The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study.
OBJECTIVE
Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.


METHODS
A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created.


RESULTS
A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history.


CONCLUSIONS
Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.
R A
RA
Scott
C
C
Langenberg
S J
SJ
Sharp
P W
PW
Franks
O
O
Rolandsson
D
D
Drogan
Y T
YT
van der Schouw
U
U
Ekelund
N D
ND
Kerrison
E
E
Ardanaz
L
L
Arriola
B
B
Balkau
A
A
Barricarte
I
I
Barroso
B
B
Bendinelli
J W J
JW
Beulens
H
H
Boeing
B
B
de Lauzon-Guillain
P
P
Deloukas
G
G
Fagherazzi
C
C
Gonzalez
S J
SJ
Griffin
L C
LC
Groop
J
J
Halkjaer
J M
JM
Huerta
R
R
Kaaks
K T
KT
Khaw
V
V
Krogh
P M
PM
Nilsson
T
T
Norat
K
K
Overvad
S
S
Panico
L
L
Rodriguez-Suarez
D
D
Romaguera
I
I
Romieu
C
C
Sacerdote
M J
MJ
Sánchez
A M W
AM
Spijkerman
B
B
Teucher
A
A
Tjonneland
R
R
Tumino
D L
DL
van der A
P A
PA
Wark
M I
MI
McCarthy
E
E
Riboli
N J
NJ
Wareham
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000208:ethnology / Q000209:etiology / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005192:Family Health / Q000208:ethnology; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008019:Life Style / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D009035:Mothers; D009043:Motor Activity; D012307:Risk Factors; D055105:Waist Circumference; D055815:Young Adult