Reference
Complete the bibliographic reference for the article according to AJE format.

Hokanson JE, Kamboh MI, Scarboro S, Eckel RH, Hamman RF. Effects of the hepatic lipase gene and physical activity on coronary heart disease risk. Am J Epid 2003;158(9):836-843.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study

To examine the impact of the LIPC-480C>T polymorphism and physical activity on clinical coronary heart disease in a population-based prospective study.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: Hepatic lipase gene (LIPC)
2. Chromosome location: 15q21-q23
3. Gene product/function: hepatic lipase, an enzyme that catalyzes hydrolysis of phospholipids, mono-, di- and tri-glycerides, and acyl-CoA thioesters; is an important determinant of HDL concentrations and LDL subclass distribution.
4. Alleles: LIPC-480C>T (LIPC-480 T and LIPC-480 C alleles) .
5. OMIM#: 151670

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

Physical activity

Clinical coronary heart disease. A coronary heart disease (CHD) event diagnosed was the primary study outcome. CHD events were defined based on a reported heart attack or electrocardiogram major Q-wave abnormality for nonfatal CHD, and ICD-9 codes 410-414.9 (acute, subacute, and chronic ischemic heart disease) for fatal CHD (cause of death determined by 3-member committee). Vital status and CHD morbidity were determined subsequent to the baseline assessment through 1998 by annual interviews, obituary monitoring, or Colorado state death certificate searches. Medical records or autopsy/coroner’s reports were reviewed. Only 2% of enrolled subjects were lost to follow-up.

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants (% of total eligible)

N/A

Cohort definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Cohort selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Cohort selection criteria: Person aged 20-74 years during 1984-1992 from randomly selected 21% sample of occupied structures in the two-county area of the San Luis Valley in rural southern Colorado. This cohort was constructed for the San Luis Valley Diabetes Study."
2. Exclusion criteria: diagnosis of diabetes or impaired glucose tolerance at baseline visit, using 1995 WHO criteria for diabetes or use of oral hypoglycemic agents or insulin. The paper does not explicitly state that persons with diagnosed coronary heart disease (CHD) at baseline were excluded from this study; examination of the survival curves in Figure 2 indicates there were a few CHD events occurring before age 20, the minimum age of eligibility.
3. Gender: 49.4% male (Hispanics), 482% male (non-Hispanic whites)
4. Race/ethnicity: 397 Hispanics (41.1%), 569 non-Hispanic whites (58.9%)
5. Age: Range 20-74 years at baseline; mean (standard deviation): 51.0 (12.6) Hispanics, 52.4 (11.3) non-Hispanic whites
6. Time period: Subjects were recruited for baseline evaluation during 1984-1992; reports of this study are based on follow-up through 1998 (follow-up times ranged from 6 to 14 years).
7. Geographic location: two-county area of the San Luis Valley in rural southern Colorado
8. Number of participants: 966 (65% of total eligible, based on 96.6% participation of eligible sampled households, 68.4% participation in baseline glucose tolerance test among eligible persons identified in eligible sampled households, and 98% follow-up of recruited participants).

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

1. Environmental factors considered for interaction:
2. Environmental factor: self-reported physical activity at work or during leisure time
3. Exposure assessment: collected by personal structured interview at baseline, in Spanish or English
4. Exposure definition: vigorous activity (any activity the study participant considered strenuous or caused fatigue, increased heart rate, or sweating) three or more times a week for at least 20 minutes vs. moderate (vigorous activity <3 times/week for at least 20 minutes) or no vigorous physical activity. Moderate and no vigorous activity were combined after preliminary analysis indicating similar relations to CHD for these groups.
5. Number of participants with exposure: at least 960 of 966

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: LIPC-480
2. DNA source: plasma collected at baseline exam after 12 hour fast
3. Methodology: digestion of the polymerase chain reaction-amplified promoter sequences with NlaIII (Guerra R, Wang J, Grundy SM et al. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1997;94:4532-7).
4. Number of participants genotyped: at least 960 out of 966

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

• Table 1
• Table 2
• Table 3
• Figures 1 & 2

The authors conclude that:

1. The hepatic lipase promoter polymorphism (LIPC-480 TT genotype) predicted a greater than two-fold increase in coronary heart disease events in their population-based prospective study of Hispanic and non-Hispanic white adults aged 20-74 years in rural Colorado;
2. The increase in coronary heart disease events associated with this high-risk genotype was seen for subjects who participated in normal, non-vigorous levels of physical activity, but not in those who reported vigorous physical activity (20 minutes three times a week or more);
3. Their data support a role for gene-environment interaction in the susceptibility to coronary heart disease and may provide an impetus for increasing levels of physical activity to prevent CHD in high-risk populations;
4. Further study is needed to confirm hypotheses regarding the nature of the effect of vigorous physical activity on the risk of CHD in persons with the LIPC-480 TT genotype (e.g., exercise-induced decrease in remnant lipoproteins and a subsequent increase in coronary flow reserve in subjects with genetic susceptibility to these abnormalities).

• A major strength of this study was its population-based, prospective cohort design, conducted as part of an original study of diabetes in a biethnic population of Hispanics and non-Hispanic whites.
• Overall combined response and follow-up completion rate was 65%, mostly due to refusal to undergo a glucose tolerance test and clinic examination. Although some information was collected for these refusers, there was no discussion of possible selection bias.
• A few prevalent CHD cases at baseline may have been included as outcomes and would preferably been excluded; however, this is unlikely to have affected results significantly.
• Physical activity was determined by structured interview at baseline. Recall bias is possible, though likely non-differential with respect to LIPC genotype and subsequent CHD. Of more concern is the likelihood that physical activity levels changed during the years of follow-up, possibly associated with risk of CHD.
• The study dealt extensively with possible population stratification in the analysis, including testing of a genotype by ethnicity in teraction in the Cox proportional hazards model. No evidence of potential confounding by ethnicity was identified. No information was provided about potential genetic variation within the Hispanic population studied in this rural area of Colorado
• Lipid levels by physical activity level or by the combination of physical activity and genotype were not reported. Such data may help understand the impact of the LIPC-480 polymorphism on lipid metabolism and modifying effect of exercise. It may have provided biologic justification for combining subjects with CC and CT genotypes in Cox proportional hazards modeling.
• This study is consistent with others that have supported the role the LIPC-480 T allele and increased susceptibility to CHD, and appears to be the first to examine the interaction with physical activity for this polymorphism.
• The estimated fraction of CHD events occurring in the study cohort from the combination of LIPC-480 TT genotype and lack of vigorous physical activity was 11%. Less than 40% of the study cohort reported participating in vigorous physical activity. Physical activity should be promoted regardless of LIPC genotype, and particularly for persons with family history of CHD and other traditional CHD risk factors.
• Additional studies are needed to elucidate the role of hepatic lipase polymorphisms on lipid levels and subsequent CHD risk, possible interactions with other candidate genes for lipid metabolism, and the potential modifying role of vigorous physical activity on lipid metabolism in presence and absence of polymorphisms of candidate lipid metabolism genes.