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TRANSMISSION DISEQUILIBRIUM TRIOS

In 1999 we received supplementary funding from the MRC to establish 900-1000 parent-offspring trios that would allow the transmission disequilibrium test (TDT) to be utilised for replication, fine mapping and candidate gene analyses.

The same standard operating procedures that were defined for the sibling pair study were used. The selection/eligibility criteria of the proband was identical to the sibling pair study, please see below:

Inclusion criteria of the proband:

White European, British origin (up to level of grand-parental ancestry).

Male or female with known hypertension.

The age of diagnosis of hypertension had to be less than 60 years with blood pressure recordings of 150/100mmHg using 1 reading, or 145/95mmHg, mean of 3 readings whilst seated.

Both parents or one parent and siblings to be able to participate in the study.

Exclusion criteria of the proband:

Individuals who consumed more than 21 units of alcohol per week.

Obese individuals defined as a BMI of 30 Kg/m2 or greater.

Diabetics.

Individuals with intrinsic renal disease.

Individuals with a history of secondary hypertension, or co-existing illness, which could confound accurate phenotyping.

Questionnaire information:

Socio-economic, personal medical history, genealogy, family history of cardiovascular disease and medication were all recorded.

Phenotypic measurements:

On treatment blood pressure recordings using the Omron HEM-705CP, portable, semi-automated oscillometric device (Omron Healthcare).

24 hour ambulatory blood pressure recordings (Spacelabs, Model 90207).

Anthropometric measurements (waist-hip ratio, skin fold thickness and body mass index).

A 12-lead electrocardiogram (ECG) was performed.

Each participant was offered an echocardiogram.

Samples, biochemistry and urinary analysis:

Venous blood was collected for biochemical analysis, DNA extraction and peripheral blood lymphocyte preparation.

Blood glucose concentration, total cholesterol, triglycerides, g-GT, urate, and electrolytes were measured at a single central chemical pathology lab in Glasgow (Members of National Quality Assurance Scheme, CPA accredited).

A 24-hour urine sample was also collected and from this 24-hour creatinine clearance, urinary electrolytes and albumin/creatinine ratio were measured.

Data protection and databases:

A unique family identification number was given to each individual and subsequently blood, urine and DNA samples were stored using this identifier.

Computerised records of all samples conformed to the Data Protection Act.

All phenotypic/biochemical and genetic data is stored in a password protected MySQL relational database. To ensure accuracy and data quality control we employed a double data entry system whereby 2 independently trained staff entered all the phenotypic information, a third person reconciled any inconsistencies. Entry of biochemical results and Minnesota coded ECGs was by direct electronic transfer.

Only the proband and any affected siblings were extensively phenotyped, not the parents as their phenotype status is not critical.

At the close of TDT recruitment 890 TDT units had been phenotyped.