Biomedical subjects
Publications and source records attributed to M I McCarthy.
Smoking and demographic variables are known to be risk factors for the development of thyroid-associated orbitopathy (TAO) among patients with Graves' hyperthyroidism, but a firm genetic basis for TAO has not been established. We show that the presence and severity of TAO are associated with an allele of the cytotoxic T lymphocyte antigen-4-gene.
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AIMS/HYPOTHESIS: Linkage between markers close to the uncoupling protein 2 and 3 genes (11q13) and resting metabolic rate and a pre-diabetic phenotype have been found. The syntenic region in mouse has been found to be linked to quantitative traits associated with obesity and diabetes. UCP2 and UCP3 could therefore have an important role in body weight regulation and susceptibility to diabetes. We investigated a recently identified variant of the UCP2 gene in exon 8 as a marker for glucose and weight homeostasis. METHODS: Length variation of the UCP2 exon 8 variant was studied by the polymerase chain reaction and agarose gel electrophoresis. Sequence variants of the UCP3 gene were sought by semi-automated DNA sequencing. RESULTS: In 453 South Indian subjects, we found an association in women between the UCP2 exon variant and body mass index (p = 0.018). These findings were replicated in a separate group of South Indian subjects (n = 143, p < 0.001) irrespective of sex. Although no association was found between the UCP2 exon 8 variant and overt obesity in British subjects, the UCP2 genotype of obese women (n = 83) correlated with fasting serum leptin concentration (p = 0.006) in the presence of extreme obesity. These observations could not be explained by tight linkage disequilibrium with a coding region variant in the region of the UCP3 gene of biological significance. Lastly, no association was found between UCP2 and Type II (non-insulin-dependent) diabetes using either a family based design (85 families) or case control study (normal glucose tolerance n = 335, impaired glucose tolerance n = 42, Type II diabetes n = 76). CONCLUSION/INTERPRETATION: We have described a UCP2 gene exon 8 variant that may affect susceptibility to weight gain by influencing regulation of leptin.
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Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.
Polycystic ovaries (PCO) are highly prevalent in women presenting with hirsutism or recurrent miscarriage but the functional significance of PCO in ovulatory women presenting with infertility remains unclear. We examined the prevalence of PCO, on ultrasonography, among women presenting with infertility. Among 289 couples classified in four main diagnostic categories, PCO were found in 81 (83%) of 98 anovulatory patients, 40 (53%) of 76 patients whose partners had sperm dysfunction, 26 (50%) of 52 patients with tubal disease and in 28 (44%) of 63 patients with unexplained infertility. By comparison, in a control group of 67 parous volunteers, 19 (28%) were found to have PCO. PCO patients with unexplained infertility had higher midfollicular luteinizing hormone and testosterone compared with the group with normal ovaries. The prevalence of PCO was significantly higher in each of the infertility groups than in controls, and a similar tendency (not significant) was observed among women with unexplained infertility. Ovulatory PCO women with infertility had higher testosterone concentrations in comparison with PCO controls. In summary, the prevalence of PCO among ovulatory women with infertility is higher than that in the normal population, suggesting that PCO may, perhaps by virtue of an effect of hyperandrogenaemia, contribute to the causes of subfertility in women with regular menses.
The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.
OBJECTIVE: To determine the consequences of applying revised American Diabetes Association (ADA) (1997) and World Health Organization (WHO) (1998) recommendations for the classification of glucose intolerance in women with previous gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: There were 192 women with previous GDM who took an oral glucose tolerance test (OGTT) 1-86 months after delivery and were classified by WHO (1985), ADA (1997, fasting glucose), and revised WHO (1998) guidelines. RESULTS: Among the 165 women without a preexisting diagnosis of diabetes, WHO-1985 and ADA-1997 provided similar estimates of diabetes prevalence (13.3% vs. 11.5%) but widely differing estimates of impaired glucose homeostasis (31.5% impaired glucose tolerance [IGT] by WHO-1985 vs. 10.9% impaired fasting glucose by ADA-1997 criteria). Overall, 56 women (34%) showed a classification discrepancy between WHO-1985 and ADA-1997 criteria, including 44 with normal fasting glucose by ADA-1997 criteria, but abnormal 2-h glucose by WHO-1985 criteria (40 IGT, 4 diabetes). The cardiovascular risk profile of these women was more favorable than that of 18 women with impaired fasting glucose. WHO-1998 recommendations reproduced ADA-1997 findings when used as a fasting screen, but behaved similarly to WHO-1985 criteria when 2-h glucose values were also analyzed. CONCLUSIONS: All criteria produced similar estimates of diabetes prevalence. However, analyses based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) failed to identify 60% of women with abnormal 2-h glucose levels. Screening women with previous GDM (and by analogy, other groups at high risk of diabetes) with a single fasting glucose has low sensitivity for the detection of abnormal glucose tolerance. Recent guidelines recommending this approach require reevaluation.
When planning an affected sib pair collection for use in a genomewide search for complex trait loci, researchers must ask: (a) Which family structures will yield the most informative pairs? and (b) Should recruitment extend beyond the index sib pair? The optimal collection strategy will depend on the trait's genetic architecture, but this is rarely known for non-Mendelian diseases. In the present report, we study the consequences of collecting only those sib pairs arising from pedigrees with a precisely specified structure as opposed to a strategy that collects all affected sib pairs at random (i.e., blind to the affection status of first-degree relatives). The former approach turns out to be risky because the power of specific pedigree structures can vary dramatically even among models producing identical observable parameters (such as population prevalence and sibling recurrence rate). In contrast, the latter approach typically involves only a modest loss of power as compared with the optimal (but unknowable) design. Further, we compare the strategy of collecting all affected sib pairs at random with the alternative of imposing some modest limitations on family structure (e.g., presence of at least one unaffected sib or parent). The latter approach generally provides some increase in power but entails additional effort to contact and phenotype relatives: the overall merit of imposing such requirements needs to be evaluated in the context of the specific disease to be studied and of the clinical and analytical resources available. In addition, these findings suggest that a further explanation for failure to replicate positive complex trait linkages lies in differences in ascertainment strategy between data sets.
OBJECTIVE: Leptin acts as a satiety factor in regulating food intake and body homeostasis, but its regulation is not well defined. Specific leptin receptors have been found in the brain and it has been hypothesized that leptin production by adipose tissue is under neuroendocrine control. A circadian rhythm has been demonstrated with highest leptin levels between midnight and early morning hours. The possibility that hypopituitarism (or pituitary surgery +/- radiotherapy) abolishes this leptin rhythm was investigated by measuring serum leptin levels during a 24-h period in patients with impaired pituitary function. PATIENTS AND DESIGN: Circulating leptin levels were measured hourly over 24-h in 14 hypopituitary patients (8 women and 6 men) using a sensitive and specific radioimmunoassay. Hypopituitarism was the consequence of pituitary tumors treated surgically and/or with radiotherapy. All patients were GH deficient and were receiving conventional replacement with cortisol (n = 13), thyroxine (n = 12) and desmopressin (n = 4) but not with GH. RESULTS: A significant diurnal variation in circulating leptin concentrations was observed in 13 of the 14 patients. The mean (+/- SEM) leptin levels for 8 women were 51.9 (+/- 10.7) ng/ml and for 6 men 11.0 (+/- 2.0) micrograms/l. The overall lowest leptin levels (29.3 +/- 7.9 ng/ml) were observed at 0830 h after overnight fasting, rising gradually to maximum levels (43.0 +/- 9.8 ng/ml) at 0200 h declining thereafter towards fasting values. The mean (+/- SEM) magnitude of circadian variation in absolute leptin levels from the calculated mean level for each patient was 5.6 (+/- 1.2) ng/ml (8.4 +/- 1.4 for women and 1.9 +/- 0.3 for men). The mean (+/- SEM) of the ratio of the amplitude versus mean leptin levels over 24 h for each individual patient was 0.18 (+/- 0.02) (0.19 +/- 0.03 for women and 0.18 +/- 0.02 for men). CONCLUSIONS: A circadian rhythm for leptin is generally present in hypopituitary patients who had undergone pituitary surgery and/or radiotherapy, with the highest serum leptin levels being obtained between midnight and early morning hours. Although some patients had some residual pituitary activity, intact hypothalamic-pituitary function is not essential for leptin's circadian rhythm.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS: We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS: In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION: Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.
A commonly occurring sequence variant in the islet-specific promoter of the glucokinase gene (-30 G to A) has been variably reported to be associated with reduced insulin secretory responses to oral glucose. The effect of this promoter variant may be subtle and only become apparent under conditions of beta-cell 'stress'. As late pregnancy is a time of increased insulin secretory demand, we have examined whether this common genetic variant was associated with impairment of insulin secretory responses to oral glucose in 92 women in the third trimester of pregnancy. The three women who were homozygous for the variant sequence had a markedly diminished 30' insulin incremental response to oral glucose (10.4, 11.4, and 17.2 pmol insulin mmol-1 glucose, respectively) compared to either heterozygous (49.3 (37.6-64.6 pmol insulin mmol-1 glucose)) (p < 0.002) or homozygous wild-type (51.4 (40.9-64.7 pmol insulin mmol-1 glucose)) (p < 0.002) Mann-Whitney U test) women. In a subset of 35 British Caucasian women with gestational diabetes, no mutations resulting in a change of amino acid sequence were detected by molecular scanning of all exons of the glucokinase gene. In summary, in a cohort of 35 British Caucasian women with gestational diabetes neither missense nor nonsense glucokinase mutations were found. However, in women in the third trimester of pregnancy, homozygosity for a common polymorphic variant in the islet-specific promoter of the glucokinase gene was associated with a highly significant reduction of early insulin secretory responsiveness to oral glucose. Under the conditions of increased secretory demand represented by late pregnancy, a promoter variant in the glucokinase gene may influence the early insulin secretory response to oral glucose.
The family histories of 976 South Indian Type 2 diabetic patients were recorded in a questionnaire-based survey to establish whether the excess maternal transmission of Type 2 diabetes reported in low prevalence Europid populations was also evident in this medium prevalence population. In 450 families (46.1%), no parental history of diabetes was reported. In 423 families with one parent diabetic, 222 fathers (52.5%) and 201 (47.5%) mothers were diabetic. In the remaining 103 (10.6%) families, both parents were diabetic. In contrast to previous studies, we found no evidence for substantial maternal excess in the transmission of diabetes (325 diabetic fathers vs 304 mothers; p = 0.4; p = 0.07 when compared using life table methods). The age of diagnosis of diabetes in probands was lower than that of their diabetic parents (p < 0.001): furthermore increasing parental history of diabetes was associated with an earlier diagnosis of diabetes in probands (p < 0.001). These results emphasize the extensive familial aggregation of Type 2 diabetes in this population but fail to replicate the evidence for excess maternal transmission evident in lower prevalence Europid populations, suggesting ethnic differences in the extent of this phenomenon.
Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p = 0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.
An association between insulin-dependent diabetes mellitus (IDDM) and polymorphisms of the insulin gene on chromosome 11p15 (INS) is a consistent finding in Europid populations. While one study suggested that the INS association is restricted to HLA-DR4-positive individuals, studies in other Europid populations have shown the disease-associated INS genotype to confer susceptibility independently of HLA-DR. We have investigated the role of INS in susceptibility to IDDM in Finland, which has the highest incidence of diabetes mellitus in the world, at two polymorphic restriction sites, 5' and 3' to the insulin gene. From the DiMe (Childhood Diabetes in Finland) Study we studied 154 diabetic children without regard to HLA-DR type; 108 DR4 positive/non-DR3 diabetic children; 39 DR3 positive/non-DR4 diabetic children; 30 DR4/DR3 positive diabetic children; 31 non-DR4/non-DR3 diabetic children; 96 matched DiMe control subjects and 86 other healthy, non-diabetic Finnish control subjects. We found an overall association between IDDM and INS in the high-risk Finnish population only with the 5' polymorphism and identified an INS haplotype negatively associated with IDDM in Finland. However, among diabetic subjects with a reduced HLA-associated susceptibility (non-DR4/non-DR3) both 3' and 5' INS loci showed an association with IDDM (p values 0.02 and 0.0002, respectively). Thus, in the Finnish population insulin gene-encoded susceptibility to IDDM exerts a maximum effect in those with reduced HLA-associated risk.
Though a genetic basis for non-insulin-dependent diabetes mellitus (NIDDM) is clear, the likely mode of inheritance is not known. The segregation of NIDDM was studied in 64 nuclear South Indian pedigrees (449 individuals) ascertained through an affected proband having both parents and more than 1 sibling alive and available for oral glucose tolerance testing. A high proportion of parents were found to be of abnormal glucose tolerance [89 of 128 (70%) diabetic and 11 of 128 (9%) impaired]. Complex segregation analysis was performed using (1) POINTER which implements the mixed model and distinguishes major gene, multifactorial and non-transmitted environmental contributions to affection and (2) COMDS which implements an oligogenic model with major gene, modifier gene and environmental contributions to a) affection and b) diathesis (an ordered polychotomy amongst non-affected family members, based on 2-h plasma glucose level). Using POINTER, there was no formal support for a major gene and the most parsimonious solutions were achieved with multifactorial models. Using COMDS, we found i) significant improvements in models when information on glucose levels in nondiabetic family members (diathesis) was included, ii) support for segregation of a diallelic gene as well as background familial resemblance, and iii) under the best-supported model, this diallelic locus featured incomplete dominance (d = 0.8) and a disease-predisposing allele frequency of 14%. In South Indians, segregation of NIDDM is inadequately described by simple major gene models: more complex models provide more satisfactory descriptions. This finding, if applicable in other populations, has important implications for the search for diabetes-susceptibility genes.
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