymphocytes can lead to a more complete characterization of disease activity in patient populations, and serve as an indicator of the patient's response to therapy.

Anti-Inflammatory Agents↗

PubMed2006

Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.

BACKGROUND: A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.

Adult↗

PubMed2006

Significant linkage of BMI to chromosome 10p in the U.K. population and evaluation of GAD2 as a positional candidate.

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genome-wide P=0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01<P<0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity.

Adult↗

PubMed2006

Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q.

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.

Adult↗

PubMed2006

Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.

Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.

Adult↗

PubMed2005

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus.

To search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2beta (TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: chi(2)=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20-2.06, intron 1+774 (G/T); chi(2)=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22-2.09, intron 1+2093 (A/C); chi(2)=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23-2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes.

Base Sequence↗

PubMed2005

Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Adult↗

PubMed2005

Prevalence and morphology of pouch and ileal adenomas in familial adenomatous polyposis.

PURPOSE: In familial adenomatous polyposis, the long-term risk of pouch polyposis and potential for pouch cancer are unknown. Our aim was to evaluate prospectively the prevalence, nature, and etiology of pouch ileal adenomas with that of nonpouch ileal adenomas in familial adenomatous polyposis. METHODS: Sixty patients with familial adenomatous polyposis pouch, 47 familial adenomatous polyposis patients with ileorectal anastomosis, and 20 younger patients with familial adenomatous polyposis who had prophylactic colectomy were examined with videoendoscopy. RESULTS: Adenomatous polyps were found in the pouches of 34 patients (57 percent). A total of 362 polyps were identified (range, 0-50 per patient). A logistic regression model confirmed that there was a significant association between the increasing age of the patient and the presence of pouch adenomas (P < 0.02) and the length of follow-up since pouch surgery (P < 0.05). There was no apparent relationship between the development of pouch adenomas and the severity of either colonic or duodenal polyposis and there were no clear genotype or phenotype correlations. Most polyps were tubular adenomas with mild dysplasia, but 11 patients had more advanced histology, including two patients with large villous adenomas. Nonpouch ileal mucosa was spared from visually observed adenomas, with only 1 of 48 (2 percent) patients with ileorectal anastomosis adenomas and 0 of 20 (0 percent) younger, precolectomy patients having terminal ileal adenomas. However, microadenomas were present on random biopsy in 4 percent to 5 percent of nonpouch ileum. CONCLUSION: The risk of pouch cancer in familial adenomatous polyposis is unclear, but follow-up periods since surgery remain relatively short. Long-term endoscopic surveillance of familial adenomatous polyposis pouches is thus recommended along with evaluation of potential therapeutic options for pouch adenomas.

Adenoma↗

PubMed2004

Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone.

CYP11A, the gene encoding p450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies.

Adult↗

PubMed2004

Evidence from a large U.K. family collection that genes influencing age of onset of type 2 diabetes map to chromosome 12p and to the MODY3/NIDDM2 locus on 12q24.

Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes.

Chromosome Mapping↗

PubMed2003

Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility.

The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE support an important role in glucose homeostasis. We sought evidence for association between IDE variation and diabetes by mutation screening, defining local haplotype structure, and genotyping variants delineating common haplotypic diversity. An initial case-control analysis (628 diabetic probands from multiplex sibships and 604 control subjects) found no haplotypic associations, although one variant (IDE2, -179T-->C) showed modest association with diabetes (odds ratio [OR]1.25, P = 0.03). Linkage partitioning analyses failed to support this association, but provided borderline evidence for a different variant (IDE10, IVS20-405A-->G) (P = 0.06). Neither variant was associated with diabetes when replication was sought in 377 early onset diabetic subjects and 825 control subjects, though combined analysis of all typed cohorts indicated a nominally significant effect at IDE2 (OR 1.21 [1.04-1.40], P = 0.013). In the absence of convincing support for this association from linkage partitioning or analyses of continuous measures of glycemia, we conclude that analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans.

Blood Glucose↗

PubMed2003

Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11.

A young onset of type 2 diabetes is likely to result, in part, from greater genetic susceptibility. Young-onset families may therefore represent a group in which genes are more easily detectable by linkage. To test this hypothesis, we conducted age at diagnosis (AAD) stratified linkage analyses in the Diabetes UK Warren 2 sibpairs. In the previously published unstratified analysis, evidence for linkage (logarithm of odds [LOD] >1.18) was found at seven loci. The LOD scores at these seven loci were higher in the 245 families with AAD <55 years (L55) compared with the 328 families with AAD >55 years (G55). Five of these seven loci (1q24-25, 5q13, 8p21-22, 8q24.2, and 10q23.2) had LOD scores >1.18 in the L55 subset but only one (8p21-22) did in the G55 subset. Two additional loci (8q21.13 and 21q22.2) showed evidence for linkage in the L55 subset alone. Another locus (22q11) showed evidence for linkage in a subset of families with AAD <45 years. Using a locus-counting approach, the L55 subset had significantly more loci (P approximately 0.01) than expected under the null hypothesis of no linkage across the LOD score range 0.59-3.0. In contrast, the G55 subset contained no more susceptibility loci than that expected by chance. In conclusion, young-onset families provide both disproportionate evidence for linkage to known loci and evidence for additional novel loci. Our data confirm our hypothesis that families segregating young-onset type 2 diabetes represent a more powerful resource for defining susceptibility genes by linkage.

Age of Onset↗

PubMed2001

Evidence for linkage of stature to chromosome 3p26 in a large U.K. Family data set ascertained for type 2 diabetes.

We have analyzed data from 573 pedigrees from the United Kingdom for evidence for linkage to loci influencing adult stature. Our data set comprised 1,214 diabetic and 163 nondiabetic siblings for whom height data were available. We used variance-components analysis implemented in GENEHUNTER 2 and a modification of the Haseman-Elston regression method, HE-COM. We found evidence for a locus on 3p26 (LOD score 3.17) influencing height in this adult sample, with less-significant evidence for loci on chromosomes 7, 10, 15, 17, 19, and 20. Our findings extend similar recent studies in Scandinavian and Quebecois populations, adding further evidence that height is indeed under the control of multiple genes.

Adult↗